bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations between chromosome 7 aneusomy and EGFR copy number with survival and response to gefitinib in NSCLC
Authors: Morrison L. E. , Jewell S. S. , Jacobson K. K. , Kaiser K. , Gale M. , Muzzafar T. , Mauer A. M. , Villaflor V. M. , Bonomi P. , Coon J. S.
Published: March 2020

7171

Background: EGFR, the presumed target of gefitinib and erlotinib, has been studied (expression, gene copy number, & mutations) for predicting response to these tyrosine kinase inhibitors (TKI), in non-small cell lung cancer (NSCLC). ’High polysomy’ and ’amplification’ of the EGFR gene, as defined by Cappuzzo et al. JNCI 97:643, using fluorescence in situ hybridization (FISH), showed significant association with objective response (Resp) and survival. We also measured EGFR and chromosome 7 (C7) copy numbers by FISH in 81 gefitinib-treated NSCLC patients (12 Resp). Using Cappuzzo’s FISH± parameter alone we saw similar trends but no statistical significance in the 81 patient group. Therefore we sought to optimize FISH parameters for these patients. Methods: FISH was performed (paraffin sections) using a 2-color probe set (Vysis LSI EGFR/CEP 7), median 80 cells per specimen. >50 parameters were derived from the data (e.g. mean EGFR/cell, C7/cell etc) and compared, using different threshold values, to Resp and survival. Results: The best single parameter associated with survival was the average C7/cell. Applying upper and lower thresholds of 3.6 and 2.0 C7/cell to delineate moderate from extreme ratios yielded median survival of 177 and 465 d, respectively (Kaplan-Meier, p < .002). A single threshold of 3.6, separating low from high, yielded survival of 201 and 522 d, respectively (p < .01). For these thresholds C7/cell was not associated with Resp, however, thresholds could be found for which both survival and Resp were significant. The best single parameter associated with Resp was average EGFR/cell. Of the 70 patients with EGFR/cell≤6.0, 63 (90%) did not respond while 5 of 11 patients (45%) with EGFR/cell >6.0 responded (p < .01). No EGFR/cell threshold could be found for which both survival and Resp were significant. Many 2-parameter combinations provided significant associations with both survival and Resp. Conclusions: Several FISH-derived parameters were significantly associated with either survival or Resp to gefitinib and a subset were associated with both. These parameters must be tested on independent data sets to determine their value in directing TKI therapy.

[Table: see text]
Detection of epidermal growth factor receptor mutation in transbronchial aspiration cytology of non-small cell lung cancer
Authors: Horiike A. , Kimura H. , Nishio M. , Ohyanagi F. , Satoh Y. , Okumura S. , Nishio K. , Ishikawa Y. , Nakagawa K. , Horai T.
Published: March 2020

7175

Background: Somatic mutations of epidermal growth factor receptor (EGFR) strongly associate with objective response to EGFR tyrosine kinase inhibitors. There are some problems to practically use it as prognostic markers. Since it is difficult to obtain sufficient tumor samples from non-small cell lung cancer (NSCLC) patients, they are often diagnosed by cytological procedure alone. Therefore, it is very useful if EGFR mutations are able to be detected in cytological samples. The aims of this study are to detect EGFR mutations in the samples of transbronchial aspiration cytology (TBAC) by using direct sequencing and Scorpion ARMS method, and to compare the sensitivities of these methods. Patients and Methods: 94 patients diagnosed as NSCLC in our institute were enrolled in this study, consisting of 63 males and 31 females with a median age of 66. In cytologic diagnosis, they were adenocarcinoma in 58, squamous carcinoma in 24, and the others in 12. DNA was extracted from the TBAC samples, and EGFR mutations were analyzed using direct sequencing (exon 19 and exon 21) and Scorpion ARMS method (E746-A750del and L858R). Results: The mutations were detected in 31patients (33%). 13 mutations (14%) (E746-A750del; 6 patients, L858R; 7 patients) were detected by direct sequencing. 27 mutations (29%) (E746-A750del; 16 patients, L858R; 11 patients) were detected by Scorpion ARMS method. Conclusion: EGFR mutations were able to be detected in TBAC samples by both methods. Scorpion ARMS method is more sensitive for the detection of EGFR mutations than direct sequencing.

