bluuebunny/crossref_metadata_2025 huggingface dataset:
Adjuvant bortezomib and dexamethasone following risk-adapted melphalan and stem cell transplant in patients with light-chain amyloidosis (AL)
Authors: Landau H. J. , Hoffman J. , Hassoun H. , Elizabeth H. , Riedel E. , Nimer S. D. , Cohen A. , Comenzo R. L.
Published: August 2020

8540

Background: Melphalan (MEL) and autologous stem cell transplant (SCT) induces both hematologic and clinical remissions in AL, and prolongs overall survival (OS) when complete hematologic remissions (CR) are achieved. We have reported improved responses (including 39% CR) at 12 mos post-SCT using risk-adapted MEL followed by adjuvant dexamethasone (Dex) and thalidomide (Thal) (BJH 2007;139:224). In this phase II trial we use bortezomib (Bort) in place of Thal in an effort to further improve frequency and depth of response. Methods: Pts with newly diagnosed AL involving ≤2 organs were assigned to MEL 100, 140 or 200mg/m2 with SCT, based on age, renal function and cardiac involvement. Response was assessed at 2–3 months (mos) and 12 mos following SCT. Pts who did not achieve hematologic CR at 2–3 mos post-SCT received adjuvant therapy with Bort and Dex for up to 6 cycles (26 weeks). The impact of heart disease on OS was determined using the log-rank test; BNP and Trop-I were correlated with OS using the Cox proportional hazards model. Results: Of 27 pts enrolled, organ involvement was kidney (63%), heart (44%), liver/GI (15%) and peripheral nervous system (7%); 33% have 2 organs involved. Two pts were removed from study prior to SCT (1 due to 3 organ involvement and 1 for comorbid illness that resulted in ineligibility for SCT). Transplant related mortality was 12% (3/25) and was restricted to pts with cardiac AL. Of 21 pts evaluable post-SCT, 5 achieved CR and 16<CR, 15 receiving adjuvant therapy. At 12 mos post-SCT, 12 pts are evaluable. In these 12 pts, the ORR was 92% (11/12) with 67% (8/12) achieving CR. Fifty percent of pts had organ improvement. Adjuvant therapy resulted in improved responses in 7/8 (88%) of pts. Cardiac involvement, BNP and trop-I were all significantly associated with OS. As either BNP or Trop-I increases, the risk of death increased (p=0.006 and p=0.007, respectively). Conclusions: Adjuvant Bort and Dex effectively eradicates clonal plasma cell disease in pts with AL following SCT and results in an unprecedented CR rate at 12 mos post-SCT. Pts with cardiac AL continue to do poorly. Baseline BNP and Trop-I both predict survival. A revised risk-adapted treatment approach incorporating these cardiac biomarkers may be warranted.

[Table: see text]
Late mortality and morbidity of patients with Hodgkin lymphoma treated in adulthood
Authors: Matasar M. J. , McCallen L. N. , Riedel E. R. , Ford J. S. , Oeffinger K. C. , Straus D. J.
Published: August 2020

8547

Background: Increased late mortality and morbidity have been observed among adult survivors of Hodgkin lymphoma (HL) treated in childhood, but are less well characterized for patients treated in adulthood. Methods: We investigated the late mortality and morbidity of adult patients treated at our center from 1975 to 2000. The study population consisted of all patients treated on one of 6 consecutive first-line trials of combined modality therapy (CMT), one of which included a chemotherapy-only arm. Cause-specific mortality was determined by chart review and National Death Index. Survival was estimated using the method of Kaplan-Meier, and cause-specific mortality using competing risk methodology. Self-report surveys were distributed to surviving patients to assess the prevalence of late morbidity; severity of morbidity was scored based on a published adaptation of the Common Terminology Criteria for Adverse Events. Results: 746 patients were eligible for assessment. At time of survey, 227 patients (30.4%) had died: 107 deaths from HL, 100 from causes other than HL, and 20 from unknown cause ( Table 1 ). 20-year OS for the cohort was 71%. Cumulative risk of death due to HL is surpassed by causes other than HL by 22 years post-treatment. Among the 521 survivors, survey data were available for 233 (44.7%), with a median follow-up of 21.6y. Late morbidity was common: 94% reported any morbidity, 48% reported at least one severe (grade 3/4) late morbidity and 22% reported two or more severe late morbidities. The most prevalent severe morbidities included second primary malignancy (SPM) (17%), cardiovascular (CV) (18%) and neurologic (18%) disease. Conclusions: Among adults treated on trials of CMT, by 22y post-treatment the risk of death due to HL is surpassed by risk of death due to other causes. Survivors of HL treated during adulthood experience substantial late morbidity. These findings underscore the importance of efforts directed at prevention of and early intervention for late morbidity in adult survivors of HL.

[Table: see text]

No significant financial relationships to disclose.
Lenalidomide and rituximab for untreated indolent non-Hodgkin's lymphoma
Authors: Fowler N. H. , McLaughlin P. , Kwak L. , Hagemeister F. , Fanale M. , Fayad L. , Pro B. , Samaniego F.
Published: August 2020

