bluuebunny/crossref_metadata_2025 huggingface dataset:
Durable responses with the antiangiogenic metronomic regimen RT-PEPC in elderly patients with recurrent mantle cell lymphoma (MCL)
Authors: Ruan J. , Martin P. , Coleman M. , Furman R. , Glynn P. , Joyce M. , Cheung K. , Shore T. , Schuster M. , Leonard J.
Published: August 2020

8525

Background: Targeting tumor microenvironment and angiogenesis is a novel therapeutic strategy in lymphoma. Two putative anti-angiogenic regimens, RT (rituximab with thalidomide) and PEPC oral metronomic chemotherapy (prednisone, etoposide, procarbazine and cyclophosphamide) are clinically active. We report phase II safety, activity, and angiogenic profiling data with the novel combination RT-PEPC in elderly patients with recurrent MCL. Methods: RT-PEPC includes an induction phase (mo 1–3) of daily thalidomide (50 mg) and PEPC with weekly rituximab x 4. A maintenance phase (mo 4 until progression) continues with daily thalidomide (100 mg), PEPC dosing titrated to ANC > 1K/ul, and rituximab q 4 months. Endpoints included safety, efficacy, and FACT-G quality of life (QoL) assessment. Translational studies assessed the angiogenic phenotypes of tumor cells, and dynamic levels of circulating endothelial and hematopoietic progenitors in response to treatment. Results: Twenty-five pts (19 males) were enrolled, with 22 evaluable (3 never received rx). At study entry, median age (N=25) was 68 yrs (range 52–81), 24 (96%) had stage ≥ III, 16 (64%) had LDH > nl, and 18 (72%) IPI 3–5. The median number of prior therapies was two (range 1 to 7), and 15 pts (60%) progressed on bortezomib. At a median followup of 30 months, overall response rate was 73% (32% CR/CRu, 41% PR, N=22). Median PFS was 12 months, and median OS 22 months. Four CRs of 4+, 28+, 46+ and 48+ months are ongoing. Toxicities included gr 1–2 fatigue, rash and neuropathy as well as cytopenias (by design) including gr 1–2 thrombocytopenia (56%) and gr 3/4 neutropenia (56%). Two thrombotic events and 5 episodes of gr 3–4 infection were observed. QoL was maintained or improved on treatment. Correlative studies demonstrated pre-therapy autocrine angiogenic loop in tumor cells evidenced by expression of VEGFA and VEGFR1. Circulating levels of hematopoietic and endothelial progenitor cells decreased on rx in responders. Conclusions: RT-PEPC has significant and durable clinical activity in MCL, with manageable toxicity and maintained QoL. Novel low-intensity anti-angiogenic approaches warrant further evaluation in MCL and other NHL subtypes, potentially as initial therapy in elderly patients.

[Table: see text]
Clinical and biological significance of microRNA profiling in patients with myeloma
Authors: Adamia S. , Avet-Loiseau H. , Amin S. B. , Moreau P. , Minvielle S. S. , Treon S. , Li C. , Anderson K. C. , Munshi N.
Published: August 2020

8539

MicroRNA, a small endogenous RNA regulating specific expressed gene function has been implicated in normal biological processes as well as in malignant transformation. Here we have investigated the role of microRNAs in multiple myeloma (MM) biology, and their influence on prognosis and clinical outcome. We evaluated profiles of 384 microRNAs in CD138+ MM cells from 79 patients with MM, 11 cell lines and 9 healthy donors using qRT-PCR based microRNA array. We detected significant modulation of expression of 61 microRNAs in myeloma cells compared to normal plasma cells. Unsupervised hierarchical clustering of filtered matured microRNAs, identified two major groups within the MM population (groups A and group B). Group A clustered with MM cell lines, indicating more aggressive course of disease. Within B group, second degree node, group B2, clustered with normal plasma cells indicating indolent course. The unsupervised clustering of all MM samples showed consistent change in miR-146b, -140, -145, -125a, -151, -223, -155, let-7f, indicative of a role of these microRNA in myelomagenesis; while supervised analysis of samples within groups A and B identified modulated expression of different sets of miRNAs. In group A miR585 and let-7f were upregulated 8–12 fold; in group B, all differentially expressed microRNAs were downregulated (p<0.001) compared to normal plasma cells. These modulated miRNAs target critical signaling molecules such as HOX9, c-myc, Bcl-2, SHP1 and SHP2. We further analyzed the effect of microRNA on clinical outcome. We have observed significantly superior event free and overall survival of patients in group B compared to patients ingroup A (2 yr estimated EFS 79% versus 54% respectively; p=0.05; and 2 yr estimated OS 94% versus 70% respectively; p =0.017). Functional analysis by modulating miRNAs 585, 155 and let-7f showed change in levels of predicted genes with consequent biological effect on growth and apoptosis in MM cell line. Taken together, this data identifies miRNAs as critical modulators of gene expression and signaling pathways and provides potential novel targets in MM to both understand biological behavior and for therapeutic application.

No significant financial relationships to disclose.
Panobinostat plus lenalidomide and dexamethasone phase I trial in multiple myeloma (MM)
Authors: Spencer A. , Taylor K. , Lonial S. , Mateos M. V. , Jalaluddin M. , Hazell K. , Bourquelot P. M. , San Miguel J. F.
Published: August 2020

