bluuebunny/crossref_metadata_2025 huggingface dataset:
First-line gefitinib for elderly patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations: A combined analysis of NEJ studies.
Authors: Narumi Sodai , Inoue Akira , Morikawa Naoto , Minegishi Yuji , Maemondo Makoto , Okinaga Shoji , Kobayashi Kunihiko , Harada Toshiyuki , Hagiwara Koichi , Nukiwa Toshihiro , Gemma Akihiko
Published: March 2020

7563

Background: The first-line treatment with gefitinib has been established as a standard of care for advanced NSCLC patients with EGFR mutation by previous studies including NEJ002. Since the percentage of elderly population in those studies was lower than that of real situation, further validation of its usefulness for elderly patients with EGFR-mutated NSCLC is warranted. Methods: The efficacy and safety data of fit elderly patients (70 years or older with PS 0-2) with EGFR-mutated NSCLC who received the first-line gefitinib in NEJ001 (phase 2), NEJ002 (phase 3), and NEJ003 (phase 2) were combined. Same population treated with the first-line carboplatin plus paclitaxel in NEJ002 (n=34) were also examined their efficacy and safety for reference. Regarding the toxicity and quality of life (QOL), the comparison between elderly patients and younger patients (< 70 years old) both treated with first-line gefitinib in NEJ002 was also performed. Results: Data from 71 patients (7 from NEJ001, 33 from NEJ002, 31 from NEJ003) treated with first-line gefitinib were combined. Patients’ characteristics were as follows; mean age: 76.8 years (range 70-89), female: 73%, never smoker: 75%, PS 0-1: 92%. Overall response rate (73.2%) and median progression-free survival (14.3 months) in this group were significantly better than those in the reference group (26.5% and 5.7 months, respectively). Despite fewer patients received second-line chemotherapy in the first-line gefitinib group, its median overall survival (30.8 months) was not inferior to that of reference group (26.4 months). Regarding toxicities such as liver dysfunction, rash, diarrhea, and pneumonitis, and QOL examined by self questionnaires, there were no difference between the elderly patients and younger patients in NEJ002. Conclusions: First-line gefitinib still achieved high efficacy with acceptable toxicity in fit elderly patients with advanced NSCLC harboring EGFR mutation. Considering that elderly patients tend to receive fewer treatment lines compared with younger patients, first-line gefitinib would be strongly recommended for this population to avoid the risk of missing its administration.
Efficacy of pemetrexed as second-line therapy in advanced NSCLC after either treatment-free interval or maintenance therapy with gemcitabine or erlotinib in IFCT-GFPC 05-02 phase III study.
Authors: Bylicki Olivier , Ferlay Celine , Chouaid Christos , Lavolle Armelle , Barlesi Fabrice , Gervais Radj , Westeel Virginie , Crequit Jacky , Corre Romain , Vergnenegre Alain , Zalcman Gerard , Monnet Isabelle , Le Caer Herve , Fournel Pierre , Linard Pauline , Perol David , Perol Maurice
Published: March 2020

7574

Background: Continuous exposure of tumor cells to maintenance therapy in advanced NSCLC might lead to resistance to subsequent treatments. IFCT–GFPC 0502 study showed a progression-free survival (PFS) benefit with gemcitabine (G) or erlotinib (E) maintenance compared to observation (O) after cisplatin-G induction chemotherapy. The trial included a pre-defined second-line therapy with pemetrexed (P), allowing post-hoc assessment of its efficacy according to previous maintenance treatment or treatment-free interval. Methods: Stage IIIB/IV NSCLC patients (pts) with a PS of 0-1 were randomized after 4 cycles of cisplatin-G chemotherapy to O or to receive maintenance therapy with G or E until disease progression. P was given as second-line treatment on disease progression in all arms. PFS and OS were assessed from the beginning of P therapy according to randomization arm. Tumor response to P and tolerance were also analyzed. Results: Of the 464 pts randomized to either O (155), G (154) or E (155), 360 pts (78 %) received P as second-line therapy, i.e. 130 (84%), 114 (74%) and 116 (75%) in O, G and E arm, respectively. Baseline characteristics remained well balanced between arms (overall median age of 58 years, 28% female, 91% stage IV, 41% PS 0, 65/19/16%, adenocarcinoma/squamous/other, 10% non-smokers and 56% responders to induction CT). Median number of delivered P cycles was 3 (1-40) in all arms. Response rate was 19%, 7% and 15% for non-squamous pts in O, G and E, respectively. Median PFS did not significantly differ between G and O (4.2 vs 3.9 months, HR [95% CI] 0.81 [0.62-1.06]) or E and O (4.2 vs 3.9 months, HR 0.83 [0.64-1.09]). OS data showed a non-significant improvement with G vs O (HR 0.81 [0.61-1.07]) or E vs O (HR 0.80 [0.61-1.05]), with a median of 7.5, 8.3 and 9.1 months for O, G and E, respectively. Results were similar when analysis was restricted to non-squamous pts. Grade 3-4 treatment-related AEs were similar in O (33.1%), G (31.6%) and E (25%). Conclusions: Maintenance therapy with continuation of G or switch to E does not impair the efficacy of second-line P by comparison with administration after a treatment-free interval.
Family history of lung cancer in never smokers with non-small cell lung cancer (NSCLC) and its association with tumors harboring epidermal growth factor receptor (EGFR) mutations.
Authors: Gaughan Elizabeth Mary , Cryer Sarah K , Yeap Beow Yong , Jackman David Michael , Costa Daniel Botelho
Published: March 2020

