bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II trial of docetaxel (D) plus gefitinib (G) in elderly (≥70 years) patients with advanced stage non-small cell lung cancer (ANSCLC)
Authors: Williams C. , Bepler G. , Begum M. , Chiappori A. , Arora R. , Haura E. , Antonia S. , Extermann M. , Simon G.
Published: March 2020

7690

Background: Adding G to first-line doublet chemotherapy did not improve survival in comparison to doublet chemotherapy alone in phase III trials (INTACT 1 and INTACT2). We hypothesized that therapy with D and G will yield similar efficacy to doublet chemotherapy but with improved toxicity profile that would be especially meaningful for elderly patients. We report here the results of a completed phase II trial. Methods: Previously untreated elderly patients with ANSCLC with ECOG performance status (PS) of 0 or 1, were eligible. D was given at 75 mg/m2 IV on day1, Q 21 days. G given orally daily; starting day 1, at a dose of 250mg. D-G was given for 2 cycles beyond maximal response. G was continued until progression. Tumors were assessed every two cycles while on D-G and every two months while on G. The RECIST criteria were used to measure responses. Results: Forty-four eligible patients were enrolled from 07/2003 to 11/2005. Demographic characteristics were M/F = 25/19; Median age 75 years (range; 70 to 84 years); ECOG PS 0/1= 27/16; Stage IV/IIIB = 38/6; Never-smoker/smoker 8/36; Adenocarcinoma/non-adeno-NSCLC 30/14; Median number of D-G cycles administered is 4 (range; 1 to 6). Median duration on maintenance D was 5 months (range; 1 to 36) Overall response rate was 29% (CR- 2%; PR- 27%) with 48% stable disease. Median progression free survival (PFS) was 8 months (95% CI: 6.2–10.6), PFS at 12 months was 34%, and 24 months was 19%. Median Overall Survival (OS) was 12 months (95% CI: 5.6–17.5). OS at 12 months was 52% and 24 months was 20%. The most common hematologic and non- hematologic adverse events were lymphopenia/anemia, and fatigue/hyperglycemia (steroid-induced)/dyspnea, respectively. Three patients had febrile neutropenia (6.8%). Detailed toxicity analyses will be reported at the meeting. Conclusion: The combination of D and G demonstrates comparable efficacy to conventionally used doublet chemotherapy regimens. The relatively favorable toxicity profile warrants further development of this approach, especially in clinical situations or special populations where toxicities are an impediment to treatment.

No significant financial relationships to disclose.
Cisplatin (CDDP) plus vinorelbine (VRB) as first-line treatment for patients with advanced non-small cell lung cancer (NSCLC): Molecular correlates
Authors: de las Peñas R. , Provencio M. , Camps C. , Cobo M. , Massuti B. , Jimenez U. , Artal A. , Cardenal F. , Taron M. , Rosell R.
Published: March 2020