No significant financial relationships to disclose.
EGFR mutation analysis in histologic and cytologic specimens of non-small cell lung cancer
Authors: Sakai H. , Akagi K. , Sudoh J. , Yoneda S. , Komagata H. , Kurimoto F. , Hommura Y.
Published: March 2020

7176

Background: Recent studies have suggested that EGFR mutations can be used to predict tumor sensitivity to gefitinib (epidermal growth factor receptor tyrosine kinase inhibitor) in patients with non-small-cell lung cancer (NSCLC). Most previous studies of EGFR mutations have used direct sequencing to analyze surgically resected specimens. More rapid, accurate, and simple techniques for analysis of EGFR mutations in histologic or cytologic specimens (i.e., transbronchial biopsy, bronchial washing, pleural effusion, lymph node aspiration) are needed to improve outcomes. Methods: DNA was extracted from histologic or cytologic specimens of NSCLC obtained from March through October 2005. The major mutations of the EGFR gene (exons 18–21) were analyzed by our original technique for fragment analysis and polymerase-chain-reaction-restriction-fragment-length polymorphism analysis. Results: About 2 days were required for mutation analysis. Pathological analysis indicated that 64 (5 histologic and 59 cytologic specimens) of 90 specimens (11 histologic and 79 cytologic specimens) were adenocarcinomas. EGFR mutations were found in 22 of these specimens (2 histologic and 20 cytologic specimens; ex19:del 13, ex19:ins 2, ex21:L858R 7). An EGFR mutation (ex19:del) was also found in a patient with large cell carcinoma. Conclusions: Our method can efficiently detect EGFR mutations in small samples of lung cancer cells obtained from histologic or cytologic specimens. This method is useful for the identification of EGFR mutations in patients with unresectable NSCLC in whom sufficient tissue specimens are difficult to obtain.

No significant financial relationships to disclose.
Erlotinib as single agent in patients (p) with advanced or metastatic NSCLC: A multivariate analysis in a prospective study
Authors: Pallares C. , Paz-Ares L. , López-Picazo J. , Pérez-Carrión R. , Montes A. , López-Vivanco G. , De Castro J. , Cobo M. , García Velasco A. , Regueiro P. , Massutí B.
Published: March 2020

7180

Background: Erlotinib is the first orally available selective EGFR tyrosine-kinase inhibitor that improves survival in 2nd and 3rd line therapy for NSCLC. This non-randomised, phase II trial evaluated the efficacy and safety of erlotinib in patients with advanced or metastatic NSCLC. Methods: Patients with previously treated advanced or metastatic NSCLC or patients that were not suitable for first line conventional chemotherapy, stage IIIB/IV, PS 0–2 were enrolled to receive erlotinib 150 mg/day until disease progression or withdrawal. The primary endpoint of the study was time to progression (TTP) in the intent to treat (ITT) population. A multivariate analysis (Cox-model) was performed. Results: 416 patients were enrolled from June 04 to March 05. Demographics: M 78%/F 22%; median age 64 y [range 28–100]; stage IV 91.6%; PS 0/1/≥2: 65 (16%)/227 (55%)/105 (25%); adeno histology 178p (43%), SCC 121p (29%), BAC 3p (0.7%), LLC 2p (20%), other 29p (7%); smoking status: yes 349 p (84%) no 62 p (15%). 1st line: 60p (14.4%); 2nd line 181p (43.5%) and ≥ 3rd line 175p (42%). 230 patients had measurable disease and were evaluable for response: 1CR, 30 PR (ORR: 13.4%), 98 SD, and 101 PD. Toxicity was predictable (mainly rash, and diarrhoea). In the ITT population the median TTP was 3.2 m [95% CI 2.8–3.6]. For evaluable population median TTP was 4.6 m in 1st line, 3.23 m in 2nd line, and 2.8 m in 3rd line. Exploratory analysis showed that ORR was associated with gender, smoking history, previous treatment and histology. The multivariate analysis for TTP showed that no smoking history (p < 0.005), adeno histology (p < 0.0001), and erlotinib as 1st line treatment (p < 0.02) correlated with better TTP. Conclusions: Erlotinib is an active and very well tolerated treatment in patients with advanced NSCLC untreated or that have previously failed to conventional chemotherapy. Our data suggest that non smoking history, adeno histology and erlotinib as 1st line treatment are associated with better TTP. The study is ongoing.

