bluuebunny/crossref_metadata_2025_split huggingface dataset:
Strategies to overcoming rituximab-chemotherapy resistance by targeting the autophagy pathway using bortezomib in combination with the Bcl-2 inhibitor obatoclax in non-Hodgkin's lymphomas (NHL)
Authors: Hernandez-Ilizaliturri F. J. , Khubchandani S. , Olejniczak S. H. , Hoskin P. , Czuczman M. S. 
Published: August 2020

8543 We found that repeated rituximab exposure leads to deregulation of Bcl-2 proteins and concomitant chemotherapy resistance. We demonstrated that obatoclax (O), a potent Bcl-2 inhibitor, enhanced the anti-tumor activity of rituximab or chemotherapy agents. The proteasome is known to regulate Bcl-2 family members expression. In the current work we study the interactions between bortezomib (B) and O against B-cell NHL. Studies were conducted in rituximab sensitive (RSCL) and resistant cell lines (RRCL), as well as in malignant B-cells derived from patients with NHL (n = 20). Cells were exposed in vitro to escalating doses of O with/without B. Cell death was determined by the Cell glow luminescent assay and DNA synthesis by [3H]-Thymidine incorporation. To further study the mechanisms of O and/or B action, RSCL or RRCL were exposed to O or B with or without caspase inhibitors; viability was evaluated as above and apoptosis by flow cytometry and PARP cleavage. Autophagy was detected by LC3 conversion and electron microscopy (EM). Changes in p53 or BH3 domain proteins were evaluated by Western blot. To determine the role of p53 and/or autophagy in O or B activity, SiRNA assays were performed. O or B monotherapy induced time- and dose-dependent cell death of all cells tested. In vitro exposure of RRCL, RSCL and lymphoma specimens to O and B resulted in significant synergistic activity. In vitro exposure of NHL cells to O lead to p53 degradation and Noxa or PUMA induction; while exposure to B resulted in Bax upregulation and Mcl-1 downregulation. The ability of O or B to induce PARP cleavage varied between patient samples and was not observed in RRCL. Inhibition of caspase activity did not affect the ability of O or B to kill NHL cells. Induction of autophagy was detected by LC3 conversion and EM not only in RSCL or RRCL but also in patient-derived tumor cells. Additionally, cell death induced by O could be inhibited by knock-down of Beclin-1 or p53. Our data suggest that O and B have a dual mechanism of action. We also provide data suggesting that both p53 and Beclin-1 have a pivotal role in response to O. Our findings strongly suggest that O added to B may result in a novel and potent therapeutic strategy against aggressive NHL. No significant financial relationships to disclose.
Retrospective analysis of CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) treated with chemotherapy with or without rituximab
Authors: Miyazaki K. , Yamaguchi M. , Suzuki R. , Niitsu N. , Ennishi D. , Tamaru J. , Kagami Y. , Katayama N. , Kinoshita T. , Nakamura S. 
Published: August 2020

8551 Background: CD5+ DLBCL comprises 5–10% of DLBCL, and shows a high incidence of central nervous system (CNS) relapse. It has been included in the 4th WHO classification as an immunohistochemical subgroup. To clarify the prognosis and incidence of CNS relapse of CD5+ DLBCL in the rituximab-era, we conducted a multicenter retrospective study. Methods: We analyzed 313 patients (pts) with CD5+ DLBCL who received chemotherapy with (n=164) or without rituximab (n=149). The current series includes 107 out of 120 pts described in our previous study (Haematologica, 2008). Intravascular large B-cell lymphoma, primary CNS DLBCL, and secondary CD5+ DLBCL were excluded from the study population. Results: 313 pts showed the following clinical features: median age, 67 (range: 15–93); M:F=163:150; elevated serum LDH level, 71%; stage III/IV, 64%; IPI HI/H, 53%. No significant difference in clinical background such as the IPI and its five components, B symptom, male sex, and bone marrow involvement was found between pts who were treated with and without rituximab. Pts treated without rituximab received more dose-intensive chemotherapies (CHOP14, third-generation regimen, and high dose cytarabine-based regimen) than those treated with rituximab (24% vs. 7%, P<0.0001). The CR rate was higher in pts received rituximab than those without (81% vs. 65%; P=0.0014). The median follow-up was 28 months in pts who received rituximab (range: 7–77) and 68 months in those who did not (range: 6–187). Overall survival (OS) was significantly superior for pts with rituximab than for those without (2-yr OS: 68% vs. 54%, P=0.003). Multivariate analysis revealed that the use of rituximab was favorably associated with OS (HR=1.81, 95% CI: 1.26–2.58, P=0.001), but dose-intensive chemotherapies did not affect OS. However, the incidence of CNS relapse was not different between the two groups (2-yr CNS relapse rate: 11.9% vs. 11.4%, P=0.91). 16 of the 20 pts (80%) with CNS relapse in the rituximab group had brain parenchymal disease. Conclusions: Our data show that rituximab improves OS of pts with CD5+ DLBCL, but does not prevent CNS relapse. Future prospective studies to decrease CNS disease for CD5+ DLBCL are warranted. No significant financial relationships to disclose.
PROPEL: Results of the pivotal, multicenter, phase II study of pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL)
Authors: O'Connor O. , Pro B. , Pinter-Brown L. , Popplewell L. , Bartlett N. , Lechowicz M. , Savage K. , Coiffier B. , Saunders M. , Horwitz S. 
Published: August 2020