7692

Background: The combination of cisplatin plus vinorelbine is a reference regimen as first-line therapy in advanced NSCLC. The correlation between predictive genetic markers and clinical endpoints may improve the prediction of treatment success and thereby the tailoring of chemotherapy. In this trial, predictive genetic markers of response to CDDP/VRB were examined in genomic DNA and cDNA derived from tumors and circulating tumors. Methods: 238 chemonaive p with stage IIIB (pleural effusion or supraclavicular lymph nodes)- IV or recurrent NSCLC were accrued at 35 sites between April 2004 and January 2006. Treatment consisted of CDDP 75 mg/m2 IV day 1 plus VRB 25 mg/m2 IV or 60–80 mg/m2 oral, days 1, 8 every 21 days. DNA samples were collected from primary tumors for the assessment of microtubule associated protein 4 (MAP4) and from serum for the checkpoint forkhead-associated and ring finger (CHFR) methylation. Results: Data on 198 p is available. Median age 62 years (38–80); males: 83.8%; smokers: 77.8%; PS 0–1: 95.3%; adenocarcinoma, 48.9% / squamous, 32.8%; stage IIIB: 16.7%, IV: 83.3%. Median cycles: 4 (1–12). Hematological toxicities (%p): grade 3/4 neutropenia, 9.6%/7.6%; grade 3/4 thrombocytopenia, 0.5%/0.5%; grade 3 anemia, 2%. Febrile neutropenia appeared in 14 cycles / 10 p (1.8%/5,1%). Non-hematological toxicities (%p): pulmonary grade 3/4, 3.0%/2.5%; nausea/vomiting grade 3/4, 7.6%/0.5%; asthenia grade 3, 13.2%; pain grade 3, 6.6%; infection grade 3, 4.1%; neurotoxicity grade 3, 0.5%. Efficacy in evaluable population: CR, 2.3%; PR, 30.8%; ORR, 33.1% (95% CI, 26.1% to 40.2%); SD, 39.7%. With a median follow up of 6.7 months, median survival for the whole population was 9 months (m), progression free survival 5.07 m, event free survival 4.8 m, 1-year survival 39.9%. Conclusions: The tolerability, efficacy and survival results of this trial confirm that CDDP/VRB is effective as first-line therapy, presenting a favorable toxicity profile in p with advanced NSCLC. Complete data on genetic markers will be presented.

No significant financial relationships to disclose.
Prognostic implication of smoking history in patients with non-small cell lung cancer (NSCLC)
Authors: Oze I. , Segawa Y. , Nogami N. , Komori E. , Sawada S. , Yamashita M. , Shinkai T.
Published: March 2020

7699

Background: The AJCC disease stage, performance status (PS), and weight loss are established and important prognostic factors in patients with NSCLC. However, it is controversial whether smoking history affects the prognosis or not. We therefore assessed prognostic implication of smoking in patients with NSCLC. Methods: This retrospective study was performed using an institutional database for 1,440 NSCLC patients between 1995 and 2005. The characteristics of these patients were as follows: median age, 68 years (range,19–93); male/female, 947/493 patients; smokers/never-smokers, 897/543 patients; ECOG PS 0–1/2–4, 1319/121 patients; AJCC disease stage I-II/III-IV, 715/725 patients; squamous cell/non-squamous cell histologies, 391/1,049 patients; and weight loss > 5%/0–5%, 229/1,211 patients. Results: At a median follow-up time of 17 months (range, 1–59.7 months), the median survival time in smokers was 25 months, and significantly shorter than that in never-smokers (52 months, P < 0.0001). In a multivariate analysis using a Cox regression model, significance of the risk of death in smoking was confirmed when adjusted for age, sex, AJCC disease stage, ECOG PS, weight loss, and histologic subtypes (HR = 1.227, 95% CI 1.018–1.478, P = 0.032). Conclusions: Smoking history was considered to be a possible prognostic factor in patients with NSCLC.

No significant financial relationships to disclose.
Secondary T790M mutation and novel G796A mutation in exon20 of EGFR gene in patients with non-small cell lung cancer who show resistance to gefitinib
Authors: Uramoto H. , Sugio K. , Oyama T. , Iwata T. , Onizuka T. , Yasuda M. , Sugaya M. , Nozoe T. , Takenoyama M. , Hanagiri T. , Yasumoto K.
Published: March 2020