8548

Background: Despite advances in therapy and a better understanding of the natural history of indolent non-Hodgkins lymphomas (NHL), the optimal treatment for newly diagnosed patients (pts) has not been determined. While several combination chemotherapy regimens have response rates approaching 90%, toxicity is common with genotoxic drugs and secondary malignancies is a concern. Lenalidomide has been shown to have single agent activity in indolent NHL, and is approved for the treatment of multiple myeloma and myelodysplastic syndrome. Rituximab is effective as a single agent and in combination with chemotherapy for indolent NHL. The aim of this phase II, single arm study is to evaluate the efficacy and safety of lenalidomide and rituximab in pts with untreated, stage III, or IV indolent NHL. Methods: Pts with indolent NHL who were previously untreated, with measurable disease (>1.5 cm), were eligible for enrollment. Pts received 20mg of lenalidomide orally once daily on days 1–21 and rituximab 375mg/m2 intravenously on day 1 of each 28 day cycle. Pts could receive up to 6 cycles of therapy. Response was assessed after 3 cycles and at the end of therapy using the International Working Group Response Criteria. Results: At time of this report 17 pts have been enrolled and 14 are eligible for safety evaluation. The median age was 55 (33–77) years and 53% were male. Therapy was well tolerated with the following grade 3 adverse events (AE) reported; myalgia (1 pt), rash (1 pt), peripheral neuropathy (1pt). There were no grade 4 AEs. There have been no reported grade 3/4 hematologic AEs. There has been no tumor flare observed. In the 5 pts eligible for response assessment, 4 pts (80%) attained a complete response (CR), 1 patient (20%) had stable disease (SD). After 3 cycles, one patient had unconfirmed stable disease who also was previously treated with combination chemotherapy for Hodgkin's lymphoma. Updates for response will be presented. Conclusions: The combination of lenalidomide and rituximab has activity and is well tolerated with minimal toxicity in patients with newly diagnosed indolent lymphoma.

[Table: see text]
Lymphoma recurrence 5 years or more following diffuse large B-cell lymphoma: Clinical characteristics and outcome
Authors: Larouche J. , Berger F. , Chassagne-Clement C. , Sebban C. , Ghesquieres H. , Salles G. , Coiffier B.
Published: August 2020

8562

Background: Diffuse large B-cell lymphoma (DLBCL) usually relapses early following treatment but some relapses happen 5 years or later. Few data exist regarding clinical characteristics and outcome of these patients (pts). Methods: We performed a retrospective analysis of all pts from two centers in Lyon/France between 1980–2003 who presented a biopsy proven relapse 5 years or later following diagnosis of DLBCL. All available biopsies were revised and immunohistochemistry (IHC) completed. Results: Among 1492 pts with DLBCL, 54 were eligible. Clinical characteristics at diagnosis were: median age 57 y; stage I-II 63% (34/54); IPI low/low intermediate 84% (41/49) and extranodal involvement (EN) 66% (35/53). IHC at diagnosis: CD20 100% (46/46), CD10 28% (10/36), bcl-6 53% (9/17), MUM1 48% (11/23), bcl-2 68% (19/28), germinal-center phenotype (GC) 57% (12/21) and non-GC 43% (9/21). 47/53 received CHOP/ACVBP-like regimens, 1 autologous transplantation (ASCT) and 1 rituximab. Median time from diagnosis to relapse was 7.4 years (5–20.5 years). 44 pts (81%) had DLBCL histology at time of relapse and 10 pts (19%) indolent histology. MUM1 expression at diagnosis was associated with DLBCL histology at relapse (p=0.037). Clinical characteristics at relapse were: median age 66 y; stage I-II 48% (26/54); 73% (31/43) with DLBCL at relapse had EN. 54% (15/28) with DLBCL at relapse had a GC phenotype and 46% (13/28) a non-GC phenotype. Treatment at relapse included rituximab in 21/54 and ASCT in 15/54 with 7 pts receiving both. Estimated 5-year event-free survival (EFS) and overall survival (OS) after relapse were 25% and 35% for all pts. Pts with DLBCL histology at relapse had an estimated 5-year EFS and OS of 18% and 28%. Pts with indolent histology had an estimated 5-year EFS and OS of 55% and 67%. Conclusions: Patients with DLBCL who present a late relapse usually had localized stage, favorable IPI and extranodal involvement at diagnosis. However, even if initial characteristics at time of first treatment were favorable, outcome of pts with DLBCL at time of relapse remains poor and aggressive treatment, such as ASCT, should be pursue whenever possible. Some patients relapsed with indolent histology and have a better outcome.

No significant financial relationships to disclose.
Evaluation of the effect of TRU-016, an anti-CD37 directed SMIP in combination with other therapeutic drugs in models of non-Hodgkin's lymphoma
Authors: Baum P. R. , Cerveny C. , Gordon B. , Nilsson C. , Wiens J. , Rafiq S. , Lapalombella R. , Muthusamy N. , Byrd J. C. , Wahl A.
Published: August 2020

8571

Background: TRU-016, a single chain anti-CD37 Fc fusion molecule has been shown to display pro-apoptotic and Fc-dependent cellular cytotoxicity activities against primary CLL cells and NHL cell lines. The pro-apoptotic signal generated by TRU-016 binding to CD37 on CLL cells has been shown to be caspase-independent and distinct from the signal generated by many other therapeutics including rituximab. We have tested drug combinations using the mantle cell lymphoma line Rec-1 and diffuse large B-cell lymphoma line SU-DHL-6 in vitro and extended these results to in vivo settings using the follicular lymphoma cell line DOHH2 treated with the combination of TRU-016 and bendamustine. Methods: To determine TRU-016 interactions with the established therapeutics rituximab, doxorubicin, rapamycin, and bendamustine, drugs were tested alone or in combination with TRU-016 and the anti-proliferative effects on cell lines measured after 96 hours. Combination index analysis was performed for drug combinations over the 20–90% effect levels using the Calcusyn software package. To determine if in vitro synergy could be recapitulated in vivo, SCID mice were implanted with DOHH2 cells and therapeutic treatment was initiated when tumor volumes reached 200 mm3. Treatments consisted of TRU-016, bendamustine, or the combination of TRU-016 and bendamustine. Results: Combination index analyses determined that TRU-016 is synergistic with rituximab, bendamustine, or rapamycin and additive with doxorubicin in NHL models. In vivo results show that treatment with the combination of TRU-016 and bendamustine resulted in increased efficacy compared to the efficacy attained with the individual drugs. This demonstrates that the in vitro synergy results were extendable to a more complex in vivo disease model. Conclusions: TRU-016 in combination with rituximab, rapamycin, or bendamustine increases cell killing of NHL cells. Furthermore, the combination of TRU-016 and bendamustine displayed greater in vivo anti-tumor activity than either agent alone against a follicular lymphoma tumor model.