7579

Background: Inherited susceptibility to lung cancer is an understudied subject, however it has been described among never smokers (<100 cigarettes/lifetime). Never smokers with NSCLC comprise an important subgroup of patients enriched for tumors harboring oncogene aberrations in the EGFR and ALK genes. We aimed to better characterize the incidence of family history of lung cancer in the setting of routine tumor genotyping among never smokers with NSCLC. Methods: Clinicopathologic data plus tumor genotype (EGFR, KRAS, ALK) from 230 consecutive never smokers seen at Beth Israel Deaconess Medical Center and Dana-Farber Cancer Institute was compiled. We retrospectively analyzed the incidence of a family history of any cancer and lung cancer in these patients. Results: In our cohort, the average age was 56 years, 67% of the patients were women, 75% were white, 41% had advanced NSCLC and 87% had adenocarcinoma histology. In these tumors, 98/230 (43%) had an EGFR mutation, 16/155 (10%) had KRAS mutations and 27/127 (17%) had an ALK translocation. Family history of any cancer was common (57%) and specific family history of lung cancer was present in 42/230 cases (18%). Out of thecases with a family history of any cancer, 22/53 (41.5%) EGFR-mutated, 1/6 (17%) KRAS-mutated and 3/20 (15%) ALK-translocated cohorts had a family history of lung cancer. The rate of family history of lung cancer to family history of cancer was significantly higher in the EGFR-mutated cohort when compared to the ALK translocated plus KRAS-mutated cohorts (p=0.023). Conclusions: Family history of lung cancer is common in never smokers with NSCLC, and there seems to be a particular link in families in which the proband has an EGFR-mutated tumor. Further study of families with EGFR-mutated NSCLC may yield insights into the pathogenesis of this tumor type.
A randomized, double-blinded, phase II study of paclitaxel/carboplatin (PC) plus CT-322 versus PC plus bevacizumab (Bev) as first-line treatment for advanced nonsquamous non-small cell lung cancer (NSCLC).
Authors: Paschold Eugene Henry , Mazieres Julien , Lena Hervé , Cruciani Giorgio , Laird Glen , Walters Ian B. , Chen Allen C. , Trifan Ovidiu C.
Published: March 2020

7584

Background: CT- 322 is a pegylated protein engineered from the tenth type III human fibronectin domain thatspecifically blocks VEGFR-2 signaling by all known ligands. This international randomized study assessed the efficacy and safety of PC + CT-322 compared to PC + Bev as first-line treatment for advanced non-squamous NSCLC. Methods: In addition to paclitaxel 200 mg/m2and carboplatin AUC 6 given on day 1 of a 21 day cycle(maximum 6 cycles), subjects, stratified by ECOG performance status, disease stage, and site, were randomized 1:1 to receive either CT-322 2 mg/kg on days 1, 8, and 15 (arm A) or Bev 15 mg/kg on day 1 and placebo on days 8 and 15 (arm B). CT -322 and Bev/placebo were continued as maintenance until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), response rate, and safety. Results: 255 subjects were randomized to arm A (n=127) or arm B (n=128). Baseline characteristics were wellbalanced. After a median follow- up of 13.8 months, 9 subjects on arm A and 24 on arm B remained on study treatment. The median treatment duration was 19 weeks in arm A and 26.3 weeks on arm B. The median PFS in arm A was 5.6 months compared to 6.8 months in arm B (HR 1.51, 1 -sided p=0.997). In all prespecified subgroups, PFS was favored in arm B. The response rate was 25.2% in arm A compared to 32.8% in arm B. Median OS was 12.5 months in arm A compared to 15.2 months in arm B. The most common grade ≥ 3 adverse events (Arm A vs B) were neutropenia (47.2% vs 49.2%), thrombocytopenia (11.8% vs 6.3%), and fatigue (10.2% in both arms). Grade ≥ 3 hypertension was more frequently reported in arm A (8.7% vs 3.1%). Grade ≥ 3 venous thrombosis (5.5% vs 6.3%), proteinuria (1.6% vs 2.3%), and bleeding events (0.8% vs 1.6%) were similar. Conclusions: PC + CT-322 failed to improve PFS, OS, or response rate compared to PC + Bev. However, thesafety profile in the PC + CT-322 arm was consistent with the anti-angiogenic mechanism of action, suggesting that CT-322 has biological activity as an inhibitor of VEGFR-2.
Clinical characteristics of KRAS mutations in NSCLC and their impact on outcomes to first-line chemotherapy.
Authors: Butaney Mohit , Porter Jennifer , Lindeman Neal Ian , Janne Pasi A. , Rabin Michael S. , Marcoux J Paul , Johnson Bruce E. , Jackman David Michael
Published: March 2020

7588

Background: KRAS is one of the most commonly mutated oncogenes in non-small cell lung cancer (NSCLC). While the impact of EGFR mutations and EML4-alk translocations has been well-described, there is limited information about the impact of these somatic mutations on response to chemotherapy. Methods: We retrospectively reviewed the demographics and clinical outcomes of patients with KRAS mutations and compared these to patients who were KRAS wild-type (WT). Eligible pts received 1st-line IV chemo for stage IV NSCLC at DFCI and had known information about both KRAS and EGFR status. Since the biology and impact of EGFR mutations on response to chemo is well-described, we excluded such pts from the analysis. The primary endpoint was progression-free survival (PFS) with first-line chemo; secondary endpoints included radiographic response rate (RR) and overall survival (OS). Results: Between 2/05 and 8/11, there were 63 eligible KRAS pts and 97 eligible WT pts. The groups were similar in age (median 65yrs in both groups), % female (K 62, WT 54) race (K 89% white/6% black, 5% other; WT 86% white,/6% black/8% other), histology (K 90%adeno/8% NSCLC NOS; WT 86% adeno/9%NSCLC NOS), and % of pts receiving 1/2/3 agents in 1st line (K 11/56/33; WT 18/53/30). KRAS pts were less likely to be never or light smokers (4% vs 33% for WT). Nonsmokers were more likely to harbor KRAS transition rather than transversion mutations (3 transition, 1 transversion), while the converse held for smokers (51 transversions, 8 transitions). Median PFS was similar for KRAS vs WT (K .65 vs WT 4.8 months, p=0.81). RR (29% for both groups), disease control rates (K 73% vs WT 78%), and median OS (K 13.5 vs WT 12.1 months, p=.525) were also similar. Outcomes of KRAS pts to 2nd line chemotherapy (PFS 2.2, OS 8.6) are similar to those seen for WT patients in this setting. There was no significant difference in outcomes based on gender, smoking status, drug received (pemetrexed-based vs taxane based), or specific KRAS genotype. Conclusions: Pts with KRAS mutations experience similar outcomes to standard chemotherapy as those who are wild-type for EGFR and KRAS. Going forward, these data can serve as a reference for control arms of KRAS-specific randomized trials.
Safety and efficacy analysis by histology of weekly nab-paclitaxel in combination with carboplatin as first-line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC).
Authors: Renschler Markus Frederic , Okamoto Isamu , Hon Jeremy K. , Hirsh Vera , Dakhil Shaker R. , Page Ray D. , Orsini James , Zhang Hui , Socinski Mark A.
Published: March 2020