8561 Background: Pralatrexate is a novel targeted antifolate designed to accumulate preferentially in cancer cells. PROPEL, a pivotal phase 2, non-randomized, open-label, international study, is the largest prospective study in patients (pts) with relapsed or refractory PTCL. Methods: Pts received 30 mg/m2 of pralatrexate intravenously weekly for 6 of 7 weeks, supplemented with B12 and folic acid. Primary endpoint = objective response rate (ORR); secondary endpoints = response duration, progression-free survival, and overall survival. Eligibility criteria: histologically confirmed PTCL, disease progression after ≥ 1 prior treatment, and ECOG performance status ≤ 2. Pathology was confirmed by independent central review, response to therapy was assessed by independent central review using International Workshop Criteria (IWC). Results: 115 pts were enrolled, 109 were evaluable for efficacy. 111 treated pts included 76 males (68%) and 35 females (32%). Pts had failed a median of 3 prior regimens and thus were heavily pre-treated. 78 pts (70%) failed CHOP, 18 (16%) had previous autologous stem cell transplant. 25% of pts never responded to any prior therapy; 53% did not respond to last prior therapy. The majority (59 pts, 53%) had PTCL not-otherwise specified. The ORR by central review was 27% (n = 29). 11 pts (10% overall, 38% of responders) had a complete response (CR), 18 pts (17%) had a partial response (PR), and 23 (21%) had stable disease. ORR by investigators assessment was 39% (n = 42). The median duration of response cannot be accurately estimated at this time, though responses of > 1 year have been observed. 69% of responses were after just 1 cycle. 5 responding pts went on to transplant. The most frequent Grade (Gr) 3–4 adverse events were mucosal inflammation (Gr 3 = 17%, Gr 4 = 4%) and thrombocytopenia (Gr 3 = 14%, Gr 4 = 19%). Conclusions: The results of PROPEL show that pralatrexate exhibits substantial activity in pts with relapsed or refractory PTCL, as assessed by a rigorous central review, with durable CRs /PRs, irrespective of the amount of prior therapy. [Table: see text]
Phase I/II study of a hybrid schedule of flavopiridol in relapsed/refractory mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL)
Authors: Tay K. , Shapiro G. , Disinski M. , Chirieac L. R. , Pittaluga S. , Jaffe E. S. , Janik J. E. , Wiestner A. , Wilson W. H. , Dunleavy K. 
Published: August 2020