[Table: see text]
Dynamic CD8 T-cell responses to tumor-associated Epstein-Barr virus (EBV) antigens in patients with EBV-negative Hodgkin's disease
Authors: Kohrt H. E. , Advani R. , Hoppe R. , Rosenberg S. , Horning S. , Lee P. P.
Published: August 2020

8573

Background: Multiple translational efforts in HD are actively investigating augmentation of the anti-tumor immune response by stimulating cytotoxic T lymphocytes (CTL) against tumor-associated EBV antigens. It has previously been believed that this therapeutic strategy and presence of EBV-specific CTLs are limited to EBV-positive HD. Here, we challenge this belief by characterizing EBV-specific CTL responses in EBV-negative HD. Methods: Among 52 consecutive patients with EBV-negative HD, CTL responses to latent antigens (LMP2, LMP2a) and lytic antigens (BMLF, BRLF) were serially assessed at diagnosis, during chemotherapy, and throughout followup for 2 years by IFN-γ Elispot and flow cytometric tetramer analysis. Results: We detected weak EBV-specific responses to both lytic and latent antigens by IFN-γ Elispot among patients with EBV-negative HD. Response to lytic antigen, BMLF1, was more robust in function and size among healthy donors compared to patients as determined by IFN-γ Elispot and flow cytometry of BMLF1-tetramer positive, CD8 T cells. Chemoradiotherapy was associated temporally with an initial decrease in LMP2A- and BMLF1-specific responses during the first 5–15 weeks of treatment, which subsequently became more robust 20–50 weeks after diagnosis, 2 to 4-fold greater compared to response at diagnosis. At final follow-up (24 months), increases in both lytic (2.6-fold) and latent (2.5-fold) CTL responses were observed with robustness of lytic-specific response equivalent to healthy controls. No significant change in control peptide response was observed. Conclusions: We confirm evidence of EBV-specific CTLs in patients with EBV-negative HD and provide the first report of dynamic variance in this population during treatment, challenging prior belief that patients with HD remain immunodeficient following therapy and arguing that the clinical significance of EBV-specific immune responses in EBV-negative HD should be further investigated.

[Table: see text]

No significant financial relationships to disclose.
Correlation of surface expression of CD11b or CD32 in polymorphonuclear cells (PMNs) and CD69 in natural killer cells (NK) with progression-free survival (PFS) following chemoimmunotherapy with rituximab and liposomal doxorubicin (LD) in patients (pts) with relapsed or refractory B-cell lymphoma
Authors: Ritesh P. , Pahuja S. , Chavez J. , Braddy W. , Skipper M. , Bernstein Z. P. , Chanan-Khan A. , Ramanarayanan J. , Czuczman M. S. , Hernandez-Ilizaliturri F. J.
Published: August 2020

8583

Antibody dependent cellular citotoxicity (ADCC) play a significant role in rituximab's anti-tumor activity. FcγRIIIa polymorphisms have been associated with clinical responses to rituximab. The predictive value of FcγRIIIa polymorphisms is lost when rituximab is combined with chemotherapy. Alternative assays to assess the immune system had not been studied in patients treated with rituximab plus chemotherapy. To this end, we prospectively studied the pre-treatment quality and function of PMNs and NK cells from pts with refractory/relapsed B-cell lymphomas in a Phase I/II trial. Forty-two B-cell lymphoma patients pts completed treatment. Demographics: 22M:20F; Median age = 61.8 (range 35–83); Patients received R (375 mg/m2/dose) on day 1 and LD (30 mg/m2/dose) on day 3 q21 day × 6 cycles. Pre-treatment flow cytometry was performed to assess surface expression of CD11b, CD62, CD69, CD16, CD32 and CD64 in PMNs or NKcells was performed. Serum or PBMC's were isolated from each patient and used 51Cr release assays to study rituximab-associated complement mediated cytotoxicity (CMC) or ADCC. To correlate laboratory parameters with response rate, and PFS patients were divided in tertiles. Overall, R+LD was very well-tolerated. Overall response rate (ORR) = 68% (39% CR, 19% PR); median time-to-progression (TTP) = 12 m. Surface expression of CD32 in PMNs, and CD69 in NKcells correlated with better response rates. Surface expression of CD11b and CD32 in the PMN's correlated with a longer PFS (P = 0.040 and P = 0.015, respectively).There was a non-statistically significant trend towards an improved in PFS in those patients whom their PBMC's exhibited a higher degree of ex-vivo rituximab ADCC. Our data suggest that R+LD is a safe and effective regimen and that the quality of the immune system prior to a chemo-immunotherapy regimen may play a role in clinical outcomes, specifically the expression of CD11b and CD32 in PMNs or CD69 in NKcells. Our data supports further research in seeking ways to enhance the quality of the immune system to improve responses to rituximab ± chemotherapy.