7592

Background: Treatment of advanced NSCLC differs by histology, with fewer options and poorer outcomes in pts with squamous histology. In a phase III trial of nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel particles) + carboplatin (C) vs solvent-based paclitaxel (sb-P) + C, the primary endpoint of ORR was significantly improved from 25% to 33%, p = 0.005, with a 1-month improvement in OS (p = NS) and improved safety. This analysis evaluated efficacy and safety by histology. Methods: Pts with untreated stage IIIB/IV NSCLC were randomized 1:1 (stratified by age, histology, region, stage, and gender) to C AUC 6 day 1 and either nab-P 100 mg/m2 on days 1, 8, 15 or sb-P 200 mg/m2 day 1 q 21 days. ORR and PFS were determined by blinded centralized review. Results: In squamous pts, nab-P/C produced a significantly higher ORR (41% vs 24%, p < 0.001), similar PFS (5.6 vs 5.7 mo, HR: 0.865) and >1-month improvement in OS (10.7 vs 9.5 mo, HR: 0.890) vs sb-P/C (Table). nab-P/C was as effective as sb-P/C in nonsquamous pts for ORR (26% vs 25%, p = 0.808), PFS (6.9 vs 6.5 mo, HR: 0.933), and OS (13.1 vs 13.0 mo, HR: 0.950). In both squamous and nonsquamous pts, nab-P/C vs sb-P/C produced lower rates of grade 3/4 neuropathy (3% vs 11% and 3% vs 12%, respectively, p < 0.001 both), neutropenia (43% vs 51%, p = NS, and 50% vs 63%, p = 0.008), and higher but manageable rates of anemia (27% vs 4% and 28% vs 9%, p < 0.001 both) and thrombocytopenia (21% vs 7% and 16% vs 11%, p < 0.001 both). Conclusions: In pts with advanced NSCLC, nab-P/C demonstrated a favorable risk-benefit profile as a first-line therapy regardless of histology. Significantly improved ORR and a positive trend in OS were observed in pts with squamous histology. [Table: see text]
Meta-analysis of progression-free survival as a predictor of overall survival in locally advanced or metastatic non-small cell lung cancer trials.
Authors: Turner Evadne Jane , McCloud Philip , Germanos Peter , Dehle Francis , Norris Sarah , Tan Jonathan
Published: March 2020

7604

Background: Access to new oncology treatments for non-small-cell lung cancer (NSCLC) could be expedited if progression free survival (PFS) was accepted by payers as a valid endpoint predictive for overall survival (OS). We investigated the relationship between PFS and OS in advanced NSCLC, which has previously been limited by available data. Methods: A systematic review of the published literature was conducted (1988 to August 2011; Medline/Embase/Cochrane). Identified studies were assessed against the following criteria for inclusion in the analysis: randomised design; NSCLC; advanced disease (Stage IIIb or IV); pharmacological treatment in 2 or more groups; reported outcomes included median OS and median PFS. For each pair of treatment groups compared, the median OS difference and the median PFS difference were calculated. The data were analysed with locally weighted least squares regression (LOWESS) to validate the linear relationship. Unweighted and weighted linear regression was used to test the significance of the relationship between OS difference and PFS difference. Results: A total of 124 clinical trials, with 40,568 patients, were included in the analysis. The studies ranged from middle aged cohorts to the elderly. Median performance status (ECOG/WHO) was 1. 70% of studies were first line and therapy type was predominantly chemotherapy (57%). 19 studies (15%) reported use of crossover or rescue therapy. Weighted linear regression demonstrated a highly significant linear relationship between OS difference and PFS difference (Table). The results suggest that a 1 month difference in PFS is associated with approximately 1.3 months difference in OS. Conclusions: Analysis of NSCLC trials showed the treatment effect on PFS was predictive of the treatment effect on OS. With increased use of multiple lines of treatment and crossover/rescue therapy in new NSCLC trials OS differences are frequently confounded, making PFS an important outcome for health care decision making. [Table: see text]
ABVD (8 cycles) versus BEACOPP (4 escalated cycles => 4 baseline) in stage III-IV high-risk Hodgkin lymphoma (HL): First results of EORTC 20012 Intergroup randomized phase III clinical trial.
Authors: Carde Patrice P. , Karrasch Matthias , Fortpied Catherine , Brice Pauline , Khaled Hussein Mustafa , Caillot Denis , Gaillard Isabelle , Bologna Serge , Ferme Christophe , Lugtenburg Pieternella , Morschhauser Franck , Aurer Igor , Coiffier Bertrand , Cantin Guy , Seftel Matthew D. , Wolf Max , Glimelius Bengt , Sureda Anna , Mounier Nicolas
Published: March 2020

