bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclophosphamide and fludarabine (CF) in advanced indolent lymphoma: Results from the ECOG/CALGB intergroup E1496 trial
Authors: Hochster H. S. , Weller E. , Gascoyne R. D. , Ryan T. , Habermann T. M. , Gordon L. I. , Frankel S. R. , Horning S. J. 
Published: March 2020

8004 Background: To determine optimal induction and the role of maintenance, the E1496 study randomized patients (pts) to induction CVP (cyclophosphamide, vincristine, prednisone) versus CF (cyclophosphamide 1 G/m2 d1, fludarabine 20 mg/m2 d1–5 every 28 d) for 2 cycles beyond best response (maximum 8). Responding and stable pts were secondarily randomized to MR (375 mg/m2 weekly × 4 every 6 months for 2 years [yr]) or observation (OBS). Methods: Due to early deaths the CF arm was closed to accrual with 115 pts randomized to CF and 119 pts to CVP (thereafter all pts were assigned to CVP prior to maintenance randomization). The results presented here compare the outcome of CF patients with the subset of E1496 pts randomized to CVP (CVPR). Results: Median follow-up on pts randomized to induction is 6.5 yr. Toxic deaths occurred in 8 (7%) CF pts during induction and 4 additional deaths (1 OBS, 3 MR) occurred among the 69 (6%) CF pts randomized to MR or OBS. Causes of death were infection (9), liver failure (2), CNS gliosis (1). CF pts received a median of 5 cycles compared to 7 cycles for CVPR. The CR rate was 51% vs 22% (p=0.00001) and the PR rate was 35% vs 55% for CF vs. CVPR, respectively. Four-yr PFS for CF vs. CVPR was 49% vs 45% (p=0.19) and OS was 66% vs. 81% (p=0.12), respectively. Of 45 CF deaths, 23 (51%) occurred without lymphoma progression compared to 5 (13%) of 38 CVPR deaths (p=0.0004). More than 90% of CF patients randomized to maintenance achieved protocol-defined minimal residual disease compared with 64% CVPR pts. Maintenance therapy had no impact on 2 yr PFS for the 67 evaluable randomized CF pts, which was 74% for MR vs. 73% for OBS (p=0.19). In contrast, 2 yr PFS was 73% for MR and 42% for OBS in randomized CVPR pts (p=0.004). Survival at 2 yr for MR vs OBS was: CF 79% vs 91% (p=0.19) compared with CVP 98% vs 93% (p=0.21). Conclusions: Induction with CF results in higher CR and miminal residual disease rates than CVP. However, gains in remission quality with CF (in the dose and schedule used here) were offset by early and late deaths in the absence of progressive lymphoma. In E1496, the benefit of MR was influenced by the induction chemotherapy. [Table: see text]
Prediction of response to bortezomib and dexamethasone resistance in myeloma (MM) by novel mutations in the NFKB pathway
Authors: Chng W. J. , Keats J. J. , Chesi M. , Baker A. , Bruhn L. K. , Dispenzieri A. , Stewart A. K. , Carpten J. , Fonseca R. , Bergsagel P. L. 
Published: March 2020

8007 Background: We recently described mutations in multiple genes in MM patients that lead to the activation of the non- canonical NF-KB pathway. Among the mutated genes, TRAF3 is the most commonly affected, and is inactivated in about 20% of patients. In this study, we further defined the clinical significance of TRAF3 inactivation in MM. Methods: Deletion of TRAF3 was identified by array- based comparative genomic hybridization using Agilent Human Genome CGH 44k oligonucleotide array and confirmed by fluorescent in situ hybridization. Mutations were detected by sequencing. We use a TRAF3 gene expression cut-off (derived from 127 Mayo clinic patients) as a surrogate for TRAF3 inactivation to investigate its association with Translocations and Cyclin D genetic subtypes, response rates, and survival using 2 large gene expression dataset: UAMS dataset (559 newly diagnosed patients treated with Total therapy II and III) and Millenium datasets (213 relapsed patients entered into randomized study of bortezomib versus dexamethasone). Results: A normalized expression level of less than 0.6 identified all but three of the known TRAF3 inactivated cases in the Mayo dataset (p<0.0001). Using this cut-off, TRAF3 inactivated cases were enriched for t(4;14) (26%, p=0.00002) and rarely D1 (mostly hyperdiploid) (9%, p=9.6E-10) in all 3 datasets. TRAF3 inactivation did not affect survival of patients treated with transplant-based therapy (UAMS and Mayo dataset) but was strongly associated with bortezomib response (89% TRAF3 low versus 40% TRAF3 normal, p0.6 had similar PFS with the two treatment. Conclusion: Mutations resulting in TRAF3 inactivation are common, particularly in non-hyperdiploid MM, and predict for response to bortezomib and resistance to dexamethasone suggesting that inhibition of the non-canonical NF-KB pathway may be one of the principle mechanisms of action of proteasome inhibitors in MM. No significant financial relationships to disclose.