[Table: see text]
Evaluation of the potential of histone deacetylase inhibitors to synergize the antineoplastic effects of the proteasome inhibitor bortezomib in mantle cell lymphoma (MCL)
Authors: Paoluzzi L. , Scotto L. , Seshan V. E. , O'Connor O. A.
Published: August 2020

8584

Background: Romidepsin (R) and belinostat (B) are inhibitors of histone deacetylases (HDACI). HDACIs are known to induce cell death in malignant cells through multiple mechanisms, including up-regulation of death receptors, disruption of Hsp90 function and generation of reactive oxygen species. Mantle cell lymphoma is an aggressive subtype of non-Hodgkin lymphoma characterized by the reciprocal translocation t(11;14)(q13;q32) leading to the overexpression of cyclin D1. Methods: We investigated the cytotoxicity of romidepsin and belinostat alone and in combination with the proteasome inhibitor bortezomib in cell lines of mantle cell lymphoma (HBL2, Granta519, Jeko1). Cell Titer-Glo assay followed by luminometric acquisition was used for all cytotoxicity assays. Drug:drug interactions in terms of synergism, additivity or antagonism were computed using the Relative Risk Ratio Analysis (RRR, GraphPad software) with a RRR < 1 defining synergism, RRR=1 additivity and RRR>1 antagonism. Results: The IC50 values for R and B alone at 24 hours were: HBL-2: R=4.7nM, B=490nM; Jeko-1: R=3nM, B=750nM; Granta519: R=45nM, B=30,700nM. As single agent, romidepsin was about 100 fold more potent than belinostat. The combination of belinostat (100–1000nM) or romidepsin (1–40nM) with bortezomib (3–4nM) showed synergism in all cell lines at different concentrations. For romidepsin plus bortezomib, RRR in Granta519=0.05–0.14, RRR in Jeko1=0.1–0.75, RRR in HBL2=0.03–0.81. For belinostat plus bortezomib, RRR in Granta519= 0.07–0.38, RRR in Jeko1=0.16–0.49, RRR in HBL2=0.04–0.69. Flowcytometry for apoptosis, cell cycle analysis and mitochondrial membrane potential as well as immunoblottings for hystone H3 acetylation, cyclin D1, Bcl-XL, Mcl-1, BIM and IKB-α suggest this strategy may modulate cyclin D1 and p27 in MCL which is known to be grossly deregulated for these proteins. Conclusions: In this analysis, while romidepsin had improved single agent activity, when combined with bortezomib both HDACI showed potent synergism.

[Table: see text]
Benefit of thalidomide (THAL) in total therapy 2 (TT2) of multiple myeloma (MM) exhibiting both cytogenetic abnormalities (CA) and low-risk (LR) by gene expression profiling (GEP)
Authors: Waheed S. , Shaughnessy J. , Szymonifka J. , Pineda-Roman M. , Hollmig K. , Sawyer J. , Crowley J. , Barlogie B.
Published: August 2020

8590

Background: We recently reported an update of TT2 and observed an unexpected preferential benefit from THAL for OS in the subgroup of patients with CA (Blood, 2008). We now re-examined these results with further follow-up of 81 months in the context of GEP-defined risk. Methods: OS and EFS were examined in the 668 patients enrolled in TT2 according to treatment arm, CA status and by GEP risk status. Results: Median overall and event-free survival (OS, EFS) are 9yr and 5yr, with a significant benefit from THAL v the control arm (p=0.04, p=0.0004). We confirmed the ongoing unique survival benefit of THAL in the CA group with 6-yr OS estimates of 53% v 35% (p<0.001), while patients not exhibiting CA had similar OS of 70% and 68%. EFS was superior with THAL regardless of CA status, 56% v 45% without CA (p=0.02) and 38% v 20% with CA (p=0.008). With respect to GEP, THAL benefited the LR group with 6-yr OS/EFS rates of 73%/56% v 63%/36% without THAL (p=0.10/p=0.002); the corresponding data for high-risk (HR) patients showed OS/EFS with THAL of 35%/19% v 15%/10% without THAL (p=0.36/p=0.43). When examined in the context of both GEP and CA, THAL only benefited the 33 patients with both CA and LR with 6-yr OS of 72% v 37% among the 47 without THAL (p=0.003). For the remaining subgroups (CA/HR; no CA/LR, no CA/HR), the addition of THAL did not impact OS. Conclusions: The unique benefit of THAL to the CA/LR subgroup may be linked to its greater efficacy in proliferative MM (enabling CA detection) that can only be sustained in the LR (lacking amplification of 1q21?) but not in the HR subset. The concomitant examinations of MM genetics by both GEP and cytogenetics enabled the discovery of this subgroup-specific treatment benefit. Data on TT3 with the addition of bortezomib will be presented in the context of the CA/GEP-risk scenario.

[Table: see text]
Use of alternate splicing to identify subgroups in uniformly treated newly-diagnosed myeloma
Authors: Munshi N. C. , Li C. , Minvielle S. , Moreau P. , Amin S. B. , Magrangeas M. , Anderson K. C. , Avetloiseau H.
Published: August 2020