7703

Background: Somatically acquired mutations in the EGFR gene in non-small cell lung cancer are associated with a significant clinical response to a tyrosine kinase inhibitor (TKI). EGFR mutations occur predominantly in exon19 and/or exon21, namely, an in-frame deletion in exon19 or a missense mutation in exon21 (L858R), which have been found to be related to the sensitivity to TKI. However, most patients with such sensitive mutations in their tumor show progression during the TKI treatment. In such resistant tumors, a secondary threonine- to-methionine mutation at codon 790 (T790M) in exon20 has been reported to be related the resistance to either gefitinib or erlotinib. Methods: EGFR mutations in exons19–21 were examined by sequencing in 37 pretreatment tumors obtained from patients with NSCLC, who were treated by gefitinib. Of the 22 cases having sensitive EGFR mutations (19del or L858R), 15 showed CR/PR and 7 showed SD/PD. Of the 15 patients with CR/PR, 4 tumor samples (2 lung, 1 liver, and 1 pleural effusion) that became refractory to gefitinib, were obtained. In pretreatment tumor samples from 4 patients, an in-frame deletion of exon19 was observed in 3 tumors and a L858R mutation of exon21 was in 1 tumor. We next examined whether a secondary mutation occurred in a tumor with acquired resistance to gefitinib in 4 patients by the sequencing of exons 19–21, with informed consent. Results: Three of 4 tumor samples had a secondary T790M mutation, which was not detected in the pretreatment tumor samples. These 3 samples also had an in-frame deletion in exon19. There were no other novel secondary mutations in exons 19,20,21. In 7 cases showing resistance to gefitinib (SD/PD) in spite of the existence of sensitive mutations, 1 tumor demonstrated the co-existence of a missense mutation (G796A) in exon20. In vitro, a stable clone of cells bearing the G796A mutation was approximately 50,000-fold less sensitive to gefitinib in comparison to the cells carrying exon19 deletion. Conclusions: The T790M mutation is common in patients with acquired resistance to gefitinb. Our results suggest that screening tumor samples for a range of EGFR mutations may therefore improve our ability to identify the patients most likely to benefit from treatment with TKI.

No significant financial relationships to disclose.
A randomized trial of intrapericardial (ip) bleomycin (BLM) after drainage for management of malignant pericardial effusion (MPE) in lung cancer patients (pts): Report of a Japan Clinical Oncology Group trial (JCOG 9811)
Authors: Kunitoh H. , Tamura T. , Shibata T. , Imai M. , Nishiwaki Y. , Nishio M. , Yokoyama A. , Watanabe K. , Noda K. , Saijo N.
Published: March 2020

7710

Background: This trial was aimed to evaluate the safety and efficacy of ip BLM instillation as compared to pericardial drainage alone in pts with MPE. Methods: Pts ≤ 75 y.o. with pathologically documented lung cancer, who had received pericardial drainage for clinical MPE within 72 hours of the enrollment, were eligible. Pts with chemo-naïve small cell cancer, major organ failure, or severe co-morbidity were excluded. Signed consent form was obtained. Pts were randomized to either Arm A: observation alone after drainage, or Arm B: ip BLM of 15mg, followed by additional ip BLM 10mg q48hours. Drainage tube was removed when daily drainage was ≤20mL; the protocol therapy was judged as primary failure, with no regulations on post-therapy, if this criteria could not be met after 7 days from enrollment. MPE was followed at 1,2,4,6 and 12 months by echocardiography. The primary endpoint was survival with MPE control (effusion failure-free survival, EFFS) at 2 months, assumed to be 60% vs. 30%. The trial was designed to provide 80% power with 5% one-sided alpha, with 80 cases. Results: From Aug./99 to Jan./06, 80 pts were enrolled, with 79 eligible. M:F=51:29, median age 60 y.o. (range: 39–75), 75 nonsmall histology, 53 with prior chemotherapy, and 20 with prior radiotherapy. Median drainage volume was 600 mL (range: 130–1930). Cytology of the effusion was positive in 58/76 examined. EFFS ( table ) tended to favor Arm B, with hazard ratio of 0.64 (one-sided p=0.030 by logrank test, 95% C.I. 0.40–1.03). No additional acute toxicities or complications were observed for Arm B. There were 2 cases with late constrictive complications in Arm B, but none was severe. The median survival was 79 days (A) and 119 days (B) (not significant). Conclusions: Although the difference of EFFS at 2 months was not statistically significant, BLM ip after pericardial drainage appears to be safe and effective in allover for management of MPE.

No significant financial relationships to disclose.