8002

Background: Escalated BEACOPP and derivatives achieved superior time to treatment failure (FFTF) over COPP/ABVD, resulting in higher overall survival (OS) for advanced HL. However, later clinical trials have failed to confirm OS superiority over ABVD. Methods: Eligibility criteria: clinical stage III/IV HL, International prognostic score (IPS) ≥ 3, age<60. We compared ABVD (8 cycles) vs. BEACOPP (escalated 4 cycles ≥ baseline 4), without irradiation. Randomization was stratified for institution and IPS. Primary endpoint was EFS, defined as treatment discontinuation, no complete response (CR) after 8 cycles, progression, relapse or death. Additional endpoints were CR, progression free survival (PFS), OS, quality of life and secondary malignancies. Outcomes were reviewed by study coordinators to ensure consistency across pts. Results: From 2002-2010, 549 pts were randomized (ABVD 275, BEACOPP 274): stage IV 74%, PS 0, 1, 2: 34, 48 and 17%, B-symptoms 81%, median age 35.2y, males 75%. IPS was 4 or higher for 59% of pts. Histology reviewed no HL in 4 cases. CR was 83% in both arms. With a median follow-up of 3.8 yrs, EFS at 4 yrs was 63.7% vs. 69.3% (HR = 0.86, 95%CI=0.64 to 1.15, p=0.312). PFS at 4 yrs was 72.8% vs. 83.4% (HR = 0.58, 95%CI=0.39 to 0.85, p=0.005). OS at 4 yrs was 86.7 vs. 90.3 (HR = 0.71, 95%CI=0.42 to 1.21, p=0.208). Toxic deaths occurred in 6 and 5 pts, with early discontinuation (prior to cycle 5) in 12 & 26 pts, respectively. There were 5 crossovers to BEACOPP and 10 to ABVD. Second malignancies occurred in 8 ABVD and 10 BEACOPP pts (myelodysplasia/leukemia 2 and 4, lung 2 and 1, NHL 3 and 2, other 1 and 3); cumulative incidence curves did not differ significantly. Conclusions: The primary endpoint (EFS) was similar between treatment arms. However, more progressions/relapses were observed with ABVD, while early discontinuations were more frequent with BEACOPP. Nevertheless, even in this high-risk group, OS was not improved with BEACOPP. Additional considerations (treatment burden and cost, fertility issues, long term relapses and immediate and late morbidity) may guide physician/patient decisions toward ABVD or BEACOPP.
A subgroup analysis of small lymphocytic and marginal zone lymphomas in the Eastern Cooperative Oncology Group protocol E4402 (RESORT): A randomized phase III study comparing two different rituximab dosing strategies for low tumor burden indolent non-Hodgkin lymphoma.
Authors: Williams Michael E. , Hong Fangxin , Kahl Brad S. , Gascoyne Randy D. , Wagner Lynne I. , Krauss John C. , Horning Sandra J.
Published: March 2020

8007

Background: Management of low tumor burden (LTB) indolent lymphoma in the rituximab (R) era is uncertain. We hypothesized that R could delay the need for chemotherapy and that maintenance R (MR) would be superior to R retreatment (RR) at progression. E4402 is a randomized phase III study comparing MR and RR for previously untreated, LTB (by GELF criteria) small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL) and FL. Results for the FL subset was previously presented (Kahl, et al. Blood 2011; 118(21): LBA 6); we now report outcomes for the non-FL patients (pt). Methods: Pt received R 375 mg/m2 weekly x 4, with responders randomized to MR (1 dose R q 3 mo) or RR (R q wk x 4 at progression), each continued until treatment failure. The primary endpoint, time to treatment failure (TTTF), was defined as progression within 6 mo of last R, no response to RR, initiation of alternative therapy, or inability to complete protocol therapy. Pt were evaluated q 3 mo, with CT scans q 6 mo. Secondary endpoints: time to first cytotoxic therapy (TTCT), quality of life (QOL) and safety. Results: From 11/03 to 9/08,137 non-FL pt were enrolled. Complete or partial response was achieved in 57 (41%), who were randomized to MR (n=32) or RR (n=25). 136 pt were stage III-IV (1 IE), and all had PS 0-1; for MR vs RR, median age 66 vs 64, and M:F 47:53% vs. 28:72%, respectively. The mean no. of R doses/pt (incl. 4 induction doses) was 17.9 (range 5- 30) for MR and 5.8 (range 4-12) for RR. With a median follow-up of 4.3 yr, TTTF was 3.74 yr for MR vs. 1.07 yr for RR (p=.0002; HR 4.95). At 3 yr, 100% of MR vs. 70% of RR pt (p=.0002) remained free of cytotoxic therapy. Grade 3-4 toxicities occurred in 2 MR pt, 1 neutropenia and 1 encephalopathy. Conclusions: A planned subgroup analysis of non-FL pt showed significant benefit in TTTF and TTTC for MR but with 2 grade 4 toxicities. This differs from the FL pt in this trial, for whom response to induction was higher (70 vs. 41%; p<.0001) and where no TTTF benefit was observed with MR. LTB non-follicular indolent lymphoma pt who achieve a CR or PR to induction R benefit from MR therapy.
Bendamustine, bortezomib, and dexamethasone (BVD) in elderly patients with relapsed/refractory multiple myeloma (RRMM): The Intergroupe Francophone du Myélome (IFM) 2009-01 protocol.
Authors: Rodon Philippe , Hulin Cyrille , Pegourie Brigitte , Tiab Mourad , Anglaret Bruno , Benboubker Lotfi , Jardel Henry , Decaux Olivier , Kolb Brigitte , Roussel Murielle , Garderet Laurent , Leleu Xavier , Fitoussi Olivier , Chaleteix Carine , Casassus Philippe , Lenain Pascal , Moreau Philippe , Petillon Marie-Odile , Mathiot Claire , Avet-Loiseau Herve
Published: March 2020

8014

Background: Bortezomib (V) plus dexamethasone (D) is a treatment of choice of RRMM. In small series, the addition of an alkylator was beneficial. Bendamustine (B) showed a high activity in advanced MM. The IFM 2009-01 trial evaluates the combination of B, V and D in elderly pts with MM progressive on or after 1st line therapy. Methods: We conducted a phase 2 trial combining B 70 mg/m2 D1-8, V 1.3 mg/m2 D1-8-15-22 and D 20 mg D1-8-15-22 every 28 days. 4 cycles were administered. In responders (PR or better), 2 additional cycles were provided followed by a maintenance phase with 6 cycles given every 2 months. Inclusion criteria were progression on or after 1 prior line of therapy, measurable disease, PS ECOG <3, ANC > 1.5x109/l, platelets > 100x109/l, creatinine < 250 mcmol/l, AST and ALT < 3xULN. Pts with prior exposure to bortezomib were excluded. Response was evaluated according to IMWG criteria. Primary end point was response at end of cycle 4, secondary objectives overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity. Results: The present analysis was restricted to the first 4 cycles. From 03/2010 to 07/2011, 73 pts were included, median age 75.8 years (range 66-86). Median time from diagnosis to inclusion was 29 months. All pts received only 1 prior therapy: MP in 12, MP-thalidomide in 44, lenalidomide-dexamethasone (LD) in 14, other in 3. 42 pts (57.5%) were responders at end of cycle 4 [CR: 8 (10.9%), VGPR: 9 (12.3%), PR: 25 (34.2%), SD: 10 (13.6%), progression: 11 (15%), early discontinuation: 10 (13.6%)]. 6pts/10 were in PR and 1pt/10 in VGPR at time of discontinuation. ORR was 67.1% (49/73 pts). 11 pts died (MM: 6, sepsis: 4, renal failure: 1). Adverse events grade 3-4 were neutropenia: 16 pts, thrombocytopenia: 7 pts, sepsis: 12 pts, gastro-intestinal: 8 pts, anaphylaxis: 1 pt. 2 pts had DVT. Peripheral neuropathy grade>1 occurred in 9 pts, all grade 2. Treatment was stopped in 20 pts (lack of efficacy: 11, toxicity: 9). Conclusions: These results compare favorably with those achieved with VD or LD. The triplet BVD combination is very effective and tolerable in elderly pts with MM in 1st progression.
Efficacy and side-effect profile of long-term bisphosphonate therapy in patients (pts) with multiple myeloma (MM): MRC myeloma IX study results.
Authors: Morgan Gareth J , Jackson Graham H. , Davies Faith , Wu Ping , Gregory Walter , Bell Sue E , Szubert Alexander , Navarro Coy Nuria , Drayson Mark , Owen Roger G. , Feyler Sylvia , Ashcroft John , Ross Fiona , Byrne Jennifer , Roddie Huw , Rudin Claudius , Boyd Kevin , Cook Gordon , Child J. Anthony ,   National Cancer Research Institute Haematological Oncology Clinical Study Group
Published: March 2020