8602

Gene function is modulated at multiple levels. Besides expression level changes, post-transcriptional changes such as alternate splicing alter specificity of gene function. Misregulation of alternate splicing is associated with various disease processes including cancer. We have analyzed alternate splicing in myeloma (MM) using high throughput exon array analysis. Affymetrix Human Exon 1.0 ST Arrays used in this investigation, besides expression levels, also provides information on presence of each exon and identifies recurrent alternately spliced genes. We evaluated 170 newly-diagnosed patients with MM treated homogeneously in tandem transplantation IFM trials using CD138 purified MM cells. Xray array tool (Biotique systems) and dChip software was modified to analyze exon array data. We first normalized gene-level expression values across samples, and then identified differentially expressed exons to identify alternate splicing events. We observed over 100 genes with alternate splicing in myeloma with frequency in more than 20% patients. Unsupervised hierarchical clustering showed two groups within myeloma patients which differ in overall survival (OS). Dividing the group based on response, 52 alternately spliced exons were identified as influencing response to therapy including CD79A exon 4, XRCC exon 3 and 17, PRKDC exon 4, NIT 2 exon 4, Calmin exon2, MADH1 exon 7, TBX5 exon 2, Amyloid beta exon 14 with the highest frequency of alternate splicing. Amongst these, 32 genes had the most influence on response with over 50% differential frequency in patients achieving CR. Similarly 85 alternately spliced genes are influencing OS between groups at 48 month survival cut-off. 49 genes within this group had the most influence on OS. Shared spliced variants between both response and survival groups suggesting their biological and functional significance. Further validation of these alternate splicing is under investigations. This study highlights that alternate splicing is observed with significant frequency and demand need for evaluation of not only the expression level of genes but also post translational modifications. The spliced genes identified here are important target for therapy as well as possible immune modulation.

No significant financial relationships to disclose.
A single center experience with high-dose (HD) IL-2 treatment for patients with advanced melanoma and pilot investigation of a novel gene expression signature as a predictor of response
Authors: Sullivan R. J. , Hoshida Y. , Brunet J. , Tahan S. , Aldridge J. , Kwabi C. , Gardiner E. , McDermott D. , Golub T. , Atkins M. B.
Published: August 2020

9003

Background: HD IL-2 remains one of two FDA-approved therapies for the treatment of patients (pts) with advanced melanoma. Initial studies conducted 15–20 years ago reported 16% response rate with 8% of pts achieving durable responses. The toxicity of HD IL-2 limits its application to pts treated in specialized centers. We present the clinical outcome of pts treated over a recent 2 year period with HD IL-2 at a single institution and an associated retrospective pilot study evaluating the predictive value of a novel tumor gene expression signature. Methods: Clinical and radiological data were collected and analyzed on 49 consecutive pts treated with HD IL-2 at Beth Israel Deaconess Medical Center from 10/05 - 10/07. Response was evaluated via RECIST. Formalin-fixed paraffin embedded tumor was obtained on consenting pts and classified as either Class 1, defined by melanocyte-specific genes including MITF, or Class 2, represented by immune genes, using the DNA-mediated Annealing, Selection, and Ligation (DASL) technique. Two-sided Fisher's Exact test was used to compare the proportion of responses for pts in the two classes. Results: Clinical response occurred in 16 of the 49 pts (32.6%), with 5 pts (10.2%) having a CR. Two other pts had stable disease > 12 mos; 3 pts who progressed after response had resection to NED. 10 pts remain disease/progression free at a minimum of 16 mos following treatment. 28 pts (including 13 of 16 responders) had sufficient tumor for DASL analysis. Among the 21 categorized as Class 1, 7 (33%) were responders. Of the 7 classified as Class 2, 6 (86%) were responders. This difference in response was statistically significant (p = 0.0286). Conclusions: The overall and CR rates in a contemporary series of pts with metastatic melanoma treated with HD IL-2 are twice that reported in initial studies suggesting some treatment selection on clinical grounds since the 1990s. Pts with tumors expressing an immune signature by DASL appeared more likely to respond. This finding requires prospective validation, but suggests immune-related gene expression might contribute to IL-2 responsiveness.

[Table: see text]
Phase I/II study of the combination of sorafenib and temsirolimus in patients with metastatic melanoma
Authors: Kim K. B. , Davies M. A. , Papadopoulos N. E. , Bedikian A. Y. , Hwu W. , Woodard K. , Washington E. W. , Dancey J. E. , Wright J. , Hwu P.
Published: August 2020

9026

Background: Inhibition of Signal transduction pathways at multiple levels may be a more effective therapeutic cancer strategy for advanced cancer patients. Sorafenib, a multikinase inhibitor and temsirolimus, an inhibitor of critical survival pathways, are targeted compounds with single agent anti-tumor activity in several solid tumors. Inhibition of mutant B-Raf and the AKT signaling pathway has been effective in vitro with melanoma cell lines. Therefore, we designed a phase I/II study of the combination of sorafenib and temsirolimus to inhibit multiple pathways for greater clinical efficacy.Methods: Patients (pts) with stage IV or unresectable or recurrent stage III melanoma and ECOG performance status of 0 to 1 were eligible. Pts with treated brain metastases were eligible if they had not progressed for 3 months. Sorafenib was given orally twice daily and temsirolimus was given intravenously once a week, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per RECIST. Results: To date, 22 pts have been enrolled and treated. Median age was 56.5, and 17 were male. Median ECOG PS was 1. The MTD doses were sorafenib 400 mg in AM / 200 mg in PM daily and temsirolimus 25 mg IV weekly. The dose-limiting toxicity (DLT) included thrombocytopenia, hand-foot syndrome (HFS), serum transaminase elevation and hypertriglyceridemia. Other common adverse events were dry skin, fatigue, taste alteration, anorexia, flatulence, diarrhea, skin rash, insomnia, neuropathy, myalgia, and headaches, anemia, hypercholesterolemia, hyperglycemia and hypophosphatemia. There were 9 pts with stable disease among 21 evaluable pts for response. Conclusions: Sorafenib and temsirolimus can be administered concomitantly although with significant toxicity at higher dose levels. Currently, pts are enrolled in a dose expansion cohort. Pharmacokinetic data will be presented. Supported in part by NCI grant UO1 CA062461 and N01 CM17003.