[Table: see text]
EGFR mutations (muts), IHC and FISH status, and chromosome 7 gene copy number combined with pAkt expression as potential predictors of survival in non-small cell lung cancer (NSCLC) patients (pts) treated with gefitinib (GEF)
Authors: Villaflor V. M. , Buckingham L. , Gale M. , Coon J. , Mauer A. M. , Muzzafar T. , Kaiser K. , Shannon M. , Morrison L. , Bonomi P.
Published: March 2020

7182

Background: EGFR and pAkt expression by immunohistochemistry (IHC), muts, and FISH status have been identified as possible molecular predictors for GEF efficacy in NSCLC (Cappuzzo, et. al, JNCI, 2005). The goal of this study was to independently evaluate these findings regarding survival (surv), and to assess the predictive value of mean chromosome 7 copy number/cell (C7). Methods: 150 consecutive Expanded Access Trial pts with >1 week GEF therapy were included for analysis. IHC (present vs not detected) was performed for 87 pts, and 58 pts were analyzed for muts by SSCP, mut-specific PCR, and sequencing. Tissue from 81 pts was evaluated for EGFR and C7 gene copy numbers by fluorescence in situ hybridization (FISH). Results: 150 pts (77 female, 73 male; median (md) age 67; 85 adenocarcinoma) received GEF; md follow-up was 5.8 months (mo). Overall response was 8% (2 CR, 10 PR); 56 pts had stable disease. Md Kaplan-Meier surv was 5.9 mo. IHC revealed that 47/87 pts (54%) had EGFR+, and 36/75 pts (48%) had pAkt + tumors. pAkt+ pts had significantly (sig) longer surv than pAkt− pts (11.4 vs 5.8 mo, p < .05). High polysomy was seen in 36/81 pts (44%) who were designated FISH+; 45 pts were FISH−. EGFR IHC and FISH positivity were not sig associated with surv. C7 was defined as low (<3.6, 63 pts) or high (≥3.6, 18 pts); md surv was 6.6 and 17.1 mo, respectively, p < .01. Muts were found in 17/58 tumors (29%). Md surv for pts with and without muts was 23.8 and 7.9 mo, respectively, p < .07. EGFR IHC− pAkt− pts (18 pts) had sig shorter surv than 57 pts with any pos value (4.7 vs 8.8 mo, p < .02). Double-positive pts had sig longer surv than pts with any neg value. Conclusions: These findings resemble but do not duplicate those reported by Cappuzzo, et al. Additionally, high C7, alone or combined with pAKT, may be an important predictor for GEF efficacy in NSCLC. Further studies of C7, a technically simple and reproducible FISH assay, are warranted.

[Table: see text]

[Table: see text]
Phase II study of the efficacy of gefitinib in patients with non-small cell lung cancer with the EGFR mutations
Authors: Sunaga N. , Yanagitani N. , Kaira K. , Tomizawa Y. , Iijima H. , Otani Y. , Tanaka S. , Suga T. , Dobashi K. , Mori M.
Published: March 2020

7183

Purpose: Recent studies have indicated that the mutations of epidermal growth factor receptor (EGFR) were associated with sensitivity of non-small cell lung cancer (NSCLC) to gefitinib, an EGFR tyrosine kinase inhibitor. The clinical objective of this study was to prospectively evaluate the efficacy of gefitinib in patients with stageIII/IV NSCLC that had the EGFR mutations. Methods: Genomic DNA was extracted from tumor specimens and EGFR mutations in exon 19 and 21 were analyzed by direct sequencing. Patients with stageIII/IV NSCLC who had the EGFR mutations were treated with gefitinib (250mg) orally. Response, survival data and toxicity were assessed. Results: From Nov. 2004 to Dec 2005, 14 patients with the EGFR mutations received gefitinib (median age: 67 years; 2 males, 12 females; 1 smokers, 13 non-smokers; all adenocarcinomas). Two patients discontinued gefitinib and came off study because of interstitial pneumonitis (grade 3) and acne (grade 3), respectively. Response data are available for 12 patients. Two achieved a complete response (CR), seven exhibited a partial response (PR) and three had stable disease (SD). Response rate and disease control rate were 75% and 100%, respectively. There were no grade 3/4 toxicities in these 12 patients. All patients were alive during median follow-up period of 8 months (range 1–13 months). Conclusions: The EGFR mutations could be an excellent predictor of response to gefitinib in NSCLC.