8015

Background: Bisphosphonates (BPs) are recommended in pts with osteolytic lesions from MM. However, data on the long-term efficacy and safety of BPs beyond 2 y is somewhat limited. The MRC Myeloma IX study has already revealed significant overall survival (OS) and progression-free survival (PFS) benefits for zoledronic acid (ZOL) over clodronate (CLO) in MM pts (N = 1960) initiating chemotherapy (Morgan GJ, et al. Lancet. 2010). We now report the efficacy and safety of BP therapy with long-term follow-up. Methods: Newly diagnosed MM pts were randomized to ZOL (4 mg IV q 21-28 days) or CLO (1600 mg/day PO) plus antimyeloma therapy. BPs continued at least until disease progression. PFS and OS were estimated using Kaplan-Meier methodology. Hazard ratios (HRs) were calculated using stratified Cox models. Adverse events (AEs) were monitored continuously and analyzed using cumulative incidence functions. Results: At a median follow-up of 5.8 y in 1960 evaluable pts, ZOL improved PFS (HR = 0.88; P = .01) and OS (HR = 0.88; P = .03) vs CLO. Both BPs were generally well tolerated, and acute renal failure events were similar between groups (ZOL 5.2% vs CLO 5.8% at 2 y, with incidence plateaued thereafter). Overall incidence of confirmed osteonecrosis of the jaw (ONJ) has remained low (ZOL 3.7% vs CLO 0.5%; P < .0001). ONJ incidence was lower among pts receiving thalidomide-containing regimens (1.4%) vs no thalidomide (2.76%; P = .041). Events were generally low-grade, most occurred between 8 and 30 mo (median time to ONJ = 23.7 mo), and cumulative incidence plateaued at ~36 mo. Ten pts had data on ONJ recovery: complete recovery in 4 pts, improvement in 2 pts, no change in 3 pts in the ZOL group; and no change in 1 CLO pt. Dental surgery or trauma preceded ONJ in 6 ZOL pts. Conclusions: ZOL provided sustained PFS and OS improvements vs CLO during long-term therapy in the MRC Myeloma IX study. Overall incidence of AEs was similar between groups, with no notable changes during long-term therapy. ONJ incidence remained low during long-term (> 2.5 y) therapy and was reduced in pts receiving thalidomide (possibly because of anticytokine effects of this agent).
Pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Outcomes in pts refractory to lenalidomide (LEN) and/or bortezomib (BORT).
Authors: Vij Ravi , Richardson Paul Gerard Guy , Jagannath Sundar , Siegel David Samuel DiCapua , Baz Rachid C. , Srinivasan Shankar , Larkins Gail , Zaki Mohamed H. , Hussein Mohamad A. , Anderson Kenneth Carl
Published: March 2020

8016

Background: Response and survival outcomesare poor in pts with RRMM who are refractory to BORT and immunomodulatory drugs. POM+LoDEX has demonstrated activity in pts with advanced multiple myeloma who have received multiple lines of therapy. This analysis evaluates outcomes in pts with disease refractory to LEN, BORT, or both, as well in pts with disease refractory to both LEN and BORT who had received prior transplant. Methods: In the MM-002 phase II trial, pts received POM (4 mg/day on days 1–21 of each 28-day cycle) alone (n=108) or in combination with LoDEX (40 mg/week) (n=113). Refractory disease was defined as documented progression during treatment or within 60 days of the last dose of treatment. Response rates were assessed using European Group for Bone Marrow Transplantation (EBMT) criteria by independent adjudication committee. Results: Patients who received POM+LoDEX were refractory to LEN (77%), BORT (73%), or both (61%). Forty-two percent were refractory to both LEN and BORT and had received prior transplant. Overall, 20% of pts achieved ≥ PR, median PFS was 3.5 months, and 1-year survival rate was 59%. Response rates and duration were comparable in pts with disease refractory to LEN, BORT, or both, and in pts who had received prior transplant (response rate 25-34%, median duration of response 5.7-7 months). Survival outcomes were similar across the groups (median PFS 3.8-4.6 months; 1-year survival rate 60-67%). Conclusions: POM, given at 4 mg/day on days 1–21 of each 28-day cycle in combination with LoDEX, 40 mg/week, is effective in pts with RRMM refractory to LEN, BORT, or both, and including those with prior transplant. These results suggest a lack of cross-resistance between POM and LEN, and confirm activity not only in BORT-refractory pts but also those for whom transplant has failed. [Table: see text]
R-CHOP14 compared to R-CHOP21 in elderly patients with diffuse large B-cell lymphoma (DLBCL): Final analysis of the LNH03-6B GELA study.
Authors: Delarue Richard , Tilly Herve , Salles Gilles A. , Thieblemont Catherine , Mounier Nicolas , Molina Thierry Jo , Haioun Corinne , Bosly Andre
Published: March 2020