[Table: see text]

No significant financial relationships to disclose.
Effect of ipilimumab treatment on 18-month survival: Update of patients (pts) with advanced melanoma treated with 10 mg/kg ipilimumab in three phase II clinical trials
Authors: O'Day S. , Weber J. , Lebbe C. , Maio M. , Pehamberger H. , Harmankaya K. , Siegel J. , Hoos A. , Humphrey R. , Wolchok J.
Published: August 2020

9033

Background: The monoclonal antibody ipilimumab targets cytotoxic T lymphocyte antigen-4. Updated survival data (≤32.5 months follow-up) from 3 Phase II trials of ipilimumab in pts with mostly pretreated advanced melanoma are reported. Methods: Study CA184008 was an open-label, single-arm study of ipilimumab 10 mg/kg. Study CA184022 was a randomized, dose-ranging study of ipilimumab 0.3, 3, or 10 mg/kg. Study CA184007 was a randomized, placebo-controlled study of the effect of budesonide on gastrointestinal immune-related adverse events in pts receiving ipilimumab 10 mg/kg. In all studies, ipilimumab was given every 3 weeks (Q3W) × 4 (induction); eligible pts could continue to receive maintenance ipilimumab Q12W from week 24. Pts continue to be followed-up to determine long-term survival. Results: With a median follow-up ranging from 10.1 to 16.3 months and reaching up to 32.5+ months, pts receiving 10 mg/kg ipilimumab showed durable survival; 12- and 18-month survival rates are presented [ Table ]. The tail of the Kaplan-Meier curve flattened at 18 months, indicating that a substantial proportion of patients continued to survive beyond the updated follow-up period in all three studies. Long-term survivors include pts with disease progression (PD) per modified World Health Organization (mWHO) criteria. Conclusions: Ipilimumab may result in a long-term survival benefit in pts with advanced melanoma, where 18-month survival rates across 3 Phase II studies range from 34.5% to 39.4% for previously treated pts. These results indicate that more than 1/3 of ipilimumab-treated pts with advanced melanoma experience a long-term survival benefit, including some pts characterized as PD by mWHO. The survival data continue to mature, and follow-up is ongoing.

[Table: see text]

[Table: see text]
The unique molecular signatures of nodular and superficial spreading melanoma
Authors: Rose A. E. , Wang J. , Pearlman A. , Doudican N. , Hernando E. , Orlow S. J. , Polsky D. , Ostrer H. , Osman I.
Published: August 2020

9047

Background: Primary nodular melanoma (NM) patients have a relatively poor prognosis compared to superficial spreading melanoma (SSM) patients. The disparity is generally attributed solely to NM's advanced thickness at presentation. In this study we attempted to define molecular signatures of NM and SSM that may explain their clinical differences. Methods: We performed an in silico gene expression analysis of 2 public data sets consisting of 36NM and 54 SSM primary melanoma tissues (CCR 2007;13 and JNCI 2006;98). We then utilized DNA microarray to generate gene expression profiles of a panel of 22 melanoma cell lines (2SSM, 4 NM, 12 met, 4 melanocytes). Differentially expressed genes and over-represented pathways in NM and SSM were identified based on a pooled analysis of the 3 data sets. We then used SNP array to define genomic alterations unique to NM and SSM but not altered in normal melanocytes. Finally, we correlated SNP array with gene expression. Results: Genes significantly overexpressed (p<0.05) in NM showed over-representation of pathways related to MAPK signaling (p=0.05) and cytoskeleton organization (p=0.02), while SSM showed over-representation of cell communication (p=0.05) and primary metabolic processes (p=0.002). Notable correlations between gene expression and copy number alteration in NM include increased copy number/overexpression of SOX5 (transcription factor related to embryonic development and cell fate) and the downregulation/deletion of ST14 (suppression of tumorigenicity 14). SSM demonstrated concordance of increased copy number/overexpression of EZR (cell adhesion protein implicated in human cancer) as well as PALLD (a protein related to motility, adhesion, and extracellular matrix interactions). Notable SSM genes showing correlation between downregulation/deletion include BNIP3 (a pro-apoptotic protein) and MTAP (often co- deleted with tumor suppressor p16). Conclusions: Simultaneous integration of gene expression with SNP array revealed molecular signatures characteristic of NM and SSM. These results suggest that NM and SSM are distinct biologic entities and that molecularly targeted adjuvant therapy may be more effective if tailored to the molecular signatures of melanoma subtypes. Validation is necessary to draw further conclusions.

No significant financial relationships to disclose.
A phase II study of gefitinib in patients with metastatic melanoma
Authors: Patel S. , Bedikian A. , Kim K. , Papadopoulos N. , Hwu P. , Vardeleon A. , Prieto V. , Bar Eli M. , Bronstein Y. , Bassett R.
Published: August 2020

9057

Background: Gefitinib is an inhibitor of epidermal growth factor receptor (EGFR), which is frequently expressed on both choroidal and non-choroidal melanoma cells. We evaluated the clinical efficacy of gefitinib in patients (pts) with metastatic melanoma. Methods: Pts with stage IV or unresectable or recurrent stage III melanoma and Zubrod performance status of 0 to 2 were eligible. For non-choroidal melanoma, pts must have received systemic cytotoxic therapy, but no more than 2 regimens; for choroidal melanoma, pts could be either chemo-naïve or have received up to 2 systemic cytotoxic therapies. The dose of oral gefitinib was 250 mg daily, and tumor response was evaluated every 6 weeks per RECIST. Ten patients with cutaneous disease were also consented for paired biopsies and blood collection for correlative studies at baseline and after 3 weeks of treatment. Results: Fifty-two pts (46 non-choroidal; 6 choroidal primay) were treated and evaluated for toxicity, and 50 pts were evaluable for response. Median age of pts was 62.5 years, with median Zubrod PS Score of 1. The median number of prior systemic treatments was 1. Forty-one pts (79%) had stage M1c disease. There were no drug-related grade 4 or 5 adverse events (AEs), and fatigue was the only grade 3 AEs in >5% of the patients. There were 2 (4%) partial responses, including a pt with metastatic choroidal melanoma, and 13 pts (26%) had disease stabilization. A median duration of response was 9.5 months among the responders. Median time to progression was 6 weeks, and median overall survival was 4.6 months. Among 7 pts with sufficient tissue on paired biopsies, there were no notable trends in the changes of the expression of pERK1/2, pAKT, or pPAK1 with treatment. Additionally, no trends were identified in serum VEGF or IL-8 levels after treatment. Conclusions: Gefitinib was well tolerated, but had minimal clinical efficacy as a single-agent therapy for metastatic melanoma of cutaneous origin. There were no consistent changes in the expressions of downstream kinase proteins with gefitinib treatment.