Revalidation of FLIPI in patients with follicular lymphoma (FL) registered in the F2 study and treated upfront with immunochemotherapy
Authors: Federico M. , Bellei M. , Pro B. , Lopez-Guillermo A. , Marcheselli L. , Trneny M. , Soubeyran P. , McLaughlin P. , Pileri S. , Solal-Céligny P. 
Published: March 2020

8008 Background: The Follicular Lymphoma International Prognostic Index (FLIPI) has become a widely accepted tool for risk assessement of FL. However, the recent shift to upfront immuno-chemotherapy (ICHT) requires confirmation studies of FLIPI discriminant power to ensure that the advent of Anti-CD20 MoAb did not modify its predictive value. Methods: We looked for the role of rituximab and its impact on the predictive value of FLIPI in the group of 1,093 patients diagnosed with FL between January 2003 and May 2005 and registered by 69 European and American Institutions in the F2-study. We identified 827 patients = 18 years of age and treated with systemic therapy. For the purposes of the present examination the prognosis was investigated in terms of progression-free survival (PFS) and the impact of rituximab explored by Cox analysis. Results: Patients characteristics are as follows: median age 57 yrs (21–93), male 50.1%, advanced stage 77.2%, elevated LDH 22.3%. To date central pathology review has been performed in 406 cases and the diagnosis of FL was confirmed in 98.3%. Patients at low risk (LR), intermediate risk (IR) and high risk (HR) on the basis of FLIPI were 40.3%, 32.6% and 27.1% respectively. Five-hundred sixty patients (67.7%) received ICHT, and 267 (32.3%) were treated with CHT only. After a median follow-up of 26 months the 3-yr PFS is 63.0%. Overall, the FLIPI remains highly predictive, being the 3-yr PFS of 77.8%, 60.5% and 49.1% for patients at LR, IR and HR respectively. Moreover, the 3-yr PFS predicted from Cox analysis is 81%, 62%, and 50% for patients at LR, IR and HR treated with ICHT (p<0.001), and 76%, 56%, 43% in those treated with CHT only (p<0.001). Finally, the relative risk for progression adjusted by the use of Anti-CD20 MoAb confirmed the efficacy of rituximab in all risk groups. The relative risk of progression for patients at IR was 2.01 as compared to patients at LR (p<0.001), and that for patients at HR was 1.47 as compared to patients at IR (p=0.021). Conclusions: Our study demonstrates that the FLIPI remains a useful tool to predict outcome even in the era of ICHT. Moreover, rituximab added to upfront chemotherapy improves the outcome of patients with FL in any risk group and in association with any chemotherapy regimen. No significant financial relationships to disclose.
Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients
Authors: Coiffier B. , Feugier P. , Mounier N. , Franchi-Rezgui P. , Van Den Neste E. , Macro M. , Haioun C. , Sebban C. , Bordessoule D. , Tilly H. 