8021

Background: In 2000, the GELA established a new standard for elderly patients with DLBCL, demonstrating survival advantage of R-CHOP21 over CHOP21. Based on RICOVER-60 results, the DSHNHL proposed R-CHOP14 as a standard. Comparison between both regimens is lacking. We report the results of the final analysis of the randomized phase III trial LNH03-6B, with a median follow-up of 56 months. Methods: Pts between 60 and 80 years old with DLBCL and aaIPI≥1 were eligible. They were randomized between R-CHOP14 and R-CHOP21 for 8 cycles. G-CSF prophylaxis was given according to physician decision. Primary objective was to evaluate the efficacy of R-CHOP14 compared to R-CHOP21 as measured by the EFS. Results: 602 pts were randomized, 600 were evaluable, 304 with R-CHOP14 and 296 with R-CHOP21. Median age was 70 years. Pts characteristics were similar between the two arms. Percentage of pts with baseline IPI3-5 was 72% in R-CHOP14 arm and 78% in R-CHOP21 arm. Median interval between 2 cycles was 14 d in R-CHOP14 arm and 21 d in R-CHOP21 arm. In R-CHOP14 arms, 89% of cycles were administered with G-CSF. Median dose-intensity for R-CHOP14 arm was 88% for cyclophosphamide and doxorubicin. There was no difference in median dose-intensity according to G-CSF administration at first cycle. Response rate (CR+CRu) was 71% in R-CHOP14 arm and 74% in R-CHOP21 arm (p=0.42). The 3-y EFS was 56% in R-CHOP14 arm and 60% in R-CHOP21 (HR 1.04; CI95% 0.82-1.31; p=0.79). Moreover, there is no difference between both arms regarding 3-y PFS (60% vs. 62%; HR 0.99; CI95% 0.78-1.26; p=0.90), DFS (72% vs. 67%; HR 0.80; CI95% 0.58-1.10; p=0.80) and OS (69% vs. 72%; HR 0.96; CI95% 0.73-1.26; p=0.75). Finally, percentage of patients with at least one serious adverse event (R-CHOP14: 51%; R-CHOP21: 47%) and rate of toxic death (4.6% and 4.7% respectively) were similar. Conclusions: Results of the final analysis of LNH03-6B demonstrate similar efficacy and safety profile between R-CHOP14 and R-CHOP21.
Long-term results of the phase II trial of the oral mTOR inhibitor everolimus (RAD001) in relapsed or refractory Waldenstrom macroglobulinemia.
Authors: Ghobrial Irene M. , Gertz Morie A. , LaPlant Betsy , Camoriano John Kelly , Hayman Suzanne R. , Lacy Martha , Chuma Stacey , Harris Brianna , Boswell Erica , Banwait Ranjit , Sheehy Patricia , Ansell Stephen Maxted , DeAngelo Daniel J , Dispenzieri Angela , Bergsagel Leif , Reeder Craig B. , Anderson Kenneth Carl , Richardson Paul Gerard Guy , Treon Steven P. , Witzig Thomas E.
Published: March 2020

8043

Background: The mammalian target of rapamycin (mTOR) signal pathway controls cell proliferation and survival. The trial's goal was to determine the anti-tumor activity and safety of single-agent everolimus (TORC1 inhibitor) in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM). Methods: Eligible patients had measurable disease (IgM monoclonal protein >1000 mg/dL with >10% marrow involvement or nodal masses >2 cm), a platelet count ≥75,000 x 106/L, a neutrophil count ≥1,000 x 106/L. Patients received everolimus 10 mg PO daily. Tumor response was assessed after cycles 2 and 6 and then every 3 cycles until progression. Results: 60 pts were treated. The median age was 64 years (range, 43-85). The median number of prior therapies was 3 (range, 1-11). All but two patients (97%) had received prior rituximab based therapy and 64% of patients had received prior alkylator based therapies. The overall response rate (complete response CR+ partial response PR+ minimal response MR) was 73% (95% CI: 60-84%), with a PR of 50% and 23% MR. The median time to progression (TTP), progression-free survival (PFS), and overall survival (OS) for the entire study population is 28 months (mos), (95% CI: 18-not reached (NR)), 22 mos (95% CI: 12 0-NR), and 55 mos (95% CI: 55-NR), respectively. The estimated PFS at 12 and 24 months is 62% (95%CI: 51-75%), and 48% (95%CI: 37-63%), respectively. The 30 patients who achieved a PR responded after a median of 2 months (range, 1-26) of treatment. The median duration of response (DR) for these patients has not yet been reached and 19 of these patients remain in response after a median follow up of 31 months (range, 3-54). All but two patients had a decrease in their serum IgM. Grade 3 or higher related toxicities were observed in 67% of patients. The most common were hematological toxicities with cytopenias. Pulmonary toxicity occurred in 5% of patients. Dose reductions due to toxicity occurred in 63% of patients. Conclusions: Everolimus has high single-agent activity with an overall response rate of 73% and manageable toxicity in patients with relapsed WM, and offers a potential new therapeutic strategy for this patient population.
Survival outcomes in marginal zone lymphomas in the rituximab era: Analysis of the Surveillance, Epidemiology, and End Results (SEER) database.
Authors: Castillo Jorge J. , Olszewski Adam J.
Published: March 2020