No significant financial relationships to disclose.
Comparative survival analysis of melanoma patients with secondary papillary thyroid carcinoma using Surveillance, Epidemiology, and End Results (SEER) data
Authors: Whitman E. D. , Bustami R. T.
Published: August 2020

9068

Background: Malignant melanoma (MM) and papillary thyroid cancer (PTC) may share genetic mutations. The expected mortality of a patient with both MM and PTC should be predominantly influenced by MM and unchanged by the PTC diagnosis, unless shared genetic abnormalities or other factors alter the phenotype of either or both diseases. We hypothesize patients with both MM and PTC have altered mortality risk compared to patients with either cancer alone. Methods: The study population included patients identified in the SEER 1973–2004 database who were diagnosed with MM or PTC as a primary tumor. The population was divided into four groups: (1) patients with MM only (MEL); (2) patients with PTC only (PAP); (3) patients who developed MM as a second primary after PTC (2MEL); and (4) patients diagnosed with PTC after MM (2PAP). Time between diagnosis and death or last follow up (December 2005) and other demographic data was obtained from SEER. Comparisons between the group death rates were made using the Chi-Square Test. A Cox proportional hazards regression model, adjusted for patient characteristics, predicted the risk of death and survival by group. Results: 9575 SEER patient records were included: 6622 in MEL, 2778 in PAP, 113 in 2MEL and 62 in 2PAP. Overall, 2095 patients (22%) died. There was a significant difference in mortality rates between the groups: MEL 27%, PAP 9%, 2MEL 21% and 2PAP 18%, p<0.001 by Chi-Square. Controlling for other variables in a multivariate Cox model, patients in the 2MEL group were significantly less likely to die than MEL patients (HR 0.52, 95% CI 0.35–0.79, p=0.002). 2PAP patients, the smallest sample, also had a reduced likelihood of death that did not reach statistical significance (HR=0.75, 95% CI 0.42–1.37, p=.35). PAP patients had the best survival (HR=0.43, 95% CI 0.36–0.50,p<0.001). Other factors (age, race, gender and radiation therapy, data not shown) also significantly affected mortality. Conclusions: This study suggests that MM patients also diagnosed with PTC are more likely to survive than patients with MM alone. Identification of the causative factor(s) for this survival benefit will require additional epidemiologic and genetic studies.

No significant financial relationships to disclose.
Progression-free and overall survival analysis in patients with metastatic melanoma undergoing first- versus second-line therapy
Authors: Allred J. B. , Suman V.
Published: August 2020

9078

Background: A frequently discussed topic at meetings of oncologists is the question of expected clinical outcomes for patients with metastatic melanoma undergoing 1st vs 2nd line systemic therapy. Differing outcomes in these two patient populations could affect interpretation of non-randomized clinical trials involving both patient populations. Some have suggested superior clinical outcome in patients undergoing 2nd line therapy. As there is little data addressing this issue, we sought to answer the question by comparing the clinical outcomes of patients with metastatic melanoma treated on 1st vs 2nd line therapy across clinical trials conducted at our institution. Methods: Data were collected from 10 phase II clinical trials for patients with stage IV melanoma for which Mayo Clinic was the data center. The 10 trials included three categories of treatments: cytotoxic chemotherapy (4), cancer vaccines (4), and biologic agents (2). In all studies, eligibility criteria required: stage IV melanoma, life expectancy >3 months, reasonable hematology and serum chemistry laboratory results, and an ECOG performance status of ≤2. Cox proportional hazards models were fit to assess the relationship between patients' “therapy” status (1st vs 2nd line) and time to events, both overall survival (OS) and progression free survival (PFS), for each treatment category. Results: We identified 318 unique eligible patients across 10 trials. Removed from the analysis were 55 patients (ocular melanoma and/or metastases involving the central nervous system) leaving 263. Cox proportional hazards results demonstrated no differences in PFS or OS for 1st vs 2nd line patients for either “chemotherapy” or “vaccine” treatment regimens. However, patient treated on “biologic” trials as 1st line therapy appeared to demonstrate a PFS advantage over 2nd line treatments (HR=1.98, p-value=0.02). There was a suggestion of an OS benefit for 1st line patients in this category, however, the relationship was not significant (HR=1.77, p=0.07). Conclusions: The presented data suggest that there is no PFS/OS difference in stage IV melanoma patients receiving 1st vs 2nd line therapy (no PFS/OS advantage to patients treated in 2nd line vs. 1st line).