Published: March 2020

8009 Background: The prospective randomized study LNH-98.5 was first reported in the N Engl J Med and J Clin Oncol with a median follow-up of 2 and 5 years. Here, we present the 7-year follow-up of the 399 patients included in the study. Methods: Patients had untreated diffuse large B-cell lymphoma and were 60 to 80 years old with a median age at diagnosis of 69 years. 60% had a poor risk lymphoma as defined by the aaIPI risk score of 2 or 3. 197 patients were randomized in CHOP arm and 202 in R-CHOP arm. Treatment consisted of 8 cycles of CHOP every 3 weeks with rituximab the same day in R-CHOP. Results: With a median follow-up of 7.1 years, 76% of the patients had an event in CHOP compared to 58% in R-CHOP, p=0.0002 ( Table ). 65% of patients died in CHOP arm compared to 47% in R-CHOP arm: 80% and 71% of them from lymphoma or treatment toxicity, 5% and 5% from another cancer, and 15% and 22% in CR from other causes, respectively. Survival curves show the same difference as reported before with a large difference in favour of R-CHOP ( Table ). Patients not expressing bcl-2 protein treated with R-CHOP have a statistically longer PFS but only a trend for OS because they responded better to salvage treatment. No statistically significant difference was observed for patients <70, 70–74, or ≥75 years old. Patients treated with R-CHOP have good survival even with poor risk parameters: 43% are alive for age ≥75 years, 38% for PS=2, 54% for B symptoms, 47% for stage IV, 45% for high LDH level, 54% for Hb ≤10 g/dl, and 42% for high aaIPI score. Death in CR was associated with high risk aaIPI score and presence of other diseases before lymphoma diagnosis. Conclusions: This analysis confirms the long term benefit associated with the combination of rituximab and CHOP and shows that older patients must be treated as younger patients even in presence of high risk characteristics or concomitant diseases. [Table: see text] [Table: see text]
Efficacy and toxicity of two schedules of R-CHOP plus bortezomib in front-line B lymphoma patients: A randomized phase II trial from the Groupe d’Etude des Lymphomes de l’Adulte (GELA)
Authors: Mounier N. , Ribrag V. , Haioun C. , Salles G. , Golfier J. , Ertault M. , Ferme C. , Briere J. , Brice P. , De Kerviler E. , Gisselbrecht C. 
Published: March 2020

8010 Background: Bortezomib is the first proteasome inhibitor that showed promising activity in hematologic malignancies. In Jan 2005, we initiated a phase II randomized trial to evaluate front-line R-CHOP + bortezomib in B lymphoma pts. Methods: 6 cycles of standard R-CHOP (d1=d21) were planned, pts were randomized between 2 schedules of bortezomib: arm A (d 1,4,8,11), arm B (d 1,8). For the first 24 pts (step1), bortezomib was administred at 1 mg/m2 in arm A and 1.3 mg/m2 in arm B. For the next 24 pts (step2), it was increased at 1.3 mg/m2 and 1.6 mg/m2 respectively. G-CSF and EPO supports were allowed. Primary endpoint was CR rate after 6 cycles. Results: The trial was closed in Apr 2006 after inclusion of 49 pts. Sex ratio M/F was 28 /21. Median age: 63 years [32–76]. Pathology: 4 Lymphoplasmocytic, 4 small lymphocyte, 8 MZL, 2 Malt, 11 FL , 7 FL with histological transformation, 4 Mantle cell and 9 DLBC without adverse factor. Performance status 2–4: 4 pts; stage 4: 33 pts; LDH>N: 16 pts and IPI 2–3: 18 pts. According to triangular-test interim analysis (Jan 2006), arm A was closed at 20 pts (11 step1, 9 step2). 29 pts received arm B (10 step1, 19 step2). 290 cycles of R- CHOP and 819 injections of bortezomid were given. In arm A, 5/20 pts received less than 90% of scheduled dose of bortezomib (all in step2); in arm B, 7/29 pts (2 step1 and 5 step2). Grade 3–4 thrombopenia occurred in 14% of cycles (35% arm A, 0% arm B, 14% step2), Grade 3–4 leucopenia in 41 % (35% arm A, 45% arm B, 43% step2). Neurological toxicity occurred in 21 pts: grade 2 in 11 (1 arm A, 10 arm B, 9 in step2) and grade 3–4 in 10 (5 arm A, 5 arm B, 9 in step 2). 6 of them were considered as serious adverse events. Other grade 3–4 toxicities were 1 constipation (1 arm B, step2), 3 infections (2 arm A, 1 arm B, 2 step 2) and 2 cardiac events (1 arm A, 1 arm B). 48 pts were evaluable for response: 40 achieved CR/CRU: 18/20 in arm A, 22/28 in arm B. There were 5 PR (1 arm A, 4 arm B), 1 SD (arm A) and 2 PD (arm B). 19/21 pts achieved CR in step 1 and 21/27 in step 2. After 1 year median follow up, OS was 100% and EFS 80%. Conclusions: R- CHOP+Bortezomid is an effective regimen with 83% CR rate. However, the higher doses of bortezomib lead to severe neuropathy and suggest that association with vinca alcaloides should be avoided. No significant financial relationships to disclose.