[Table: see text]
Toxicities in a phase II study of accelerated high dose thoracic radiation therapy (TRT) with concurrent chemotherapy for limited small cell lung cancer (LSCLC) (RTOG 0239)
Authors: Komaki R. , Moughan J. , Ettinger D. , Videtic G. , Bradley J. , Glisson B. , Choy H.
Published: March 2020

7717

Background: Accelerated fractionation proved beneficial in INT0096, but the total dose was low and local recurrence was high with higher acute grade (Gr.) 3+ esophagitis. RTOG 0239 was a phase II trial to improve local control and survival with LSCLC with acceptable acute Gr. 3+ esophagitis using accelerated high dose TRT and concurrent cisplatin/etoposide. This is the first report of acute Gr.3+ esophagitis and Gr.5 toxicities. Methods: Patients (pts) with LSCLC without pleural effusion, contralateral hilar or contralateral supraclavicular nodes and PS 0–1 were enrolled. TRT was given to large fields to 28.8 Gy at 1.8 Gy per fraction, 5 days per week for 16 fractions followed by BID with large field in AM, boost in PM, then off-cord boost BID for last 5 days, all at 1.8 Gy per fx for a total dose of 61.2 Gy in 34 fx in 5 weeks. Concurrent chemotherapy was started with TRT with cisplatin, 60 mg/m2 i.v. day 1; etoposide, 120 mg/m2 i.v. day 1; etoposide, 240 mg/m2 p.o. per day or 120 mg/m2 i.v. per day on days 2 or 3. Cycles were repeated q.3 wks during and for 2 cycles after TRT. Pts who have achieved complete response one month after completion of 4 cycles of chemotherapy were asked to participate in a prophylactic cranial irradiation (PCI) study. Common toxicity criteria (CTC) 2.0 was used for acute toxicity. Results: From 10/2003 to 5/2006, 72 pts were accrued. Median age was 63 yrs with 52% females. Survival data is still maturing. Acute toxicity information is available for 68 pts. Eleven pts (16%) experienced acute Gr. 3 and 1 pt (1%) had acute Gr. 4 esophagitis. 47 pts (69%) had grade 4 blood/bone marrow toxicities. There were 2 (3%) Gr. 5 toxicities reported [1 infection with neutropenia; 1 pulmonary (pneumonia)]. Conclusions: This accelerated high dose TRT with concurrent chemotherapy for LSCLC resulted in 17% acute Gr.3+ esophagitis compared to 27% with BID TRT with 45Gy in 3 weeks by INT0096. There were 3% grade 5 toxicities. This preliminary report suggests that RTOG-0239 has tolerable toxicity. The acute Gr3+ esophageal toxicity correlated with V20 and V40 will be presented. Pts continue to be followed for the primary endpoint of 2-year survival.

No significant financial relationships to disclose.
Phase II trial of gemcitabine and irinotecan in previously treated patients with small-cell lung cancer
Authors: Nishio M. , Ohyanagi F. , Horikike A. , Okano Y. , Satoh Y. , Sakae O. , Ishikawa Y. , Nakagawa K. , Nakagawa K. , Horai T.
Published: March 2020

7718

Background: Gemcitabine and irinotecan has been shown to have an antitumor activity as a single agent against previously treated SCLC. The objective of this study was to assess the efficacy and safety of gemcitabine combined with irinotecan in patients with refractory or relapsed SCLC. Methods: Patients with histologically or cytologically confirmed SCLC, 20 to 74 years in age, performance status 0–2, with a history of receiving one platinum-based chemotherapy were eligible for the study. Treatment consisted of gemcitabine (1,000 mg/m2) and irinotecan (150 mg/m2) on days 1 and 15 of a 28-day cycle.The primary endpoint was the response rate (RR), and planned sample size for this phase II study was 30 patients (Simon's two-stage minimax design). Results: Thirty-one patients were enrolled and 30 patients (24 males/6 females, 10 refractory/20 sensitive, median age, 65 years) receive protocol treatment in this phase II trial. The median treatment cycles were 3 (1–10). The overall response rates was obtained in 39.3% (95% CI: 18.1% to 60.5%) of the patients, including two patients with refractory disease and 9 patients with sensitive disease. The median overall survival time was 14.4 months, and the 1-year survival rate was 51%. The median survival time of the patients with refractory disease was 7.4 months, compared with 14.4 months for patients with sensitive disease. The chief grade 3/4 toxicities included neutropenia (42%), thrombocytopenia (3%), diarrhea (9%), and liver dysfunction (3%). The only grade 4 toxicities were one case of grade 4 neutropenia (3.3%) and one case of grade 4 thrombocytopenia (3.3%). Conclusion: Gemcitabine plus irinotecan is an active regimen that seems to be well- tolerated by patients with previously treated SCLC.