8542

Background: Panobinostat (LBH589) is a highly potent pan-deacetylase inhibitor (pan-DACi), affecting with epigenetic and non-epigenetic pathways of cancer. In vivo experiments demonstrated potent MM cytotoxicity of the triplet panobinostat + lenalidomide + dexamethasone. Methods: Trial started with 5 mg panobinostat (po, TIW) combined with fixed doses of lenalidomide (25 mg po, QD, Days 1–21) and dexamethasone (40 mg po, Days 1–4, 9–12, 17–20, Cycles 1–4), in a 28-day cycle. MTD of panobinostat in this combination for second-line MM will be established based on data from cohorts of ≥6 evaluable patients (pts). Safety, tolerability, PK/PD, and preliminary efficacy will be assessed. Results: Twenty-two pts with relapsed or relapsed refractory MM were treated in three dose levels to date. Dose escalation started at 5 mg panobinostat (po, thrice weekly) combined with fixed doses of 25 mg lenalidomide (po, qd, Days 1–21) and 40 mg of dexamethasone (po, Days 1–4, 9–12, 17–20, Cycles 1–4), in a 28-day cycle. Data from all eight patients in Cohort 1 were evaluated. The median number of prior lines of therapy was two (range 1–3). Six out of eight patients in Cohort 1 remain on therapy. Median follow-up is six cycles (range 4–8+). No DLT was observed. In Cohort 2, eight patients were treated at the dose level of 10 mg of panobinostat, with one single DLT: a Gr 1 increase of QT interval duration was detected on Day 3, persisting on Day 8 with therapy withheld, meeting DLT definition although not deemed clinically relevant. Cohort 3 is enrolling with six patients at 20 mg of panobinostat, thus far. SAEs included fever (two pts), anxious depressive syndrome, respiratory infection, atrial fibrillation, exertional dyspnea, cellulitis, superficial blood clot of thigh, phlebitis, hypokalemia. All, but fever in one patient, were assessed by the investigator as not study drug related. Conclusions: The potential for anti-myeloma activity of this triple combination is strongly supported by in vivo preclinical data. In this first clinical trial assessing this triple oral combination, the 5 and 10 mg dose level of panobinostat appear safe. Updated safety, early efficacy, and subsequent dose-level patient data will be presented.

[Table: see text]
Phase I/II study of concurrent chemoradiotherapy for localized nasal NK/T-cell lymphoma: Final results of JCOG0211
Authors: Yamaguchi M. , Tobinai K. , Oguchi M. , Isobe Y. , Ishizawa K. , Maseki N. , Wasada I. , Ishizuka N. , Hotta T. , Oshimi K.
Published: August 2020

8549

Background: Nasal NK/T-cell lymphoma is rare and its standard therapy has not been established. Tumor cells express P-glycoprotein concerning multi-drug resistance (MDR). Anthracycline-containing chemotherapy is not effective and %2-yr overall survival (OS) of radiotherapy (RT) alone is only 45%. Methods: To explore a more effective treatment for localized nasal NK/T-cell lymphoma, we conducted a phase I/II study of concurrent chemoradiotherapy consisted of 50 Gy of RT and 3 courses of DeVIC [carboplatin (CBDCA), etoposide (ETP), ifosfamide (IFM), dexamethasone (DMS)]. Patients (Pts) with newly-diagnosed, localized (IE & contiguous IIE with cervical node involvement) diseases, 20–69 years of age and PS 0–2 were eligible. The 3-D conformal RT planning was required to cover adequately target volumes (2 cm margin to gross tumor, entire nasal cavities and nasopharynx) and to minimize doses to organs at risk. Primary endpoint of the phase II portion was 2-yr OS and the enrollment of 24 pts to the phase II portion was planned. Based on the results of the phase I portion (ASH 2005, #2685), 2/3-dose of DeVIC (CBDCA 200mg/m2 d1 IV, ETP 67mg/m2 d1–3 IV, IFM 1.0g/m2 d1–3 IV, DMS 40mg/body d1–3 IV; every 3 wks) was applied for the phase II portion. RT quality assurance review confirmed no protocol violation (ASTRO 2008, #2682). Results: From Sep 2003 to Dec 2006, 33 pts were enrolled in the phase I/II study. 27 pts evaluated in the phase II portion showed the following features: age 21–68 yrs (median 56), M:F=17:10, stage IE 18, stage IIE 9, B symptom (+) 10, elevated serum LDH 5, PS2 2. With a median follow-up of 32 months (range, 24–62), %2-yr OS was 78% (95% CI, 57–89). Of 26 pts evaluable for response, 20 achieved CR, 1 PR, 2SD, and 3PD. %CR and %ORR were 77% (95% CI, 56–91) and 81%, respectively. The most common grade 3 non-hematologic toxicities were mucositis due to RT (30%) and infection (30%). Grade 4 hyponatremia and dermatitis due to RT were observed in each 1 pt. No treatment-related death was observed. Conclusions: Concurrent chemoradiotherapy using MDR-non-related agents and ETP is a safe and effective treatment for localized nasal NK/T-cell lymphoma, providing the basis for subsequent studies.

No significant financial relationships to disclose.
Bortezomib, bendamustine, and rituximab in patients (pts) with relapsed (rel) or refractory (ref) follicular lymphoma (FL): Dose-finding results of the VERTICAL study
Authors: Matous J. , Letzer J. , Rosen P. , Noga S. , Fowler N. , Smith S. , Amin B. , Shi H. , Parasuraman S. , Cheson B.
Published: August 2020

8550

Background: FL is an incurable indolent B-cell non-Hodgkin's lymphoma. Survival has improved in the past decade with the introduction of rituximab (Rituxan, R), but response decreases with repeated exposure. Bortezomib (Velcade, V) plus R was active and generally well tolerated in rel/ref FL [de Vos ASH 2006 Abs694], and bendamustine hydrochloride (Treanda, B) plus R has also shown activity in heavily pretreated FL [Robinson JCO 2008]. The current single-arm, multi-center study evaluates the efficacy and safety of VBR in pts with rel/ref FL. Here we report the safety of dose escalation of B in combination with VR. Methods: Pts with relapsed FL with ≥4 prior doses of R (no prior V or B), ≥1 measurable tumor mass, no active central nervous system lymphoma, KPS ≥50%, adequate hematologic, renal and hepatic function, and no peripheral neuropathy ≥G2 were eligible. Pts received five 35d cycles of V 1.6 mg/m2 (d1, 8, 15, 22), B 50, 70, or 90 mg/m2 (d1, 2) and R 375 mg/m2 (d1, 8, 15, 22, cycle 1; d1, cycles 2–5). B dose escalation continued based on cycle 1 dose-limiting toxicities (DLTs), defined as: treatment-related platelet count <25,000/mm3 for >7 days or any platelet count <10,000/mm3; G4 neutropenia for >7 days; any treatment-related ≥G3 non-hematologic toxicity other than inadequately treated nausea, vomiting, or diarrhea; or any toxicity resulting in >1 week treatment delay. Results: Sixteen pts (4 at B 50 mg/m2, 6 each at B 70 and 90 mg/m2) with a median of 3 prior therapies (range 1–13; 31% prior stem-cell transplantation) have been treated (15 evaluable for DLT); median age was 54.5 (44–80) yrs. There was one DLT at B 70 mg/m2 (severe rash; pt discontinued), and one DLT at 90 mg/m2 (G3 thrombocytopenia requiring cycle 2 d1 delay). Hematologic AEs were manageable and included 4 (25%) ≥G3 neutropenia and 1 (6%) G4 thrombocytopenia. Non-hematologic AEs ≥G3 in >1 pt were diarrhea (31%), fatigue (25%), vomiting (13%), and nausea (13%). Peripheral neuropathy was reported in 6 pts (38%; 1 G3). Evidence of antitumor activity has been observed. Conclusions: Enrollment is continuing in the phase II portion of the study with B 90 mg/m2, the highest planned dose.