8045

Background: Despite prognostic models developed for marginal zone lymphoma (MZL), the impact of different characteristics and treatments on survival in the population is largely unknown. We studied survival of MZL patients included in the SEER database. Methods: Records of MZL adult cases diagnosed between 1989-2008 were studied using descriptive methods and analysis of overall (OS) and lymphoma-specific (LSS) survival based on Kaplan-Meier function, stratified log-rank tests and Cox proportional hazard models. Results: 13,957 patients with MZL were identified and classified as splenic (SMZL; n=1,111, 8%), nodal (NMZL; n=4,101, 29%) or extranodal MALT-type MZL (MALT; n=8,745, 63%). The median age was 68 years, 74% of patients were white and 55% were women. Median follow-up was 40 months. MALT was more common in non-Caucasians (p<10-27). B-symptoms were more common in SMZL (p<10-5). Both LSS and OS were significantly better for MALT (p<10-60) with no difference between SMZL and NZML (p=0.30). 10-year LSS estimates were 67% for SMZL, 67% for NMZL, 84% for MALT. There was evidence for improved LSS since 2000 in MALT (HR 0.69, 95% CI 0.59-0.82, p=0.0003) and NMZL (HR 0.64, 95% CI 0.54-0.77, p<10-5), but not for SMZL (HR 0.85, 95% CI 0.56-1.28, p=0.43). Similar results were found for OS. There were differences in survival in MALT subtypes depending on primary site (p<10-12; Table). Conclusions: In the rituximab era, survival has improved for MALT and NMZL, but not for SMZL, possibly due to disparate treatment paradigms. The prognosis of MALT is different depending on primary site of involvement. [Table: see text]
Effect of short-duration chemoimmunotherapy plus radioimmunotherapy on response rates in relapsed follicular lymphoma: A U.K. NCRI Lymphoma Group Study, CR UK/07/038.
Authors: Illidge Timothy M , Bates Andrew T. , Davies Andrew John , Pettengell Ruth , Andrews Barry , Dent Louise , Hampson Grace , Zivanovic Maureen , Gallop-Evans Eve , Radford John A. , Johnson Peter W. M. ,   UK NCRI Lymphoma Group
Published: March 2020

8056

Background: Radioimmunotherapy (RIT) and rituximab (R) maintenance have been investigated after chemotherapy (CT) or R-CT in first line treatment of follicular lymphoma (FL), but less is known about the efficacy of RIT after R-CT in relapsed FL. This phase II study was conducted to examine efficacy and safety of abbreviated R-CT followed by 90Y Ibritumomab tiuxetan in patients with recurrent FL. Methods: Patients (pts) had FL, at 1st or 2nd relapse after response to R-CT or CT alone. All had WHO/ECOG performance status ≤2, and adequate bone marrow (BM), kidney, liver and cardiac function. BM involvement by lymphoma had to be <25% prior to infusion of 90Y Ibritumomab tiuxetan, but could be higher at study entry. Pts received 3 cycles of either R-CHOP or R-CVP, followed by 90Y Ibritumomab tiuxetan (15MBq/Kg, maximum 1200 MBq). No maintenance R was given. Results: 52 pts were enrolled from 6/2008 to 7/2010. Median age was 62 years (range 31-87). 46% had high FLIPI score at entry, 31% intermediate. 80% were at 1st recurrence. Median duration of best prior remission was 27.7 months. 65% pts had previously received R and 25% doxorubicin. 71% pts had R-CHOP and 29% R-CVP, prior to RIT. Overall response rate (ORR) after 3 cycles R-CT was 94% (CR/CRu 10%) and after RIT ORR 96% (CR/CRu 28%). Grade 3/4 thrombocytopenia occurred in 58% pts (median duration 16 days): 3/52 pts after R-CT and 27/52 after RIT. Grade 3/4 neutropenia occurred in 62% pts: 15/52 pts after R-CT and 27/52 after RIT. 5 pts had a total 8 grade 3 infections, only 1 attributable to RIT. 6 pts required platelets and 4 red cell transfusions. 1 pt developed myelodysplasia 10 months after 90Y Ibritumomab tiuxetan, but no other second malignancy was recorded. PFS was 31.4 months (95% CI 15.8 - not reached). There was no difference in PFS according to FLIPI score at entry or reinduction CT (R-CHOP vs R-CVP). Pts with CR/CRu following RIT showed a trend to improved PFS compared to those with PR (12 month PFS 90% versus 63%, p=0.06). Conclusions: Abbreviated R-CT and consolidation with 90Y Ibritumomab tiuxetan is an option for pts with recurrent FL, with responses of comparable duration to those seen after a full course R-CHOP.
Efficacy and safety of bexarotene combined with psoralen/ultraviolet A light (PUVA) compared to PUVA treatment alone in stage IB-IIa mycosis fungoides (MF): Final results from EORTC cutaneous lymphoma task force (CLTF) phase III clinical trial 21011.
Authors: Whittaker Sean , Ortiz-Romero Pablo L. , Dummer Reinhard , Ranki Annamari , Hasan Baktiar , Meulemans Bart , Gellrich Sylke , Knobler Robert , Stadler Rudolf , Shash Emad
Published: March 2020

8076

Background: Skin-directed treatment with methoxsalen (PUVA) is the current treatment standard in stage IB-IIA MF. A combination of PUVA and bexarotene might be of additional clinical benefit for MF stage I/II patients (pts). Methods: EORTC 21011 was a randomised, open label phase III study comparing combined bexarotene and PUVA versus PUVA alone in pts with stage IB and IIA MF. Study primary endpoint was response (complete clinical + partial response, CCR+PR) rate; secondary endpoints: cumulative dose of UVA and number of PUVA sessions necessary to achieve a CCR, duration of CCR, time to relapse, safety and percentage of drop-outs. Results: The study recruited stage IB/IIA MF pts and was prematurely closed due to low accrual after 93/145 required pts (65%) were randomized; 45 to PUVA, 48 to PUVA+bexarotene. Median number of PUVA weeks were 12 (1-17) in PUVA vs. 10.5 (1-16) in combination arm. Total UVA doses were 107J/cm2 (1.4-489.9) in PUVA vs. 101.7J/cm2 (0.2-529.9) in combination arm. Few grade 3-4 toxicities were observed in both arms (liver enzyme elevation, neutropenia, anemia, increased cholesterol, photosensitivity, pruritus, rash, hypertriglyceridemia). Best overall response (CCR/PR) rate was 71.1% (33/45) for PUVA alone and 77.1% (37/48) for combination arm (p-value=0.57). The median of duration of response was 9.6 for PUVA vs 5.8 months for combination arm (p value=0.33). CCR was seen in 25 pts, 10 in PUVA (CCR 24%) and 15 in combination therapy (CCR 33%) (pvalue=0.45). Similarily, a lower UVA dose was required to achieve a CCR in the combination arm (median of 55.8 J/cm2) compared to the PUVA arm (median of 117.58 J/cm2) (p value=0.5). Conclusions: No significant difference in response rate was observed in this study. There was a trend towards fewer PUVA sessions and lower UVA dose to achieve CCR in the PUVA/bexarotene combination arm (median of 27.5 vs. 22,p-value = 0.11) but this did not achieve statistical significance due to insufficient power. The safety profile was acceptable, as there were only few grade 3-4 toxicities observed in both arms.
Dual-point FDG-PET: A novel scanning technique in Hodgkin lymphoma with bulky disease.
Authors: Gallamini Andrea , Bianchi Andrea , Borra Anna , Zaucha Jan M. , Malkowski Bogdan , Thyss Antoine , Mounier Nicolas , Razzouk-Cadet Micheline , Darcourt Jacques , Zwarthoed Colette , Chauvie Stephane , Biggi Alberto
Published: March 2020