Radioimmunotherapy with 131-I tositumomab enhanced survival in good prognosis relapsed and high-risk diffuse large B-cell lymphoma (DLBCL) patients receiving high-dose chemotherapy and autologous stem cell transplantation
Authors: Vose J. , Bierman P. , Bociek G. , Loberiza F. , Enke C. , Hankins J. , Armitage J. 
Published: March 2020

8013 Background: The 5-year overall survival (OS) for pts with relapsed chemosensitive DLBCL with standard transplantation is approximately 40–50%. We previously piloted the addition of standard outpatient radioimmunotherapy (RIT) with 131-I tositumomab to the transplant regimen for patients with relapsed chemoresistant NHL. This phase I study demonstrated a 3 yr OS of 55% in these poor prognosis patients (JCO 23: 461–467, 2005). The current study is a follow-up phase II study in good prognosis relapsed and high risk DLBCL patients using 131-I tositumomab with BEAM (BCNU, etoposide, cytarabine, and melphalan) followed by an autologous stem cell transplant. Methods: Forty patients were accrued to the study between 2000–2005. The patients had a median age of 54 yrs (26–75) and all had a diagnosis of DLBCL. The patients had a median of two prior chemotherapies before transplant and 88% had received prior Rituximab. All patients had chemotherapy sensitive disease at the time of stem cell transplant. Following stem cell collection, all patients received a stem cell preparative regimen of 75 cGy total body dose of 131-I tositumomab (dosimetric dose day -19 and therapeutic day -12) followed by a standard BEAM transplant regimen. Autologous unpurged stem cells were infused on day 0. The median time of follow-up of the survivors is 28 months (3–68). Results: Seventy eight percent of the patients had a complete remission following the transplant. The 3 year progression free survival (PFS) is 70% (95% CI - 48 - 84%) and the 3 year OS is 81% (95% CI - 61 - 91%). The entire transplant can be delivered on an outpatient basis. No increased toxicity compared to a similar cohort receiving BEAM alone could be detected. Conclusions: The addition of 131-I tositumomab to BEAM and autologous stem cell transplant for relapsed or high-risk chemosensitive DLBCL produces a 3-yr OS of 81% without excess toxicity. This compares favorably to historical controls. This regimen is currently being tested in a phase III trial in the BMT/CTN of Rituximab/BEAM vs. 131-I tositumomab/BEAM in patients with relapsed chemosensitive DLBCL. No significant financial relationships to disclose.
Impact of prior thalidomide (T) therapy on the efficacy of pegylated liposomal doxorubicin (PLD) and bortezomib (B) in relapsed/refractory multiple myeloma (RRMM)
Authors: Sonneveld P. , Hajek R. , Nagler A. , Spencer A. , Bladé J. , Robak T. , Zhuang S. H. , Harousseau J. L. , Fruchtman S. , Orlowski R. Z. 