[Table: see text]
Long-term treatment of CTCL with the oral PNP inhibitor, forodesine
Authors: Duvic M. , Forero-Torres A. , Foss F. , Olsen E. , Pinter-Brown L. , Kim Y.
Published: August 2020

8552

Background: Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to T-cell selective intracellular accumulation of dGTP, resulting in apoptosis. Methods: An open-label dose escalation study of oral forodesine (40–320 mg/m2 daily) for 4 wks with extended therapy was performed to determine the maximum tolerated and/or optimal biologic dose (OBD). Additional subjects were accrued at an OBD (80 mg/m2) to further assess safety and clinical efficacy. Subjects with refractory CTCL, stages IB-IV were eligible. The primary efficacy endpoint (objective response rate [ORR]) was defined as ≥ 50% improvement by a severity-weighted assessment tool (mSWAT). Results: The overall intent to treat response rate was 17 of 64 (27%) subjects or 14 of 36 (39%) at the OBD. As of October 2008, nine of 64 subjects (14%) have received forodesine treatment for >12 months. This cohort of 9 subjects is further examined. Six discontinued treatment (median time on treatment 440 days): 4 for progressive disease, 1 withdrew consent, and 1 due to an adverse event (Diffuse Large B-cell Lymphoma). Three are continuing on therapy for 416, 710, and 863 days. Median age was 68 years (range 42, 81), and all but one was ≥ stage III. They had received a median of 3 prior systemic therapies including 8 of 9 with prior bexarotene. Five of 9 subjects had a response (2 with complete response, 3 with partial response, and 4 with stable disease). Related AEs were experienced by 7 of 9 subjects. The most frequent were nausea (44%), fatigue, peripheral edema, dyspnea, and urinary casts (all 22%). Grade 3 or higher related AEs were experienced by 2 of 9 subjects (Diffuse Large B-Cell Lymphoma as previously mentioned and peripheral edema). There were no hematologic or infection AEs related to forodesine. Grade 3 lymphopenia and CD4 count < 200 were noted in 8 of 9 and 4 of 9 subjects respectively. The risk of any infection AE regardless of cause in these 9 subjects was 15 per 100 person-months of forodesine exposure compared to 59 in all other subjects (n=55). Conclusions: Forodesine has an acceptable safety profile and efficacy in these CTCL subjects treated for 12 months or longer.

[Table: see text]
Effect of Aurora A kinase inhibitor MLN8237 combined with rituximab on antitumor activity in preclinical B-cell non-Hodgkin's lymphoma models
Authors: Zhang M. , Huck J. , Hyer M. , Ecsedy J. , Manfredi M.
Published: August 2020

8553

Background: Aurora A kinase is a serine/threonine protein kinase that is essential for the successful transit of cells through mitosis. MLN8237 is a selective small molecule inhibitor of Aurora A kinase that has demonstrated anti-tumor activity in animal models of solid human tumors. In this study we explored the anti-tumor effect of MLN8237 in vivo in pre-clinical models of human Diffuse Large B-cell Lymphoma (DLBCL) both as a single agent and in combination with the anti-CD20 monoclonal antibody Rituximab. Methods: Three human DLBCL models were examined in SCID mice. In two of the models (Ly19 & WSU) the tumor cells expressed a constitutively active luciferase, enabling tumor burden analysis in either a subcutaneous or disseminated setting. The third model was a primary DLBCL recently obtained from a patient. Tumor bearing animals were treated for 21 days with MLN8237 (QD PO dosing at 3–20mg/kg), Rituximab (Q7D IV dosing at 10 mg/kg), or the two agents combined. Tumor burden was measured in the disseminated models as a function of luciferase-induced photon flux, and in the subcutaneous models using vernier calipers. Results: MLN8237 induced anti-tumor activity that was dose-dependent in all three models. In LY19 disseminated model, 3 mg/kg of MLN8237 combined with Rituximab induced synergistic anti-tumor activity (n=2); while 10 mg/kg MLN8237 (dosed QD) combined with Rituximab was additive. Importantly, combining MLN8237 with Rituximab led to complete cures in 100% of the animals. In the WSU model, combining MLN8237(3–10mg/kg) with Rituximab resulted in additive tumor growth inhibition. The mean survival endpoint was significantly longer (p=0.003 and <0.001 respectively) in the combination group when compared to the individual group. In the primary lymphoma model, MLN8237(10–20mg/kg) caused a significant anti-tumor effect during treatment period (TGI = 83–95%). Combining MLN8237 and Rituximab in primary model resulted in additive anti-tumor effect. Conclusions: MLN8237 combined with Rituximab was found to reduce tumor burden in an additive and/or synergistic mechanism in multiple DLBCL tumor models. MLN8237 is currently being tested as a single agent in a phase I clinical trail in patients with DLBCL.