No significant financial relationships to disclose.
Phase I evaluation of carfilzomib (PR-171) in hematological malignancies: Responses in multiple myeloma and Waldenstrom’s macroglobulinemia at well-tolerated doses
Authors: Stewart K. A. , O’Connor O. A. , Alsina M. , Trudel S. , Urquilla P. R. , Vallone M. K. , Molineaux C. J. , Goy A. , Orlowski R. Z.
Published: March 2020

8003

Background: Carfilzomib is a novel, irreversible tetrapeptide proteasome inhibitor derived from the natural product epoxomicin. Carfilzomib was well tolerated in preclinical animal studies when administered on a two-week cycle, QDx5; proteasome inhibition one hour after dosing at the MTD was >80%. Two Phase I dose-escalation studies are ongoing, aimed at determining the safety, tolerability, and biological response to carfilzomib. Methods: Carfilzomib was administered according to two different dose-intensive schedules. In PX-171–001, carfilzomib was administered on a two week cycle, QDx5 with nine days rest; in PX-171–002, carfilzomib was administered on a four week cycle, QDx2 weekly for three weeks with 12 days rest. Eligible patients have multiple myeloma (MM), Non-Hodgkin's Lymphoma (NHL), Hodgkin's Disease (HD), or Waldenström's Macroglobulinemia (WM). Results: Thus far, a total of 54 subjects have been enrolled. Although the maximum tolerated dose (MTD) has not yet been identified on either study, responses seen on both protocols have established 11 and 15 mg/m2 as the minimal effective doses (MEDs) on PX-171–001 and 002, respectively. Of 3 patients with MM or WM treated on the 001 protocol, one MM patient has had a Partial Response (PR) and one WM patient had a Minimal Response (MR). Of 8 patients with MM treated on the 002 protocol, 3 patients have had PRs. 6 additional patients have had Stable Disease lasting longer than 6 months and symptomatic improvement has been seen in patients on both protocols. 11 subjects remain on study with stable disease or better. Proteasome inhibition in whole blood at the highest dose levels exceeded 80% one hour after the first dose. Carfilzomib has been well tolerated at doses at and above the MED thus far. There has been no incidence of painful peripheral neuropathy on either study. No dose-limiting toxicities (DLTs) have occurred on PX-171–001; one DLT (Gr 4 anemia and thrombocytopenia) was observed at 27 mg/m2 on PX-171–002. Conclusions: Thus far, intensive dosing with carfilzomib is well-tolerated at proteasome inhibition levels of more than 80%. Five responses have been observed, and several subjects have achieved long lasting SD and/or symptomatic improvement.

No significant financial relationships to disclose.
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.

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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]
CVP alternating with fludarabine (CVP/F) chemotherapy prior to idiotype vaccination for follicular lymphoma (FL)
Authors: Ai W. Z. , Hsu F. J. , Timmerman J. M. , Czerwinski D. , Taidi B. , Levy R. , Horning S.
Published: March 2020