No significant financial relationships to disclose.
Hospice utilization by men dying of prostate cancer
Authors: Bergman J. , Saigal C. S. , Miller D. C. , Hanley J. , Gore J. L. , Lorenz K. , Litwin M. S.
Published: August 2020

9501

Background: The 25,000 American men who die of prostate cancer each year often suffer from fatigue, bone pain, and weight loss. Enrollment in hospice programs improves both the quality of life and the quality of death for this cohort. However, previous data suggest that hospice is often used inappropriately, either through underuse or through improperly timed referral. We sought to characterize sociodemographic and clinical factors that affect appropriate and inappropriate utilization of hospice services by men with metastatic prostate cancer in a population-based dataset. Methods: We used linked data from Surveillance, Epidemiology, and End Results and Medicare data to identify a cohort of beneficiaries who died of prostate cancer between 1992 and 2005. We then evaluated the bivariate association between sociodemographic and clinical data and any hospice enrollment. Hospice referrals within 7 days of death or more than 180 days before dying were considered inappropriate. Results: Of the 14,521 men dying of prostate cancer, 7,646 (53%) utilized hospice resources. Enrollment within 7 days of death was noted in 1699 subjects (22% of hospice users), and enrollment more than 180 days prior to death was seen in 717 participants (9% of hospice users). Subjects who utilized hospice within the appropriate time frame were enrolled for a mean of 47 days (S.D. 41, range 7–180 days) prior to death, with a median of 31 days. In our bivariate analysis, white ethnicity, partnered status, and achieving at least a high school diploma were significantly associated with hospice use ( Table ). Conclusions: Hospice utilization rates in our cohort compared favorably with previous analyses, but the frequency of improperly timed hospice referrals was similar to prior reports and provides an opportunity for improvement.

[Table: see text]

No significant financial relationships to disclose.
A survey of U.S. and Canadian oncologists’ attitudes toward the cost, cost-effectiveness (CE), and reimbursement of cancer drugs
Authors: Neumann P. , Berry S. R. , Nadler E. , Evans W. C. , Palmer J. , Bell C. , Strevel E. , Fang H. , Ubel P. A.
Published: August 2020

9502

Background: Drug costs and reimbursement issues offer significant challenges to U.S. and Canadian oncologists even though they practice in substantially different health care systems. However, little is known about the attitudes of American and Canadian oncologists towards these issues. Methods: We surveyed 1,379 U.S. and 356 Cdn oncologists to assess their attitudes to cancer drug costs, CE and reimbursement policies. Results: Response rate was 57% in the U.S. and 48% in Canada. Oncologists in both countries stated that patients' “out-of-pocket” drug costs influenced their treatment recommendations (84% U.S., 80% Cdn respondents). Most respondents felt that every patient should have access to effective cancer treatments regardless of cost (66% US; 54% Cdn), while 59% of U.S. and 72% of Cdn and respondents believed that patients should only have access to effective cancer treatments that provided “good value for money.” 70% of U.S. and 64% Cdn respondents felt that <$100,000 per life year gained was a reasonable definition of “good value for money” but less than half of respondents (42% US, 49% Cdn) felt well prepared to interpret and use CE information in their treatment decisions. A majority of respondents (57% US, 69% Cdn) felt government price controls for cancer drugs are needed while a minority felt that more cost-sharing by patients was needed (29% US, 37% Cdn). Most oncologists felt that evaluating whether a drug provides “good value” should be overseen by an independent non-profit agency (57% US, 71% Cdn) or physicians (61% US and Cdn); in contrast, few believed that government (21% US, 33% Cdn), patients (36% US, 37% Cdn) or insurance companies (6% US, 10% Cdn) should determine “good value”. 79% of U.S. and 69% of Cdn respondents felt more use of CE data in coverage and reimbursement decisions is needed. Conclusions: Oncologists in the U.S. and Canada share many similar attitudes to cancer drug costs, CE, and reimbursement policies despite differences in their health care systems. In both countries, oncologists favor more use of CE information.

No significant financial relationships to disclose.
Pregabalin for hot flashes in women: NCCTG trial N07C1
Authors: Loprinzi C. L. , Qin R. , Stella P. J. , Rowland K. M. , Graham D. L. , Erwin N. , Dakhil S. R. , Jurgens D. J. , Burger K. N.
Published: August 2020

9513

Background: Hot flashes are a major problem in many women for which better treatment options are needed. Given the known efficacy of gabapentin for decreasing hot flashes, it was decided to evaluate pregabalin, with hopes that it would work better and/or with fewer toxicities. Methods: A three-arm, double-blinded, placebo-controlled randomized trial was developed. Women with bothersome hot flashes (at least 28/week) were randomized to receive either a placebo or target pregabalin oral doses of 75 mg bid or 150 mg bid (starting at 50 mg/d and then increasing the dose at weekly intervals to 50 mg bid, then 75 mg bid, and then, in the higher dose arm, 150 mg bid); patients were treated for 6 weeks. Hot flash numbers and scores (hot flash number times mean severity) were measured using a validated daily hot flash diary. A one-week baseline period preceded initiation of study tablets. The primary endpoint was the average intra-patient difference in hot flash score between baseline and week six, comparing the higher dose pregabalin arm and the placebo arm. With the planned sample size of 55 patients per arm, there was an 80% power and two-sided 5% Type I error rate to detect a difference of 0.54 standard deviations, or 1.08 hot flashes per day, or 2.7 units of hot flash score per day. Results: 207 patients were randomized between 6/20/2008 and 8/21/2008. The study arms were well balanced. Mean/median daily hot flash scores and frequencies for all pts at baseline were 15.7/13.4 and 8.3/7.7, respectively. The table shows the decreases in hot flashes from the baseline to the sixth treatment week. Larger numbers illustrate greater hot flash reductions. Toxicity information, quality of life information, and information regarding the effects of hot flashes on subjective symptoms will be available at the meeting time. Conclusions: Pregabalin reduces hot flashes in women. There appears to be similar effects with both studied doses.

[Table: see text]

No significant financial relationships to disclose.