[Table: see text]
Observer variation in FDG PET-CT for staging of lymphoma
Authors: Hofman M. , Smeeton N. C. , Rankin S. C. , Rankin S. C. , Nunan T. , O'Doherty M. J.
Published: August 2020

8557

Background: Evaluation of observer agreement is fundamental in the assessment of any new imaging modality. While many studies demonstrate high accuracy of positron emission tomography (PET) for lymphoma staging, few assess observer variation. This study aims to quantify intra- and inter- observer agreement amongst experienced readers for staging lymphoma with PET-CT. Methods: One hundred consecutive patients with biopsy proven lymphoma deemed appropriate for staging with PET-CT were reported independently by three experienced readers, with two readers reviewing each series a second time. Primary outcome variables were agreement of Ann Arbor stage, number of nodal regions and presence of extra-nodal involvement. Secondary outcome variables were agreement of specific nodal and extra-nodal sites. Weighted kappa (κw) was used to compare ratings from two readers, and interpreted according to the Landis-Koch benchmarks. Interclass-correlation coefficient (ICC) was used to assess total of nodal regions involved. Results: Both intra- and inter-reporter agreement for Ann-Arbor stage (κw=0.79–0.91), total number of nodal regions involved (ICC=0.83–0.93) and presence of extra-nodal disease (κ=0.74–0.86) was substantial or almost perfect. High agreement was also observed for specific nodal regions (κw>0.60) except hilar (κw=0.56–0.63) and infra-clavicular regions (κw=0.14–0.37). Conclusions: Amongst experienced readers there was a high level of agreement utilising PET-CT for lymphoma staging. This complements other studies demonstrating high accuracy and supports use of PET-CT as a robust non-invasive staging tool. Further research is needed to evaluate reporter variability for restaging during and after completion of chemotherapy.

[Table: see text]

No significant financial relationships to disclose.
Mature T-/NK-cell lymphomas: Prognostic factors and treatment outcome of patients treated on studies of the German High-Grade Lymphoma Study Group (DSHNHL)
Authors: Schmitz N. , Ziepert M. , Nickelsen M. , Wolf S. P. , Truemper L. , Loeffler M. , Ho A. , Metzner B. , Rosenwald A. , Pfreundschuh M.
Published: August 2020

8564

Background: T-cell lymphomas represent a heterogeneous group of malignancies difficult to diagnose and to treat. We evaluated patients (pts) diagnosed according to WHO standards and treated on prospective studies of the DSHNHL. Chemotherapy regimens (CHOP-14 and CHOEP) had significantly improved outcomes of patients with aggressive B-NHL. Methods: Between 1993 and 2006 we treated 329 pts with ALK-positive ALCL (73 pts), ALK-negative ALCL (108 pts), PTCL, NOS (68 pts), AITL (28 pts), NK-/T-cell lymphoma (18 pts), and rare T-cell lymphomas on prospective studies. All pts received CHOP ± etoposide (E) every 2 or 3 weeks; in pts <=60 yrs C, H, and E were escalated to further improve outcomes. Results: The majority of pts with ALK-positive ALCL presented with IPI 0, 1 (62%) or IPI 2 (26%) and had an excellent overall survival (OS) of 89 % and event-free survival (EFS) of 75% at 3 yrs. E significantly improved TTTF for pts <=60 yrs (p=0.007). Pts with other histologies did significantly worse (OS 58%, EFS 44 % at 3 yrs). The IPI discriminated between pts with a favorable (IPI 0, 1: OS 73%), moderate (IPI 2: OS 55%), and poor prognosis (IPI 3: OS 35%; IPI 4, 5: OS 19%) at 3 yrs. OS, EFS were significantly better for ALK-positive ALCL but did not significantly differ for pts in other histological subgroups. Neither shortening of the treatment interval (CHOP-14) nor the addition of E (CHOEP-21 or -14) significantly improved outcome of elderly pts. In younger pts (ALK-positive ALCL were excluded) and good-risk disease (LDH <= N) there was a trend for better EFS after the addition of E to CHOP (EFS 63% vs. 48%, p = 0.065). The MegaCHOEP protocol (Schmitz et al., CANCER 2006) failed to improve treatment results for younger pts with poor-risk disease (EFS at 3 yrs: 25.9%, 95% CI: 10.4–41.4); the prospective study comparing MegaCHOEP with CHOEP-14 was stopped for pts with T-cell lymphoma. Conclusions: CHO(E)P results in excellent OS of pts with ALK-positive ALCL and selected pts with other histologies and low IPI. All other pts did poorly; CHOP-14 or the addition of E failed to significantly improve outcomes. Notably, also the MegaCHOEP protocol characterized by repetitive high-dose therapy and ASCT did not result in significant improvement.

No significant financial relationships to disclose.
Complete response (CR) to ifosfamide, gemcitabine, and vinorelbine (IGEV) and outcome in relapsed/refractory Hodgkin's lymphoma (HL) patients
Authors: Anastasia A. , Mazza R. , Giordano L. , Balzarotti M. , Magagnoli M. , Castagna L. , Spina M. , Michieli M. , Tirelli U. , Santoro A.
Published: August 2020

8568

Background: High dose chemotherapy with autologous stem cells transplant (ASCT) is the gold standard in patients with relapsed/refractory HL. Response to induction chemotherapy (chemosensitive patients) plays a major role in prognosis, however the role of CR status after induction therapy has not been established. Methods: One hundred twenty one patients with relapsed/refractory HL received 4 courses of IGEV followed by single (N=59) or tandem (N=19) ASCT (Santoro et al., Haematologica 92, 2007). Response to IGEV was evaluated by Cheson criteria (1999).The aim of this study was to evaluate the role of CR versus no-CR to IGEV induction therapy on the outcome in terms of progression free survival (PSF) and overall survival (OS). Statistical analysis was performed by using the Kaplan-Meier method and Cox proportional hazard model. Results: IGEV induced an overall response rate of 75% with 46% of CR. In the univariate analysis favourable factors for outcome were CR vs no-CR to IGEV (PFS: p <0.001, OS: p 0.002), A vs B symptoms (PFS: p 0.003; OS: p 0.05), limited vs advanced stage (PFS: p 0.03; OS: p 0.03), and 1 vs≥2 previous chemotherapy lines (PFS: p 0.03, OS: p 0.02); response to last therapy (relapsed vs refractory) influenced PFS (p 0.03) but not OS (p 0.70). The multivariate analysis confirmed the favourable prognostic role of CR to IGEV (PFS HR: 2.5, CI 95%:1.3; 4.6 - OS HR 2.3, CI 95%:1.1;4.8) and of the number of previous chemotherapy lines (PFS HR:1.8, CI 95%:1.0;3.2 - OS HR 2.1, CI 95%:1.1;3.9). Conclusions: According to our data, we conclude that: 1. CR to IGEV is the strongest indicator of outcome in relapsed/refractory HL. 2. Achievement of CR to IGEV overcomes the role of initial disease status. 3. Efforts are warranted to increase the CR rate by induction therapy.