No significant financial relationships to disclose.
IFCT0401 trial: Phase II study of gefitinib administered as first line treatment in non-resectable, pneumonic-type adenocarcinoma (P-ADC)
Authors: Cadranel J. , Quoix E. , Debove P. , Moro-Sibilot D. , Brãchot J. M. , Souquet P. J. , Soria J. C. , Morin F. , Milleron B.
Published: March 2020

7186

Background: P-ADC is a peripheral lung ADC with a pneumonic radiological presentation, most often containing the bronchioloalveolar carcinoma variant in the 2004 classification. In this setting, EGF receptor tyrosine kinase inhibitors have shown promise. We therefore conducted a prospective multicentric phase II trial to evaluate gefitinib (G) (250 mg/d) as first line treatment in non-resectable P-ADC. Methods: Inclusion criteria: previously untreated, non-resectable cyto/pathologically proven P-ADC with > 3-month expected survival. Primary objective: disease control rate (DCR) - objective response (OR) plus stable disease (SD) for 3 months. Secondary objectives: tolerance, quality-of-life, time-to-progression (TTP), survival, and identification of clinical, pathological and biological markers associated with DC. Results: From 04/04 to 06/05, 88/90 enrolled patients were eligible. All had stage IV disease, with pulmonary (n = 86) and/or extra-thoracic metastasis (n = 10). After review by the clinical trial panel 85/88 were evaluable for response. Tissue-biopsies were collected for central pathological review and molecular analyses. Patients: all Caucasians, median age 64 yrs (27–84), PS <2 in 80.7%, 48 females (54.5%), 33 never (38.6%), 49 former, and 5 current smokers. At 3 months, DC was achieved in 25/85 patients (DCR: 29.4%, CI = [20–39]), including 11 OR (13%, CI = [6–20]) and 14 with SD (16.5% CI = [9–24]). The longest duration of OR is 19.5+ months (4+ to 19.5+) and SD 18+ (5 to 18+). Median TTP is 2.9 months (CI = [2.5–3.3]) but median survival time was not achieved after a 12-month follow-up median time. No death-related toxicity was observed. Only 1 patient stopped G because of skin toxicity (GIII). DC was associated with female gender (p = 0.095, and 0.002 for OR), non-mucinous tumor (p < 0.001, and 0.006 for OR) and absence of rales (p = 0.009) but not with smoking (except for OR, p = 0.024), PS, bronchorrhea, hypoxemia, extra-thoracic metastasis, or Tx presentation. Conclusions: Gefitinib is active and well-tolerated as first-line treatment of non-resectable P-ADC in a Caucasian population, with a 13% OR rate and a 30% DCR. Interestingly, DC was maintained on a long term under G, maybe resulting in improved survival time.

[Table: see text]
Clinical factors affecting the late resistance to gefitinib in patients with non-small cell lung cancer (NSCLC)
Authors: Segawa Y. , Hotta K. , Umemura S. , Fujiwara Y. , Shinkai T. , Ueoka H. , Takigawa N. , Tabata M. , Kiura K. , Tanimoto M.
Published: March 2020

7191

Background: The mechanism of late resistance of NSCLC to gefitinib is unclear. In this study, we assessed clinical factors affecting the late resistance in patients with NSCLC. Methods: Between 2000 and 2004, 197 consecutive patients with NSCLC underwent treatment with gefitinib in our institutions. Of those, 56 patients who had received a prior chemotherapy and continued treatment with gefitinib during at least 6 months were included in this study. The characteristics of these patients were as follows: median age, 62.5 years (range, 28 to 77 years); male/female, 22/34 patients; PS 0/1/2/3/4, 15/31/8/0/2 patients; and adeno/nonadenocarcinoma, 52/4 patients. Thirty-two patients never smoked and 24 were former or current smokers. Nineteen patients underwent surgical resection of NSCLC. Numbers of chemotherapy regimens were one in 31 patients, two in 18, three in 6, four in 1, respectively. Results: Of 56 patients, three achieved a CR and 39 attained a PR, with an overall response rate of 75% (95% CI, 69.2 to 80.8%). The remaining 14 patients had a long SD. At a median follow-up time of 21.6 months (range, 7.7 to 59.7 months), median time to progression was 19.5 months, with progression-free survival rates of 68.5% at 1-year, 33.6% at 2-year, and 21.2% at 3-year, respectively. In a univariate analysis regarding progression-free survival, presences of metastasis to brain (p = 0.008), bone (p = 0.025), liver (p = 0.046), and adrenal (p = 0.008), decreased levels of hemoglobin (p = 0.021) and albumin (p = 0.017), and use of multiple chemotherapy regimens prior to treatment with gefitinib (p = 0.026) were significant factors. In a multivariate analysis using Cox proportional hazard model, presence of brain metastasis was a significant factor clinically affecting the late resistance to gefitinib (hazard ratio, 2.14; 95% CI, 1.10 to 4.17, p = 0.025). In addition, decreased hemoglobin level (p = 0.074) and prior multiple chemotherapy regimens (p = 0.069) were tended to be significant. Conclusions: In patients undergoing treatment with gefitinib, presence of brain metastasis was an important factor indicative of the emergence of late resistance in this study. It is needed to confirm this finding in a large cohort of patients with NSCLC.