8077

Background: Interim 18F-FDG-PET (iPET) is the most important prognosticator in advanced-stage ABVD-treated Hodgkin Lymphoma (HL), but in early stage w/ or w/o bulky lesion a low PPV of iPET was reported. Dual-point PET scan (2P-PET) has been used to discriminate unspecific inflammatory from neoplastic FDG uptake. At the Tx end, with a single FDG-avid mass (SFAM), the specificity of PET in Tx response evaluation was sub-optimal. We report here preliminary results from a cohort of HL patients (p) presenting with bulky lesions, scanned with 2P-PET with the aim to increase specificity and PPV. Methods: From 12.2008 till 01.2012 24 HL bulky p from Italian, French and Polish centers underwent 2P-PET at baseline (2P-PET-0), after 2 ABVD (2P-PET-2) and at Tx end (2P-PET-end). 2P-PET scanning technique consisted in 2 consecutive image acquisitions +60’ (EaS) and +120’(LaS) after single, standard-dose FDG injection. Tx was ABVD (x4 or x6) ± consolidation RxT. No Tx change was done based on iPET results. Scans were reviewed by 2 expert readers in a consensus session. Standardized-Uptake Value (SUV)MAX was calculated both in EaS and LaS using Volume of Interest Regions (VOIs) in sites of residual FDG uptake already recorded in PET-0. ΔSUVMAX and FDG retention index (RI) were calculated from SUVs in the same VOIs of both scans. Results: In 24 p (1 stage I,12 II, 4 III, 7 IV), 34 2P-PET were done.10 p underwent 2P-PET-0: in 10/10 SUVMAX increased from EaS to LaS (ΔSUVMAX 1-4.3). 15 p had a 2P-PET-2: 12 with a mean-follow-up of 18.36 months were evaluable, 3 too short ( +1, +5, +6 months). 7/12 p showed a RI reduction of 55% (200-14): all are in continuous CR (CCR). 5/12 p. showed a 20% (11-26) RI increase: all progressed +1 to +9 months after Tx end. Overall 3/12 cases (1 false +, 2 false- with a Deauville score 4 and 2,3 respectively) were correctly classified after 2P-PET. 9 p with a SFAM had a 2P-PET-end: in the 5/9 with an increased RI of 23% (9-43) a biopsy proved HL relapse. In 4/9 a reduced RI of -29% (9-45) was found: in 2 biopsy disclosed presence of residual thymic along with inflammatory tissue and 2 were in CCR +2 to+8 after Tx end. Conclusions: DSUV Max increased at baseline and in all relapsing patients, and decreased in patients in CCR. The PPV and a PNV of 2P-PET were 100%.
The incorporation of rituximab (R) and liposomal doxorubicin (LD) into CODOX-m/IVAC for untreated Burkitt lymphoma (BL): Final results of a prospective multicenter phase II study.
Authors: Evens Andrew M. , Carson Kenneth Robert , Nabhan Chadi , Islam Nahida , Jovanovic Borko , Barr Paul M. , Caimi Paolo Fabrizio , Gallot Lillia , Gregory Stephanie A. , Gordon Leo I.
Published: March 2020

8080

Background: Two-year survival rates remain <65-70% for adult BL. Further, there is a paucity of data examining the addition of R with CODOX-M/IVAC. Methods: 25 patients (pts) with classic BL enrolled onto this phase II study (3/07-4/11). Pts were classified as low risk (LR) or high risk (HR); LR received 3 CODOX-M, while HR had 4 alternating CODOX-M/IVAC (Mead et al, Blood 2008). LD (40 mg/m2) was used in lieu of doxorubicin, while intravenous R (500 mg/m2) was given days 0 + 8 of CODOX-M and days 0 + 6 of IVAC cycles. Ejection fraction (EF) was assessed at baseline, s/p 2 cycles and completion. Results: Median age was 44 years (yrs) (23-70). There were 20 HR and 5 LR pts; 3 HR and 1 LR pt were HIV+. 15% of HR pts had + CNS disease. In addition, 35% of HR pts had bulk >10 cm and 40% had bone marrow involvement. 24/25 pts were evaluable for toxicity and response. Therapy was completed at a median of 13 weeks (11-20) for HR pts and 10 weeks for LR (9-12). Myelosuppression (62% grade 4 thrombocytopenia, 4% grade 4 anemia) and mucositis (33% grade 3, 13% grade 4) appeared comparable with prior CODOX-M/IVAC data. Other grade 3 toxicities were infection (38%), neutropenic fever (29%), transaminitis (33%), diarrhea (8%), creatinine (8%), seizure (4%), vomiting (4%). Notably, there was no grade 3 or 4 neuropathy. Two grade 2 and three grade 3 cardiac events occurred (all depressed EF, no clinical CHF). Two of the three grade 3 cardiac events occurred in pts age >65 yrs. Among all pts, the median change in EF at baseline vs study end was -2% (-22% to +11%). The overall response rate (modified Cheson with FDG-PET) after 2 cycles was 100% with a 67% complete remission rate. At a median follow-up of 2.3 yrs, 2-year PFS and OS rates for all pts were 86% and 86%, respectively (LR 2-yr PFS and OS: both 100%; HR 2-yr PFS and OS: both 82%). Furthermore, 2-yr PFS and OS for HR, HIV-negative BL were 91% and 91%, respectively (disease-specific survival: 100%). Conclusions: The integration of R and LD into CODOX-M/IVAC for adult BL is feasible and associated with similar tolerability compared with prior reports. Moreover, this regimen was associated with excellent survival rates, especially for HIV-negative BL.