No significant financial relationships to disclose.
ABT-263 activity and safety in patients with relapsed or refractory lymphoid malignancies in particular chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
Authors: Wilson W. , O'Connor O. O. , Roberts A. W. , Czuczman M. , Brown J. , Xiong H. , Xiong H. , Chiu Y. , Krivoshik A. , Enschede S. , Humerickhouse R.
Published: August 2020

8574

Background: ABT-263, a novel, orally bioavailable, BH3 mimetic, binds with high affinity (Ki ≤ 1nM) and inhibits multiple antiapoptotic Bcl-2 family proteins. ABT-263 displays activity (EC50 ≤ 1μM) against human lymphoid and small cell lung cancer cell lines. Mechanism based preclinical toxicities include reductions in circulating lymphocytes, apoptosis of circulating platelets, and decreased spermatogenesis, mediated by inhibition of Bcl-2, Bcl-XL, and Bcl-w, respectively. Methods: Safety and activity of ABT-263 in 2 enrolling phase I studies in relapsed/refractory lymphoid malignancies (M06–814) and CLL (M06–873) was evaluated. Patients (pts) were dosed on days 1–14 of a 21 d cycle, 10–440mg (M06–814) or 10–250mg (M06–873). Continuous 21/21 d dosing (CD) post lead-in dose is being explored in both studies. Results: 55 pts, 14/21 d dosing, enrolled in the 2 studies. ABT-263 PK were linear from 10 - 440mg (N=55) and the terminal half-life was 14 - 20 h (n=35). Among 27 CLL/SLL pts, 3 have confirmed radiographic partial responses (PR) (99%, 92% and 72%) and 2 have unconfirmed regressions, 51% and 72%. 6 pts maintained a ≥50% decrease in circulating lymphocytes for ≥ 2 months and 11 pts have stable disease; of these 5 experienced minor radiographic responses (range of 36% to 49%). In addition, among 40 (M06–814) lymphoma pts, 3 with follicular lymphoma achieved PR and one had a minor response (49% regression). With CD dosing (16 pts), activity includes 1 unconfirmed PR in SLL & and 3 CLL pts with ≥50% lymphocyte reduction for ≥2 months duration. Pharmacodynamic toxicities included dose-dependent thrombocytopenia (TCP) resulting from on-target activity against Bcl-XL. Dose limiting toxicities, 14/21 d dosing, in M06–814 occurred at 160mg (bronchitis), 315mg (elevated ALT and grade 4 TCP) and 440mg (worsening pleural effusion in a pt with underlying afib), and in M06–873 at 110mg (tumor lysis and grade 4 TCP) and 250mg (grade 4 TCP). Conclusions: ABT-263 showed favorable PK and safety profiles with anti-tumor activity in relapsed/refractory CLL/SLL and follicular lymphoma. Identification of optimal dose and schedule for phase II trials continues.

[Table: see text]
Final results of a phase I study of oral belinostat (PXD101) in patients with lymphoma
Authors: Zain J. M. , Foss F. , Kelly W. K. , DeBono J. , Petrylak D. , Narwal A. , Neylon E. , Blumenschein G. , Lassen U. , O'Connor O. A.
Published: August 2020

8580

Background: Belinostat (Bel) is a histone deacetylase inhibitor with broad preclinical activity. A phase I of oral Bel in patients (pts) with solid tumors found a recommended dose for day (d) 1–14, q3w, of 750 mg QD, with option for intra-patient dose escalation if limited toxicity. The current study was initiated to assess if the same dose could be utilized in pts with lymphoma. Methods: Objectives included safety and efficacy of oral Bel in cohorts of 3–6 pts (A 750; B 1000; C 1250; mg QD) treated d 1–14, q3w. Pts with relapsed/refractory non-Hodgkin lymphoma (NHL) or Hodgkin's disease (HD) with evaluable disease and acceptable organ functions were eligible. Dose limiting toxicity (DLT) assessed in cycle 1 included: related non-hem grade (gr) 3/4 tox; gr 4 neutropenia > 5 d or with fever > 100.5 °F; gr 4 thrombocytopenia > 7 d. Results: 9 pts (3 per cohort), median age 51 (range 21–92), median 5 (range 2–7) prior regimens (83% had BM transplants, including 1 pt with allogeneic) have been enrolled. Diagnoses include mantle cell lymphoma (MCL; 4 pts), HD (3 pts), other NHL (2 pts). Most frequent adverse events (regardless of attribution or gr) in 7 pts fully evaluable for tox: anorexia (7 pts), fatigue, (6 pts), diarrhea (6 pts), and constipation, fever, and cough (each in 3 pts). Non-hem gr 3 events (no gr 4 noted): diarrhea (1 pt each in cohorts A and B, both in cycle 2), fatigue, anorexia, and leg DVT (each in 1 pt; all after cycle 1). One gr 3, and 1 gr 4 (from baseline gr 2; duration gr 4 <7 d) thrombocytopenia were seen in cohort C. In 6 pts evaluable for efficacy, stable disease have been noted in 5 pts for 3 to +7 cycles, including 3 of 3 pts (one refractory) with MCL and 2 of 2 pts (both refractory) with HD. Tumor shrinkage of 43 to 49% have been found in 1 HD and 2 MCL pts after cycle 2. Conclusions: Oral Bel can be delivered safely with a d 1–14, q3w schedule in pts with lymphoma at a daily dose higher than what has been established for pts with solid tumors. No protocol defined DLTs have yet been encountered in the dose range 750 to 1250 mg QD in pts with lymphoma. Final evaluation will include additional pts and possible dose escalation. The safety profile and early tumor shrinkage noted in MCL and HD warrants continued evaluation of Bel, especially in combination with other active compounds.