No significant financial relationships to disclose.
Factors impacting survival of patients with post-surgical disease recurrence in non-small cell lung cancer (NSCLC)
Authors: Banerji S. , Nugent Z. , Demers A. , Navaratnam S.
Published: March 2020

7223

Background: There are no standard recommendations for follow-up of NSCLC patients post surgery. To be of value, follow-up should detect disease recurrence early enough to allow timely initiation of effective treatment leading to clinical benefit. Methods: Patients diagnosed with NSCLC in Manitoba, Canada, who underwent a surgical procedure at the two teaching hospitals between January 1996 and December 2001, were identified using the Cancer Registry. We included 435 patients who underwent complete surgical resection of pathologic Stage IA to IIB disease. To date, a detailed retrospective chart review has been completed on 249 of these patients. Median follow-up of this population was 3.45 years. Results: The median age was 66.4 years and 51% were male. 68% had Stage I disease. Lobectomy (73%) was more commonly performed over wedge resection (14%) and pneumonectomy (13%). The most frequent histological diagnosis was adenocarcinoma (52%) followed by squamous cell (29%) and bronchoalveolar carcinoma (13%). Disease recurred in 68% of patients. Recurrence was detected in 52 patients by routine imaging during follow-up. 117 had symptoms suggestive of disease recurrence prompting additional investigation. Median time to recurrence was 1.2 and 1.5 years (NS) respectively for the symptomatic and asymptomatic group. The median overall survival of the asymptomatic patients (4.19 years) was significantly (p = 0.007) greater than the symptomatic patients (2.66 years). Similarly, the median survival from the time of recurrence was greater for the asymptomatic patients (1.6 vs. 0.7 years, p = 0.004). A multivariate analysis identified symptoms (p = 0.02) at the time of recurrence and stage (p = 0.01) of the disease at the initial presentation as significant independent factors impacting overall survival. Only the absence of symptoms had a significant association (p = 0.006) with improved survival after diagnosis of recurrent disease. Conclusions: The diagnosis of recurrence while patients are asymptomatic resulted in better survival. This may suggest that routine post-surgical follow-up of patients with early NSCLC is justified.

No significant financial relationships to disclose.
Phase II study of rituximab + CHOP followed by 90Y-ibritumomab tiuxetan in patients with previously untreated mantle cell lymphoma: An Eastern Cooperative Oncology Group Study (E1499)
Authors: Smith M. R. , Chen H. , Gordon L. , Foran J. , Kahl B. , Advani R. , Gascoyne R. D. , Weller E. , Horning S. J.
Published: March 2020

7503

Background: Because mantle cell lymphoma (MCL) has a continuous relapse pattern with current treatments, we designed a study to determine the safety and efficacy of the anti-CD20 radio-immunoconjugate,90Y-ibritumomab tiuxetan (90Y-RIT), after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) induction. Methods: Patients (pt) with untreated stage II-IV MCL (CD20+, cyclin D1+) ≥18 yr were eligible if they had measurable/evaluable disease, adequate organ function (WBC >2,500/μl; platelets >100,000/μl unless marrow-positive) and gave informed consent. At 4–8 weeks after 4 cycles of R-CHOP, stable and responding pt meeting standard marrow and hematologic criteria received 0.4 mCi/kg 90Y-ibritumomab tiuxetan. Objectives were to evaluate response and toxicity after R-CHOP and 90Y-RIT with a primary endpoint of time to treatment failure (TTF). Results: 56 of 57 accrued patients are eligible pending central pathology review. Characteristics included 73% male, median age 60 (33–83) yrs, 91% stage III/IV, 64% >1 extranodal site, 75% marrow-positive. IPI was 0–2 in 50%, 3–5 in 43% and unknown in 7%. After 90Y-RIT 53% had grade 3/4 neutropenia with no febrile neutropenia and 45% had grade 3/4 thrombocytopenia with recovery at 12 weeks in 19/20 pt. 50 pt are evaluable for response after R-CHOP and 44 pt after 90Y-RIT. Best response after R-CHOP (n = 50) was: CR/CRu 14% (n = 7), PR 58% (n = 29), SD 26% (n = 13), PD 2% (n = 1). After 90Y-RIT, responses improved in 15 of 37 pt with <CR/CRu: PR to CR/CRu (n = 12) and SD to CR (n = 1) or PR (n = 2) for a final response rate of 84% and CR rate of 45%. Conclusions: 90Y RIT after 4 cycles of R-CHOP in untreated MCL is safe and improves the number and quality of responses. Further follow-up is needed to determine TTF.