8065

Background: Reducing the tumor burden prior to vaccination facilitates an effective immune response (IR) against the idiotype in FL. In this context, we evaluated the efficacy and toxicity of a novel cytoreductive regimen, CVP/F. Methods: Newly diagnosed, advanced stage FL patients (pt) were treated with CVP (cyclophosphamide 400 mg/m2 PO d1–5, vincristine 2 mg d 1, prednisone 100 mg/m2 d1–5) alternating with F (25 mg/m2 IV d1–5) every 21 days for 2 cycles beyond best response (maximum 8). Pt judged to be cytoreduced adequately were vaccinated monthly × 5 with idiotype protein made from their FL. Results: Among 34 enrolled pt, median age was 45 years (yr), and FLIPI scores were: 18% low, 71% intermediate and 12% high. 38% pt had grade 1 and 62% had grade 2 FL. There were no toxic deaths or opportunistic infections. With 233 cycles (117 CVP and 116 F) given to 33 evaluable pt, neutropenic fever occurred in 7 cycles (3%). 20 cycles (17%) of CVP and 29 cycles (25%) of F were dose reduced for leukopenia. 18 pt (53%) achieved a CR (16) or CRu (2), and 13 pt (38%) had a PR. 22 pt (65%) treated with CVP/F proceeded to vaccination; 10 additional pt (29%) were vaccinated after secondary chemotherapy was given for further cytoreduction. At median follow-up of 11.2 yr, 15-yr overall survival (OS) was 85%. Two of 5 deaths occurred without lymphoma progression. TTF (time to treatment failure = second treatment, relapse, death) at 11 yr was 38%. Anti-idiotype antibody and T cell IR were seen in 44% and 31% pt, respectively. There were no differences in TTF or OS according to IR. Conclusions: CVP/ F was effective in advanced FL, comparing favorably with our historical experience with CVP in terms of CR rate, proportion proceeding to vaccination, TTF and OS after vaccination. This favorable outcome may have been due to the novel alternating CVP/F cytoreductive regimen, idiotype vaccination or both. The idiotype vaccine is now being tested in phase III trials. The CVP/F regimen also warrants further evaluation.

No significant financial relationships to disclose.
Clinical and pathological prognostic markers for survival in adult patients with post-transplant lymphoproliferative disorders: BCL2 as a prognostic marker
Authors: Oton A. B. , Hong W. , Melhem M. , George D. , Foon K. , Ghobrial I. M.
Published: March 2020

8073

Background: PTLD is the most serious hematological complications of solid-organ transplantation. We determined clinical and immunohistopathological prognostic factors for overall survival (OS) in patients with PTLD. Methods: Eighty-four patients with PTLD between 1980 and 2004 at University of Pittsburgh were identified. Immunohistochemistry staining was performed on tumor at diagnosis for BCL2, BCL6, cMYC, p53, PS6k, HSP90 and NFkB. Univariate associations between individual clinical and immunohistopathological features and OS were compared using Cox proportional hazard models. Survival curves were generated via the method of Kaplan-Meier. Results: The median age at the time of diagnosis of PTLD was 53 years. Thirty four percent of patients presented with early PTLD. Sixty-four percent of patients were EBV positive by in situ hybridization. Lung transplant was significantly related to grafted organ involvement (p=0.035). Lung and multiorgan transplants were associated with a higher risk for early PTLD (p=0.0033 and p=0.054), while renal transplant was associated with risk for late PTLD (p=0.0011). The median survival for all patients was 20.8 months, 95% CI: (7.4–77.6). On univariate analysis for OS, poor prognostic factors were identified: age of transplant >60 yr (p=0.02), multiorgan transplant (p=0.02), ECOG>2 (p<0.0001), grafted organ involvement and extranodal disease at the time of diagnosis (p<0.011), early PTLD (p<0.0001), and elevated white blood cell count (WBC) 1 month prior to diagnosis (p=0.01). Good prognostic factors included late PTLD, monomorphic disease, CD20 positive and rituximab use. Only BCL2 strongly correlated with prognosis (p=0.002). A final clinico-pathological model for survival was constructed using three factors: ECOG >2, elevated WBC one month prior diagnosis and BCL2 overexpression. Patients with these three risk factors had median survival of 10 days (95% CI: 0–41), in comparison with patients with none of these risk factors had median survival of 1,414 days. Conclusions: Patients who had 3 factors ECOG >2, elevated WBC one month prior diagnosis, and BCL2 overexpression in tumor tissue had worse median survival than the patients with none of these three factors.

No significant financial relationships to disclose.