[Table: see text]
An open-label, multicenter, phase II study of AT-101 in combination with rituximab (R) in patients with untreated, grade 1-2, follicular non-Hodgkin's lymphoma (FL)
Authors: Kingsley E. , Richards D. , Garbo L. , Gersh R. , Robbins G. , Leopold L. , Brill J. , Di Bella N.
Published: August 2020

8582

Background: Bcl-2 family proteins are overexpressed in the majority of patients with FL and contribute to resistance to therapy. AT-101 is a pan-Bcl-2 inhibitor (Bcl-2, Bcl-XL, Bcl-W, and Mcl-1) and potent inducer of proapoptotic proteins. It is active as a single agent and in combination with R in NHL tumor models. Methods: Patients with untreated FL who did not require immediate chemotherapy were eligible. Treatment consisted of an induction cycle of AT-101 (30mg po daily × 21) and R (375 mg/m2 weekly × 4) followed by up to 4 maintenance cycles of AT-101 (30mg po daily × 21) and R (375 mg/m2) every 8 weeks in nonprogressors. Endpoints evaluated the response rate (RR) at week 8 (primary), overall response rate (ORR), molecular response rate (BCL-2JH rearrangement in blood and bone marrow), and safety of the combination. A mini-Max, 2-stage design (52 pts planned) was used to detect >70% RR with power of 90% and alpha of 0.10. Results: 23 pts enrolled: median age 64 yrs; FLIPI 0–5: 0%/17%/65%/13%/4%; Grade 1/2: 61%/39%; bulky disease (>5cm3): 35%; stage: 1–4 4%/4%/30%/61%; bone marrow + 48%. All pts received induction and 18 pts received 1 or more maintenance cycles. RR following induction was 26% (95%CI=10.2–48.4), 4% CR and the best ORR was 70% (95%CI=47.1–86.8), 35% CR. Molecular response analysis is ongoing. Grade 3/4 AEs that occurred in ≥2 pts: nausea 4(17%), vomiting 2(9%), abdominal pain 2(9%), fatigue 2(9%), and small bowel obstruction 2(9%). AT-101 was reduced to 20mg daily x 21 which improved GI tolerability. Conclusions: The combination of AT-101 and R was well tolerated. The week 8 RR did not meet statistical criteria to enroll stage II. The best ORR is at the upper limit of reported ORR for R alone; therefore a randomized trial is required to definitively determine activity of the combination.

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Methylation reversal in high-grade B lymphoma cell lines and novel epigenetic changes conserved between immunocompetent and HIV-positive hosts
Authors: Bower M. , Syed N. , Papoudou-Bai A. , Stebbing J. , Naresh K. , Hatzimichael E. , Powles S. , Crook T.
Published: August 2020

8585

Background: Methylation-dependent transcriptional silencing is an important mechanism of tumour suppressor gene inactivation in neoplasia, including lymphoma. Methods: Pharmacological “unmasking” of transcriptionally silenced genes in B lymphoma cell lines was achieved using 5' deazacytidine ± Trichostatin A and subsequent analysis of mRNA levels on micro-array. Candidate genes thus identified, were further analysed by qPCR, methylation-specific PCR (MSP) and bisulphite sequencing in B lymphoma cell lines and by MSP in clinical samples from sporadic (immunocompetent) (18 cases) and HIV-infected patients (14 cases). Samples in both patient groups were diffuse large B cell lymphoma (DLBCL) and Burkitt's lymphoma (BL). Additionally, we analysed 8 cases of marginal zone lymphoma (MZL) from the immunocompetent group. Results: We report the identification of 13 novel genes, not previously described in the literature, which are subject to methylation-dependent transcriptional silencing in high-grade lymphoma and whose expression can be reactivated by demethylating agents. The novel genes encode proteins involved in diverse functional classes and include pro-apoptotic members of the p53 pathway (Scotin), transcriptional regulators (Baz2B) and regulators of telomerase (Smrf2). The frequency of methylation in individual genes varied from approximately 10% to 75% in specific lymphoma subtypes, but was in general similar in high grade lymphomas in immunocompetent and HIV-infected hosts. Conclusions: Using pharmacological reversal of methylation, we have identified a number of genes, not previously implicated in human neoplasia, which are subject to transcriptional silencing in high-grade B lymphomas. The similar frequencies of methylation, observed in immunocompetent and HIV positive patients implies that the genes are fundamental in suppression of lymphomagenesis. Detection of methylated DNA of one or more of these genes may have utility as biomarkers of clinical outcome in each patient group.

No significant financial relationships to disclose.
Evaluation of the melanocortin-1-receptor gene in melanoma predisposition, progression, and recurrence
Authors: Sidash S. , Ostrer H. , Goldberg J. D. , Belitskaya-Levy I. , Lobach I. V. , Polsky D. , Shapiro R. L. , Berman R. S. , Osman I. , Manga P.
Published: August 2020

9018

Background: The melanocortin-1-receptor (MC1R) gene is highly polymorphic in humans. Multiple studies have shown the association between MC1R allelic variants and increased risk of melanoma. Over seventy MC1R single nucleotide polymorphisms (SNPs) have been identified making MC1R a likely target for the development of genetic markers for melanoma predisposition and progression. Alleles described as R and r result in a protein with reduced function compared to wild type, with r alleles having the greatest effect. We sought to investigate the impact of MC1R genotype on risk of developing melanoma and will test for association with disease progression and recurrence in a cohort of melanoma patients enrolled in a prospective study. Methods: Our cohort includes 291 newly diagnosed melanoma patients seen at the New York University Langone Medical Center. The control cohort included 449 subjects. DNA was isolated from leukocytes and analyzed for MC1R SNP status by PCR and direct sequencing. Associations were tested for R-variant R151C and r-variants V60L and V92M. Fisher's Exact test was used to detect significant differences in allele frequency. Odds ratios and confidence intervals were computed for each SNP. Results: Allele frequencies were significantly different in cases and controls for each of the variants (p<0.01). The greatest effect was seen with V60L (Odds Ratio=6.281 95% Confidence Interval 1.77- 22.20). Conclusions: Variants that result in reduced MC1R function increase an individual's risk of developing melanoma. We will continue to test associations with additional variants and determine if these alleles also contribute to risk of disease progression and recurrence. In addition, these variants will be tested for utility as biomarkers for risk assessment of melanoma in a clinical setting.