[Table: see text]
Recommendations for revised response criteria for malignant lymphoma
Authors: Cheson B. D. , Pfistner B. , Juweid M. E. , Horning S. J. , Coiffier B. , Gascoyne R. D. , Fisher R. I. , Hagenbeek A. , Hoppe R. T. , Diehl V.
Published: March 2020

7507

Background: Standardized response criteria are needed to interpret and compare clinical trials, and for approval of new therapeutic agents by regulatory agencies. Methods: The International Working Group (IWG) criteria (Cheson et al, JCO 17:1244, 1999) were widely adopted but were reevaluated because of limitations identified, and recent advances, notably FDG-PET, immunohistochemistry (IHC) and flow cytometry. Results: We propose the following modifications for non-Hodgkin’s lymphoma (NHL) and Hodgkin lymphoma (HL). For predictably PET avid histologies (PA)(e.g., diffuse large B-cell NHL (DLBCL), HL, follicular (FL) and mantle cell lymphoma (MCL), PET pretreatment is strongly encouraged to define sites of disease, but not required. For histologies not predictably PET+ (NPA), PET should only be done if response is an endpoint. Although PET performed after ≥1 cycles of chemotherapy correlates with treatment efficacy, in the absence of data that altering therapy because of PET results improves outcome, mid-treatment PET should only be done in a clinical trial. PET is essential to assess response in DLBCL and HL, but only in FL and MCL if response is the endpoint. For NPA histologic subtypes, PET should only be used if PET+ prior to therapy and response is a major endpoint. Present data are inadequate to recommend PET for routine post-treatment surveillance. The new definition for CR includes: 1) no signs or symptoms of disease; 2) PET- in a PA lymphoma, or negative CT in NPA lymphoma. 3) Normal bone marrow by morphology, or if indeterminate, negative by IHC, flow and/or molecular genetic studies. CR unconfirmed (CRu) is no longer included. PR is defined as 1) ≥ 50% decrease in tumor size, but PET+ at prior PA sites, or 2) ≥ 50% decrease in tumor size, but CT+ and PET- if PET- prior to treatment. Bone marrow is irrelevant if positive pre-treatment. Stable disease is neither PR nor progressive disease, PET+ only at prior sites of disease. Progressive/ relapsed disease requires ≥ 50% increase in disease or new lesions that are PET+ if PA lymphoma. PET does not replace a biopsy before initiating new therapy. Conclusions: We hope these revised recommendations will be adopted by study groups and regulatory agencies to facilitate the development of new and more effective therapies to improve patient outcome.

No significant financial relationships to disclose.
Update of the FL2000 randomized trial combining rituximab to CHVP-Interferon in follicular lymphoma (FL) patients (pts)
Authors: Foussard C. , Mounier N. , Van Hoof A. , Delwail V. , Casasnovas O. , Deconinck E. , Tilly H. , Fitoussi O. , Gressin R. , Salles G. , Gela-Goelams
Published: March 2020

7508

Background: The GELA-GOELAMS FL2000 trial investigated the role of rituximab in the first line treatment of FL pts. Methods: This prospective randomized study compared the CHVP regimen (12 courses) +18 months α2b-IFN (CHVP-I) to 6 CHVP courses combined with 6 rituximab infusions + 18 months IFN (R-CHVP-I). The primary endpoint was event-free survival (EFS). Inclusion criteria consisted in untreated stage II-IV FL pts; 18–75 years old; with a high tumor burden defined by at least one of the following criteria: B symptoms, ECOG PS>1, LDH>normal value, β2-microglobulin ≥3 mg/L, largest tumor ≥7 cm, 3 distinct nodes ≥3 cm, serous effusion, compression or symptomatic spleen enlargement. Results: From 05/00 until 05/02, 358 eligible pts were randomized (CHVP-I 183 pts and R-CHVP-I 175 pts) with the following characteristics: M/F = 1; median age = 60 years [25–75]; ECOG > 1 = 8%; B symptoms = 27%; AA stage > II = 87%; bone marrow involvement = 58%; β2-m ≥3 mg/L = 31%; LDH > N = 37%; Hb <12 g/dL = 18%; FLIPI score ≥3 in 57% of the pts. The first analysis [ASH 2004] showed a significant better treatment response in R-CHVP-I as compared to CHVP-I and a improvement of event free survival (EFS) in the R-CHVP-I arm (Log-Rang, P = .003). As initially planned, a second analysis on all pts has now been performed with a median follow-up of 3½ years, all pts with data >01/01/05. The median EFS for the whole population has not yet been reached. In the CHVP-I arm, median EFS was 3 years and 46% of the pts are event-free at 42 months (mo.). In contrast, the median has not been reached in the R-CHVP-I arm and the EFS is 67% at 42 mo. (P < .0001). This improvement in EFS was found both in the 150 pts with a low or intermediate FLIPI score (P = .019) and in those (n = 201) with a high score (P = .0005). When considering the 230 pts responders at the end of 18 mo. of therapy, 42 mo. EFS is 62% in CHVP-I arm versus 81% in R-CHVP-I arm (P = .002). Finally, the overall survival at 42 mo. of patients in the CHVP-I arm is of 84% versus to 91% in the R-CHVP-I arm (P = .029) with a reduction of death risk by approximately 2 (RR = 0.55). Conclusions: These results demonstrate that rituximab combined with CHVP-I has a durable benefit, in all FLIPI risk groups, allows to reduce the duration of chemotherapy and improves overall survival in high-tumor burden FL pts.