Published: March 2020

8023 Background: IMIDs and proteasome inhibitors offer novel therapeutic options for patients with RRMM. T+Dex is approved for the treatment of newly diagnosed MM (Rajkumar JCO 2006). Wang et al (ASCO 2006, ASH 2006) suggested prior T exposure resulted in partial cross resistance to subsequent treatment with lenalidomide (L). Our objectives were to determine 1) whether resistance also existed to PLD+B in patients receiving prior T vs no prior T and 2) if the efficacy and safety profile of PLD+B was comparable to that previously reported with L+Dex in T failures. Methods: We performed a post hoc analysis of a previously reported phase III trial comparing PLD+B vs B alone (Orlowski ASH 2006). RRMM patients receiving ≥1 prior therapy and randomized to receive PLD at 30 mg/m2 given on D4 of each cycle along with B at 1.3 mg/m2 on D1, 4, 8, and 11 of every 21-day cycle were analyzed based on prior T exposure or no prior T. Treatment was continued for up to 8 cycles or for at least 2 cycles beyond a CR unless disease progression was observed or unacceptable toxicity occurred. Results: 324 patients were randomized to PLD+B (n=194 [T naïve], n=130 [T exposed]) and included in this analysis. Baseline albumin was 3.8 g/dL, 3.8 g/dL and 4.8 g/dL for the PLD+B (T naïve), PLD+B (T exposed) and L+Dex (T exposed), respectively. Baseline β2 microglobulin was 5.2 g/dL, 5.4 g/dL and 3.7 g/dL for these groups, respectively. Conclusions: These results demonstrate that PLD+B provide a consistent efficacy benefit in both T exposed and T naïve patients with no evidence of cross resistance to prior T. Compared to L+Dex in a similar patient population with prior T exposure, PLD+B has comparable response rates and time to progression, but the risk of TVE is substantially reduced. These results should be considered when choosing treatment options for RRMM who have failed prior T treatment and confirmed in a prospective randomized study. [Table: see text] [Table: see text]
Efficacy and safety of denileukin diftitox (Dd) in a phase III, double-blind, placebo-controlled study of CD25+ patients with cutaneous T-cell lymphoma (CTCL)
Authors: Negro-Vilar A. , Dziewanowska Z. , Groves E. S. , Stevens V. , Zhang J. K. , Prince M. , Martin A. , Sterry W. 
Published: March 2020

8026 Background: ONTAK®(Dd), a genetically engineered fusion protein combines the enzymatically active domain of diphtheria toxin with the sequence of interleukin-2 (IL-2), designed to target IL-2 receptor expressing malignancies. Dd received FDA accelerated approval for the treatment of CTCL in patients with the CD25 component of the IL-2 receptor. Methods: The confirmatory placebo- controlled L4389–11 phase III trial evaluated 9 and 18μg/kg/d Dd in 144 patients with CD25(+) CTCL. Patients (=3 prior treatments, stages Ia - III) received Dd or placebo IV for up to 8 cycles, consisting of Dd once daily for 5 days every 3 weeks. Tumor burden in skin, blood and lymph nodes and a physician's global (PGA) were assessed relative to baseline and before every treatment cycle beginning with cycle 2. Confirmation of tumor response required two more consecutive cycles (3 observations). Investigator assessments were ratified by an independent Drug Evaluation Review Committee. Results: Initial analysis of activity and benefit shown below. Both Dd treatment arms were greatly superior to placebo in a dose dependent fashion. Population demographics were the same across treatment arms (median age 59 years, 55% male). Randomization was stratified by disease status at baseline, 67% were = stage IIa, 33% were =stage IIb. Response between stage groups within each arm did not differ significantly. Many responses were confirmed after 5 or more cycles. AEs were similar to those in previous Dd studies. The only significantly different Grade 3/4 adverse event was nausea (2% in Placebo and 15% in 18μg/kg/d). No differences in serious adverse events among treatment arms were observed. The frequency of AEs and SAEs markedly decrease after the first two cycles of treatment. Conclusions: This is the largest randomized, placebo controlled trial conducted in CTCL, providing clear evidence for efficacy and clinical benefit for Dd. No significant financial relationships to disclose. [Table: see text]
Survival of CD23-positive (CD23+) mantle cell lymphoma (MCL) compared to classic CD23-negative (CD23-) MCL: Biologic correlates and clinical outcomes in a 10-year analysis
Authors: Evens A. M. , Kelemen K. , Aranha O. , Jovanovic B. , Miyata S. , Nelson B. P. , Goolsby C. , Rosen S. T. , Winter J. N. , Peterson L. C. , Gordon L. I. 