No significant financial relationships to disclose.
Effect of TKI258 on plasma biomarkers and pharmcokinetics in patients with advanced melanoma
Authors: Shi M. , Kim K. B. , Chesney J. , Wang X. , Motwani M. , Wang J. , Steed M. , Anak O. , Jones G. , Saro J. , Kirkwood J.
Published: August 2020

9020

Background: TKI258 (dovitinib lactate), is a multi-tyrosine kinase inhibitor of VEGF receptors-1,2,3, FGF receptors-1, 2, 3, PDGFR-β, and c-KIT. A phase I study was conducted to determine the maximum tolerated dose (MTD), the biological activity and the preliminary efficacy of TKI258 in patients with advanced melanoma. A panel of plasma biomarkers of angiogenesis and soluble receptors were evaluated to determine the pharmacodynamic effect of TKI258. Methods: Patients were treated orally with 200, 300, 400 or 500 mg/day on a once daily continuous dose schedule. The MTD was defined at 400 mg/day. Plasma samples from 43 patients were collected. Plasma concentration of TKI258 was measured by LC/MS/MS. Plasma VEGF, placental growth factor (PLGF), basic FGF (bFGF), and soluble VEGFR1 and VEGFR2 (sVEGFR1 and 2), and c-Kit were measured by multiplex assays using the Meso-Scale Discovery platform. Plasma FGF23 was evaluated by ELISA as a pharmcodynamic marker of FGFR1 inhibition. Results: Following 400 mg or 500 mg continuous daily dosing, the mean plasma exposure (AUC24hr) was approximately 3000 ng/mL*h and 4100 ng/mL*h, respectively. No accumulation in TKI258 plasma exposure was observed at doses of 400mg or below, while accumulation up to 2.5-fold was observed on day 15 following the 500 mg daily dose. At the end of the first treatment cycle, mean plasma VEGF, PLGF and FGF23 levels increased over baseline by 100%, 198% and 68%, respectively, while mean plasma sVEGFR2 levels decreased by 15% in patients treated with 400 and 500 mg/day TKI258. Further analysis of correlations with pharmacokinetic and clinical parameters is ongoing. Conclusions: TKI258 therapy is associated with increases of plasma VEGF and PLGF as well as decreases of sVEGFR2 suggesting VEGFR inhibition. Induction of plasma FGF23 suggest that FGFR may be inhibited at doses of 400 mg/day and above. This panel of circulating proteins may have utility as pharmacodynamic biomarkers of TKI258 activity in patients with advanced melanoma.

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Phase I/II study of the tumor-targeting human L19-IL2 monoclonal antibody-cytokine fusion protein in combination with DTIC in metastatic melanoma patients
Authors: Garbe C. , Romanini A. , Spitaleri G. , Giovannoni L. , Zardi L. , Neri D. , Shaw A. , Menssen H. D. , deBraud F. , Eigentler T. K.
Published: August 2020

9064

Background:L19-IL2 is a tumor targeted immunocytokine constituted by a single chain Fragment variable (scFv) format directed against the ED-B domain of fibronectin and the human cytokine interleukin-2 (IL2). The recommended dose (RD) for monotherapy of advanced solid cancer patients was established to be 22.5 Mio IU IL2 equivalent on day 1, 3, and 5 of a 21-day cycle. Here we report clinical results of the dose escalation part of a phase I/II study assessing L19-IL2 in combination with DTIC chemotherapy in metastatic melanoma patients. Methods: L19-IL2 was administered as an i.v. infusion at doses of 10 (n=3), 15 (n=3) and 22.5 MioIU IL2 equivalent dose (n=4) on days 1, 3 and 5 every 21 days in combination with DTIC 1000 mg/m2 on Day 1 for up to 6 treatment cycles. Serum samples for PK evaluation and induction of human antifusion antibodies to L19 (HAFA) were collected. Flow cytometry (T and NK/B cell panels) was performed. Data on safety and activity were evaluated using CTC v3.0 and RECIST criteria, respectively. Results: All 10 patients had progressive metastatic melanoma and the majority had already received prior systemic therapy. Median age at start of treatment was 62 years (52–74). There were no treatment related deaths and the treatment was well tolerated, details of CTC evaluation will be presented. The dose of 22.5 Mio IU day 1, 3, and 5 in combination with 1000 mg DTIC/m2 on day 1, repeated on day 22 was defined as the RD for up to 6 treatment cycles. 10 patients were evaluable for response. We observed 1 partial remission at the 15 Mio IL2 dose level after 4 treatment cycles. Immunophenotyping analysis showed transient stimulation of NK cells, T4 cells, and CTLs. Pharmacokinetic data will be presented. Conclusions: L19-IL2 at a dose of 22.5 Mio IU IL2 equivalent on days 1, 3, and 5 of a 3-weekly schedule can be safely combined with standard DTIC in metastatic melanoma patients. Toxicity was manageable and reversible. Preliminary evaluation suggests clinical activity of the L19IL2/DTIC regimen in metastatic melanoma patients.