[Table: see text]
Bortezomib in relapsed or refractory mantle cell lymphoma (MCL): Results of the PINNACLE study
Authors: Goy A. , Bernstein S. H. , Kahl B. S. , Djulbegovic B. , Robertson M. J. , Boral A. , Shi H. , Fisher R. I.
Published: March 2020

7512

Background: Bortezomib (VELCADE, Vc), a novel proteasome inhibitor, is approved in relapsed multiple myeloma and has shown activity in MCL in phase 2 NHL studies. Methods: Patients (pts) with relapsed or refractory MCL with a maximum of 2 prior therapies received Vc 1.3mg/m2 i.v. on d 1, 4, 8, and 11 of a 21-d cycle for up to 1y. Full accrual (155 pts) was completed in this multicenter, phase 2 study. Primary endpoint was TTP, secondary endpoints included RR and duration of response (DOR). Response (International Workshop Criteria) was assessed by the investigators and separately by the sponsor using central radiology review. Results: Data are available for 154 pts. Baseline characteristics included median age 65y, 81% male, 28% KPS <90%, 35% LDH > normal, 43% IPI ≥3, 74% stage IV MCL. 90% of pts had prior intensive therapy (e.g. Hyper CVAD, CHOP, EPOCH), 96% had prior rituximab, and 14% had prior stem cell transplant. Median duration of Vc treatment was 4 cycles. 138 pts were evaluable for response. By investigator assessment, RR was 35% (CR + CRu = 8%) and median DOR was 9.2 mo. Median TTP was 5.5 mo (all patients, n = 154). Using central radiology review RR was 31% (CR + CRu = 7%), median DOR was 4.6 mo and median TTP was 4.1 mo. With median follow-up of 10 mo, median survival has not been reached. The most common non-hematologic AEs were fatigue (14% ≥grade 3), GI events (≥grade 3 diarrhea, abdominal pain, and nausea/vomiting in 5%, 4%, and 3%, respectively), and peripheral neuropathies (7% ≥grade 3). Hematologic toxicities were minimal except for transient thrombocytopenia (10% ≥grade 3), as previously seen with Vc. Conclusions: This study confirms the activity of Vc in relapsed/refractory MCL in a multicenter international setting and supports its rapid development as a new treatment for relapsed MCL. Vc is also being studied in the first-line setting in combination with standard chemotherapy.

[Table: see text]
Lack of necessity of granuloctye-colony stimulating factor (GF) in Hodgkin’s disease (HD) treated with ABVD
Authors: Evens A. M. , Cilley J. , Gounder M. , Ortiz T. , Miyata S. , Catsaros K. , Rademaker A. , Tallman M. S. , Winter J. N. , Gordon L. I.
Published: March 2020