Published: March 2020

8039 Background: MCL has been historically classified as CD23-, but CD23+ immunophenotype (IP) is identified in a significant minority of patients (pts). It is unclear whether clinicopathologic or survival differences exist between CD23- and CD23+ MCLs. Methods: MCL diagnosis was based on morphology, IP with associated cyclinD1-positivity and/or t(11;14). We identified MCL pts treated at our institution from 1997–2006. We investigated IP (CD23 by flow cytometric analysis), pt characteristics, prognostic factors, and survival. Results: We identified 54 pts (16F/38M), of whom 89% had stage IV disease, IPI = 3 in 57%, 38% elevated LDH, 26% high B2- microglobulin, 30% bulky disease (= 7cm), and 39% with peripheral blood involvement. Thirty-three pts (61%) had CD23- disease, 14 (26%) CD23+ MCL, and 7 (13%) had variable CD23 expression (CD23+/CD23- varied in tissue sites). The only clinicopathologic differences between CD23- and CD23+ pts were increased incidence of extranodal disease (besides marrow or gastrointestinal [GI]) in the former (58% vs. 21%, respectively; p=0.029; most commonly lung or CNS disease); while splenomegaly was more common in the latter (71% vs. 42%; p=0.11). Ki67 staining was not predictive of CD23 status or survival among either IP. Treatment was overall similar in both CD23 groups. Table 1 shows survival for all pts and CD23- pts compared to CD23+ MCL. Cox regression prognostic analysis among all pts (n=54) showed that IPI = 3, bulky disease, and high B2-microglobulin were associated with inferior event-free survival (EFS), while CD23+ MCL and stem cell transplant in first remission were associated with improved EFS (all <0.05). IPI = 3, bulky disease, and presence of extranodal disease besides marrow/GI were associated with inferior overall survival. Conclusions: Over 25% of MCLs are CD23+. CD23+ MCL is associated with a more indolent course and improved outcomes compared with ‘classic‘ CD23- MCL. No significant financial relationships to disclose. [Table: see text]
Prediction of response and progression in multiple myeloma (MM) with serum-free light chains (sFLC): Corroboration of the International Myeloma Working Group (IMWG) criteria
Authors: Khoriaty R. N. , Hussein M. A. , Lally J. , Kelly M. , Kalaycio M. , Baz R. 
Published: March 2020

8047 Background: The sFLC assay was proposed as a tool for the assessment of response in patients with non-secretory or oligosecretory MM and patients with primary amyloidosis. Response and progression criteria have been proposed by the IMWG, but have not been thoroughly validated. Methods: Electronic records of patients (pts) with MM enrolled in various clinical trials at the Cleveland Clinic between 4/2004 and 12/2006 were reviewed. Response to treatment and progression were assessed using the European Blood and Bone Marrow Transplantation (EBMT) criteria for all pts. sFLC responses were defined per IMWG criteria: response (R, decrease in the difference between the involved and uninvolved light chain by greater than 50%), progression (P, increase in the difference between the involved and uninvolved light chain by greater than 25%), and stable disease (SD, not meeting the criteria for either R or P). sFLC responses were assessed in pts with involved FLC =10 mg/dL (=100mg/L) per the IMWG criteria. Results: 89 pts were identified. The median age was 61 years (range 41–87) and 58 pts were males. The involved light chain was kappa in 67 pts (75%), and lambda in the remainder. By EBMT criteria, 4 pts had a complete response, 22 a partial response, 34 stable disease, 26 progressive disease and 3 were inevaluable. Only 43/89 pts (48%) had an involved sFLC=10mg/dL; of which 14 had R, 8 had SD, 18 had P, and 3 were inevaluable. Table 1 reviews the test characteristics for sFLC assay for the prediction of response or progression. Conclusions: sFLC reliably predicts response and progression in MM pts. However, half the pts had an involved sFLC that would not be considered evaluable by IMWG, which limits its potential use. No significant financial relationships to disclose. [Table: see text]