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Prospective analysis of predictors of survival in melanoma patients with brain metastases
Authors: Zakrzewski J. A. , Geraghty L. , Hamilton H. , Christos P. , Krich D. , Mazumdar M. , Polsky D. , Darvishian F. , Pavlick A. , Osman I.
Published: August 2020

9074

Background: Melanoma patients (pts) with brain metastases (BM) have limited survival, and BM remains an exclusion criterion in most clinical trials. A recent retrospective analysis at Memorial Sloan Kettering Cancer Center (MSKCC) identified 4 clinical variables that were associated with worse post BM survival (Raizer J et al, Neuro Oncol 2008). In this study, we investigated whether primary tumor features could improve the predictability of post BM survival and examined the reproducibility of the variables identified in MSKCC study. Methods: Melanoma pts with BM prospectively enrolled in an interdisciplinary database at NYU Medical Center from 2002 to 2008 were studied. Six primary tumor characteristics, 21 clinical variables, and treatments were examined. Univariate associations were analyzed using Kaplan Meier survival analysis and the independent effect of identified predictors was assessed by multivariate cox proportional hazards regression analysis. Results: Eighty-nine pts (36 F, 53 M, median age 57) were identified. Median post BM survival was 5.75 months. Median follow-up time based on survivors was 4.2 months. Ulceration and mitotic index ≥3/field were univariately associated with worse post BM survival (p=0.004, p=0.009 respectively). Age >65, ≥3 BM lesions, presence of neurological symptoms, and extracranial metastases were also univariately associated with worse post BM survival (the same 4 variables identified in MSKCC retrospective study). An additional 4 clinical parameters were significant by univariate analysis: frontal lobe location (p=0.01), bilateral lesions (p=0.01), ≥2 neurological symptoms (p=0.005), and weakness/fatigue (p<0.0001). After reproducing the significance of the 4 MSKCC variables in a multivariate model, ulceration of the primary tumor was also an independent predictor of post BM survival (hazard ratio [HR] = 2.75; 95% CI = 1.30, 5.83; p=0.008) whereas mitotic index ≥3/field was not (HR=1.24; 95% CI = 0.57, 2.71; p=0.59). Conclusions: Data suggest that ulceration of the primary melanoma might indicate an adverse biologic behavior that impacts post BM survival. Our data also lend independent support for the predictive model of post BM survival.

No significant financial relationships to disclose.
Effect of denosumab on bone mineral density (BMD) in women with breast cancer (BC) and men with prostate cancer (PC) undergoing hormone ablation therapy
Authors: Smith M. R. , Ellis G. , Saad F. , Tammela T. , Bone H. , Egerdie B. , Ke C. , Jun S. , Dansey R. , Goessl C.
Published: August 2020

9520

Background: Hormone ablation therapies, including adjuvant aromatase inhibitor (AI) therapy and androgen deprivation therapy (ADT), improve recurrence-free survival in patients (pts) with BC and PC, respectively. However, these treatments increase bone resorption, leading to bone loss and fractures. RANKL is a key mediator of osteoclast-mediated bone resorption. In this 24 month (mo) comparison, we investigated the effects of denosumab, a fully human monoclonal antibody against RANKL, on preserving BMD across both populations. Methods: Two trials were conducted: a 24-mo BC study and a 36-mo PC study. Postmenopausal women with low BMD receiving AI therapy for nonmetastatic BC and men receiving ADT for nonmetastatic PC (with low BMD or history of osteoporotic fracture if < 70 yrs) were randomized to receive placebo or denosumab 60mg subcutaneously every 6 mos. All pts in both studies were prescribed calcium and vitamin D supplements. The primary endpoint was % change from baseline in lumbar spine (LS) BMD at 12 mos for the BC study and at 24 mos for the PC study. Herein, we present changes in BMD at 24 mos at LS, total hip (TH), and 1/3 radius from both studies. Power calculations were based on enrollment of at least 208 patients in the BC study (for primary endpoint only) and 1226 in the PC study (for primary and key secondary endpoints). The actual numbers randomized were 252 and 1468, respectively. Results: Denosumab increased BMD of the LS, TH, and 1/3 radius compared with placebo at 24 mos in both pt populations ( Table ). In both studies, differences between denosumab and placebo at each skeletal site were consistent, and the effects of denosumab were statistically significantly different from placebo as early as 1 month at the LS in both studies. The overall safety profile was similar to placebo in each study. Conclusions: Denosumab consistently increased BMD at all 3 skeletal sites compared with placebo in both women with BC undergoing AI therapy and in men with PC undergoing ADT.

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Patient preference as a determinant of breast cancer adjuvant chemotherapy use in older women: CALGB #369901
Authors: Mandelblatt J. , Sheppard V. , Hurria A. , Kimmick G. , Isaacs C. , Taylor K. , Luta G. , Noone A. , Kornblith A. , Barry W.
Published: August 2020

9544

Background: Decisions about use of breast cancer chemotherapy in women 65 and older (“older”) can be complex due to comorbidity, uncertain efficacy and limited data on patient preference. Methods: Older women diagnosed with invasive, non-metastatic breast cancer between 2004 and 2008 were recruited from 53 CALGB sites for an observational study of preferences and chemotherapy use. Data on preferences and other factors were collected from patient interviews and clinical data were abstracted from charts. Generalized estimating equation regression was used to assess associations between chart-reported chemotherapy and independent variables; associations were also evaluated in 2 subgroups: “chemotherapy indicated” (estrogen receptor [ER] negative and/or node positive) and “consider chemotherapy” (ER positive and node negative). Results: Among 935 eligible women registered, 815 (87.2%) completed interviews. The mean age of the cohort was 73 years (range 65–100); 38% were node positive, 82% were ER positive and all had tumors ≥ 1 cm (44% were AJCC stage 1, 44% stage 2 and 12% stage 3). Based on ER and nodal status, chemotherapy was “indicated” for 47% and could be “considered” for 53%. Crude chemotherapy rates were 70% in the “indicated” group and 17% in the “considered” group, for an overall rate of 42%. Women who would choose chemotherapy for an increase in survival of ≤12 months were 4.1 times (95% CI 2.5–6.7, p<.0001) more likely to receive chemotherapy than women who would only choose chemotherapy if it added more than 12 months, controlling for age, tumor factors, comorbidity and other covariates. Stronger preferences were seen among women with “indications” for chemotherapy (OR 7.9, 95% CI 3.7–17.0, p<.001) than in those where treatment might be “considered” (OR 1.8, 95% CI 0.9–3.4, p=.08). Higher patient rating of communication with providers was independently related to a decision to use chemotherapy among women where chemotherapy could be “considered” but not among those where chemotherapy was “indicated”. Conclusions: Beyond clinical indications, older women's preferences and communication with providers are important correlates of chemotherapy use.

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