8563 Background: Continuous infusion and bolus schedules of flavopiridol in MCL have yielded disappointing results. However, a pharmacologically derived hybrid schedule of administration is effective in refractory, genetically high-risk CLL, though life-threatening tumor lysis syndrome (TLS) may occur in patients with very high lymphocyte counts. Because flavopiridol decreases cyclin D1 and mcl-1 and induces apoptosis in MCL cells, is significantly toxic for cell lines derived from the activated B-cell-like type of DLBCL (OCI-Ly3) and down-regulates NF-kappa B, we investigated the hybrid schedule in MCL and DLBCL. Methods: Flavopiridol was administered as a 30-minute bolus (mg/m2) followed by a 4-hour continuous infusion (mg/m2), weekly for 4 doses every 6 weeks. Separate escalation rules applied to cycle 1 week 1 (C1W1) and all other weeks of treatment. Dose levels on C1W1 were DL1: 25/25 (4 pts); DL2: 30/30 (10 pts) and DL3: 30/50 (6 pts). Dose escalation on subsequent weeks was not possible due to toxicity and all pts received 30/50. All patients received TLS prophylaxis. Paired biopsy samples obtained before and after the first dose were analyzed for cdk targets. Results: Patient (n=20) characteristics: median age: 59 (r 24–80); male 15 (75%); median prior regimens 2 (r 1–6). 10 had MCL and 10 had DLBCL. Responses were PR in 2 (1 MCL; 1 DLBCL) pts (10%); SD in 5 (25%); and PD in 13 (65%). DLTs were TLS and severe vomiting/diarrhea in 2 pts at DL3. The MTD and phase II dose has not yet been defined. Other toxicities were grade 4 ANC (10 pts) requiring prophylactic G-CSF, TLS (1 pt) and bowel perforation (1 pt). Decreased Rb staining at the S807/811 phospho-site was noted in 8 of 9 paired samples analyzed (r 20–75%; p = 0.027) and at the S780 site in 7 of 8 paired samples (r 38–91%; p = 0.00016), suggestive of G1 cdk inhibition. In 1 sample in which p53 was detected, there was an increase post-treatment, suggestive of cdk9 inhibition. Conclusions: The hybrid schedule of flavopiridol has modest activity in relapsed MCL and DLBCL. TLS occurred infrequently and was reversible. DLTs were TLS and gastrointestinal toxicity. Accrual continues. Analysis of cell cycle and transcriptional cdk targets is ongoing. No significant financial relationships to disclose.
Prediction of treatment response in subtypes of non-Hodgkin's lymphoma by in vivo 31P MR spectroscopy before treatment
Authors: Arias-Mendoza F. , Leach M. O. , Koutcher J. A. , Griffiths J. R. , Heerschap A. , Glickson J. D. , O'Connor O. A. , Brown T. R. 
Published: August 2020

8565 Background: To determine if the intracellular tumor marker of phosphoethanolamine plus phosphocholine normalized by nucleotide triphosphates (PPN) monitored non-invasively by phosphorus MR spectroscopy (31P-MRS) correlate with indicators of treatment response in non-Hodgkin's lymphoma (NHL) subtypes. Methods: The PPN value was obtained in 33 diffuse large B-cell lymphomas (DLBCL), 18 follicular lymphomas (FL) and 16 other types (OT) of NHL using in vivo 3D-localized, 1H-irradiated 31P-MRS prior to standard treatment. Results: The PPN values (mean ± standard error) for complete responses (CR) and not complete responses (NCR) in DLBCL were significantly different (CR: 1.42±0.10, n=19 and NCR: 2.25±0.15, n=14; p<0.00002). A Fisher test with a cutoff maximizing PPN sensitivity and specificity (1.78) showed a p<0.004 (sensitivity=0.6, specificity=1.0). Further, when the PPN was combined with the international prognostic index (IPI) to predict treatment response, the Fisher test increased significance (p<0.0002; sensitivity and specificity=0.9). In addition, the two groups dichotomized by the PPN-IPI combination showed a significant difference for drug-free survival (p<0.0001)with one group with survival below 20 months. FL patients did not show PPN significance (CR: 1.40±0.16, n=4 and NCR: 1.75±0.15, n=14). Although this could be due to the lower number of patients, the mean PPN value of the NCR group of FL was significantly lower than that of DLBCL (p<0.01). In the OT group there was only one CR observation but the PPN of its NCR cases was 2.51±0.25, n=13. This value was not significantly different from that of DLBCL but was against that of FL (p<0.007). Conclusions: Our results show that: 1) the pretreatment PPN can predict treatment response in DLBCL identifying a group of DLBCL patients with DFS below 20 months; 2) FL and DLBCL showed distinctive metabolic behaviors; and 3) the number of CR cases was low for FL and OT limiting analysis of PPN until larger cohorts of patients are accrued. No significant financial relationships to disclose.
Efficacy and safety of lenalidomide oral monotherapy in patients with relapsed or refractory mantle-cell lymphoma: Results from an international study (NHL-003)
Authors: Reeder C. B. , Witzig T. E. , Zinzani P. L. , Vose J. M. , Buckstein R. , Haioun C. , Bouabdallah R. , Polikoff J. , Pietronigro D. , Czuczman M. S. 
Published: August 2020

8569 Introduction: Relapsed or refractory MCL patients demonstrated a promising overall response rate (ORR) of 53% with a median duration of response (DR) of 13.7 months to single-agent lenalidomide when analyzed as a subset in a recent a phase II study (NHL-002). A supporting international phase II trial (NHL-003) of single-agent lenalidomide was initiated for patients with relapsed or refractory aggressive NHL. In this report, we analyze the current results from the MCL patients enrolled in this trial. Methods: Patients with relapsed or refractory MCL and measurable disease 2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg of lenalidomide orally once daily on days 1–21 of every 28-day cycle. Patients continued therapy until disease progression or toxicity. The 1999 IWLRC methodology was used to assess response and progression. Results: Fifty-four MCL patients were enrolled and were evaluable for response assessment. Median age was 69 years (33–82) and 40 patients (74%) were male. Median time from diagnosis was 3.2 years (0.4–10.4), patients had received a median of 3 prior treatments (1–8), 17 of the patients (32%) had received prior bortezomib therapy (MCL-bortezomib), and 14 (26%) had received a prior stem cell transplant (MCL-stem cell). Response rates are shown in the Table. The most common grade 3 or 4 adverse events were neutropenia (43%), thrombocytopenia (22%) and anemia (11%). Conclusions: This is the second study to demonstrate that lenalidomide oral monotherapy is effective in the treatment of patients with relapsed or refractory MCL, with manageable side effects. [Table: see text] [Table: see text]
The prognostic significance of the number of extranodal sites in the patients with disseminated diffuse large B-cell lymphoma treated with R-CHOP
Authors: Yoo C. , Sohn B. , Kim J. , Yoon D. , Huh J. , Kim S. , Lee D. , Kim S. , Lee J. , Suh C. 
Published: August 2020

8570 Background: The combination of rituximab and CHOP chemotherapy (R-CHOP) has improved survival of patients with diffuse large B-cell lymphoma (DLBCL). Recently, several reports have shown that standard International Prognostic Index (IPI) became less powerful prognostic predictor in patients with DLBCL in the era of R-CHOP. We evaluated the prognostic factors of DLBCL patients treated with R-CHOP. Detailed analysis was planned regarding the number of extranodal sites because of its higher frequency in Korea. Methods: Between January 2002 and May 2008, 126 patients with stage III/IV DLBCL treated with R-CHOP were identified. We performed the retrospective analysis of the clinicopathologic factors and verified the predictive power of standard IPI and revised IPI (R-IPI) which was reported by the study group of British Columbia. Various numbers of extranodal sites were analyzed for further stratification and we set E-IPI as the IPI when the number of extranodal sites is stratified in ≤2 vs >2. Results: In the univariate analysis, the number of extranodal sites (≤2 vs >2) was a significant prognostic factor for complete response (CR) (p=0.04), event-free survival (EFS) (p=0.01) and overall survival (OS) (p<0.001). Age was also significant for EFS (p=0.03). When the number of extranodal site was stratified differently (0 vs >0, or ≤1 vs >1), these were not associated with CR, EFS and OS. On the multivariate analysis, the number of extranodal sites (≤2 vs >2) remained significant for EFS (p<0.01, HR 2.6) and OS (p<0.01, HR 3.5). The standard IPI identified 3 risk groups with 2-year EFS; 68%, 55%, 56% (p=0.17) and 2-year OS; 85%, 68%, 58%, respectively (p=0.04). The R-IPI classified 2 risk groups with 2-year EFS; 65%, 50% (p=0.02) and 2-year OS 76%, 62%, respectively (p=0.04). The E-IPI represented 3 risk groups with 2-year EFS; 79%, 56%, 42% (p=0.01) and 2-year OS; 86%, 70%, 39%, respectively (p=0.001). The patient group with survival of less than 50% was only recognized by E-IPI. Conclusions: The number of extranodal sites (≤2 vs >2) is the most significant prognostic factor of EFS and OS. Although all three indices remain predictive, E-IPI is the best model to identify the prognostic group in this cohort with stage III/IV DLBCL treated with R-CHOP. No significant financial relationships to disclose.
A phase I/II trial of the kinesin spindle protein (KSP) inhibitor SB-743921 dosed q14d without and with prophylactic G-CSF in non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL)
Authors: Gerecitano J. F. , O'Connor O. , Van Deventer H. , Hainsworth J. , Leonard J. , Afanasayev B. , Chen M. , Seroogy J. , Escandon R. , Wolff A. , Conlan M. 
Published: August 2020

8578 Background: KSP is a mitotic kinesin essential for cell cycle progression. SB-743921 (SB-921), a selective KSP inhibitor, blocks mitotic spindle assembly with cell cycle arrest in mitosis and cell death. In the first-in-humans (FIH) trial, the MTD was 4 mg/m2 q21d. Since neutropenia was the major DLT, with recovery by ∼d15, a q14d schedule without (-GCSF) and with prophylactic G-CSF (+GCSF) is being explored. Methods: In phase I of this phase I/II trial, DLT and MTD of SB-921 given on d1 and d15 q28d (-GCSF) and (+GCSF) will be determined. Eligible patients (pts) have relapsed or refractory HL or NHL, aggressive (a) or indolent (i), have had at least 1 prior chemotherapy (CT) regimen, and have relapsed after or were not candidates for stem cell transplant. This is a standard 3+3 dose escalation trial design, starting at 2 mg/m2 and escalating by 1 mg/m2. Once DLT (-GCSF) is identified, (+GCSF) dosing starts at the (-GCSF) MTD, escalating until (+GCSF) DLT is identified. Results: 39 pts were treated (-GCSF) at 6 dose levels (2–7 mg/m2). 5 pts had DLT: 1/3 at 4 (grade 3 hepatic enzymes; found retrospectively); 2/10 at 6 (both sepsis with neutropenia), and 2/7 at 7 (both grade 4 neutropenia lasting >5d) mg/m2. MTD (-GCSF) was 6 mg/m2. 12 pts were treated with SB-921 (+GCSF) at 6 (n=4), 7 (n=3), 8 (n=3) and 9 (n=2) mg/m2, with 1 DLT of neutropenia at 9 mg/m2. Expansion of the 9 mg/m2 (+GCSF) cohort to n=6 is ongoing. For all 51 pts treated to date, mean age was 52 yr; 53% were male; 39% HL, 33% aNHL, and 28% iNHL; 76% had ≥3 prior CT regimens. The most frequent grade 3/4 toxicity was neutropenia: 58% at ≥MTD (-GCSF) and 42% (+GCSF). Other grade 3/4 events were uncommon. There was no neuropathy or alopecia >grade 1. There were 2 partial responses (PR), both in elderly pts with HL with ≥2 prior CT regimens, 1 at 6 (-GCSF) and 1 at 8 (+GCSF) mg/m2, ongoing at Cycle 4+. Conclusions: The MTD of SB-921 (-GCSF) on a q14d schedule was 6 mg/m2. This dose density (0.43 mg/m2/d) is >2-fold higher than in the FIH trial with a q21d schedule (0.19 mg/m2/d). Dose escalation (+GCSF) is continuing. SB-921 is well tolerated with minimal toxicity other than hematologic. Activity has been observed in HL, with 2 PRs at doses ≥6 mg/m2. [Table: see text]
Vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma: A phase I study
Authors: Siegel D. S. , Weber D. M. , Mitsiades C. S. , Dimopoulos M. A. , Harousseau J. L. , Rizvi S. , Howe J. , Reiser D. , Anderson K. C. , Richardson P. G. 
Published: August 2020

8586 Background: Novel drug combinations may improve patient outcome in relapsed/refractory multiple myeloma (MM), which remains especially challenging to treat. Preclinical studies suggest that the histone deacetylase inhibitor vorinostat may have synergistic potential when combined with lenalidomide and dexamethasone. This phase I, multicenter, open-label study evaluated vorinostat plus lenalidomide and dexamethasone in patients (pts) with relapsed or refractory MM. The primary objective was to determine the maximum tolerated dose (MTD); other endpoints included overall safety and tolerability, as well as activity of the combination. Methods: Pts aged ≥18 years with relapsed or refractory MM were enrolled sequentially into 1 of 5 dosing levels ( Table ) using a standard 3+3 design for ≤8 cycles. Barring dose-limiting toxicities (DLTs) in the first cycle, dose escalation continued until the MTD was established. Response was assessed, and adverse events (AEs) were recorded. Results: Of 12 pts accrued to date, 11 (92%) have experienced ≥1 AE, with drug-related AEs reported by 6 pts (96% ≤Grade 2). The most common drug-related AEs (each in 4 pts) were fatigue and thrombocytopenia. Serious AEs in 2 pts (17%) were not considered drug-related. No pts discontinued due to AEs, and no DLT has been observed to date. Dose escalation to dose level (DL) 4 was achieved as no DLTs were observed in DLs 1–3. The MTD has not yet been reached. Of 11 pts evaluable for efficacy, best responses include: complete response in 1 pt, partial response in 2 pts, minimal response in 2 pts, and stable disease in 3 pts; 3 pts had progressive disease (PD). Currently, 9 pts remain on treatment, with 3 pts discontinuing treatment due to PD. Conclusions: These preliminary data suggest that vorinostat with lenalidomide and dexamethasone represents a well tolerated and active novel oral combination therapy for the treatment of relapsed/refractory MM. [Table: see text] [Table: see text]