7515

Background: DI is important in the therapy of HD, and GF has been used to maintain DI. Recent data suggest that toxicity (bleomycin pulmonary toxicity [BPT]) is higher in patients (pts) who receive GF (JCO 2005;23:7614). We reviewed all HD pts treated since Jan 1996 with attention to GF use, DI, blood counts, BPT and survival. Methods: We analyzed biopsy-confirmed HD pts who received all of their therapy at NU from Jan 1996 to Oct 2005. BPT was defined as: pulmonary symptoms, bilateral infiltrates on scans and no infection. Results: We identified 95 pts, of whom 77 (81%) received ABVD, 7 (7.4%) Stanford V, and 11 (11.6%) other. Of the 77 ABVD pts, 51 completed all cycles with no GF, 23 received GF and 3 are unknown. In the “no GF” group, median age was 31 yrs, 31% had stage III/IV disease (33% Hasenclever Index > 3); 18% had bulky disease, 37% B symptoms and 53% received radiation (RT). In the GF group (n = 23), median age was 33, 42% had stage III/IV disease (21% Hasenclever index > 3); 17% had bulky disease, 42% B symptoms and 50% had RT. Among the 51 “no GF” ABVD pts (287 cycles), median treatment-day ANC were 0.9, while % monocytes were consistently elevated (see Table). There were no dose adjustments or treatment delays for ANC on day of treatment. Normalized DI was > 99% for all treatment days and median cycle duration was 28.6 days (planned = 28 days). 1/51 of these pts had BPT and 2 episodes of uncomplicated neutropenic fever were seen (2/287 cycles = 0.6% incidence). If Stanford V pts are included (n = 7, 2 without and 5 with GF), BPT occurred in 1/53 with “no GF” and 2/28 with GF (see Table). CR rate (100%), PFS and OS were similar in all groups (see Table). Conclusion: 1) GF is not necessary in order to administer ABVD at > 99% DI, and its absence is associated with low toxicity. 2) ABVD should be given at 100% dose with no delay despite ANC on day of treatment. 3) GF should not be used routinely in HD pts treated with ABVD.

[Table: see text]

No significant financial relationships to disclose.
Lenalidomide plus high-dose dexamethasone provides improved overall survival compared to high-dose dexamethasone alone for relapsed or refractory multiple myeloma (MM): Results of a North American phase III study (MM-009)
Authors: Weber D. M. , Chen C. , Niesvizky R. , Wang M. , Belch A. , Stadtmauer E. , Yu Z. , Olesnyckyj M. , Zeldis J. , Knight R.
Published: March 2020

7521

Background: Lenalidomide is a novel, orally administered, immunomodulatory drug (IMiD) that has single-agent activity against MM and additive effects when combined with dexamethasone (Dex). Methods: In this phase 3, multicenter, double-blind trial, 354 patients (pts)with relapsed or refractory MM were treated with Dex 40 mg daily on days 1–4, 9–12, 17–20 every 28 days and were randomized to receive either lenalidomide (Len) 25 mg daily orally on days 1–21 every 28 days or placebo. Beginning with cycle 5, Dex was reduced to 40 mg daily on days 1–4 only, every 28 days. Patients were stratified with respect to B2M (≤ 2.5 vs. > 2.5 mg/mL), prior stem cell transplant (none vs. ≥ 1), and number of prior regimens (1 vs > 1). The treatment arms were well balanced for prognostic features. Results: The overall response rate was greater with Len-Dex than with Dex-placebo (59.4% vs. 21.1%; p < 0.001). Complete responses were achieved in 12.9% of pts treated with Len-Dex and 0.6% of pts treated with Dex-placebo. The median time to progression (TTP) for pts treated with Len-Dex was 11.1 months compared to 4.7 months for pts treated with Dex-placebo (p < 0.000001). Median overall survival was higher with Len-Dex (not reached) compared to Dex-placebo (24 months) (hazard ratio 1.76, p = .0125). Grade 3–4 neutropenia was more frequent with combination therapy than with Dex-placebo (24% vs. 3.5%), however ≥ grade 3 infections were similar in both groups. Thromboembolic events occurred in 15% of pts treated with Len-Dex and in 3.5% of pts treated with Dex-placebo. Atrial fibrillation occurred in 8 pts and CHF developed in 4 pts treated with Len-Dex. Conclusions: Considering the ease of oral administration, higher response rate, longer time to progression and overall survival benefit, the combination of lenalidomide-dexamethasone may very well represent the treatment of choice for early refractory or relapsing multiple myeloma. The relatively infrequent side effects should not detract from these improvements, but the use of prophylactic antithrombotic therapy should be considered for patients treated with the combination of lenalidomide and dexamethasone.

[Table: see text]
Phase II study of alemtuzumab in lymphoplasmacytic lymphoma: Results of WMCTG trial 02–079
Authors: Hunter Z. R. , Boxer M. , Kahl B. , Patterson C. J. , Soumerai J. D. , Treon S. P.
Published: March 2020

7523

Background: Alemtuzumab (Campath-1H) is a fully humanized anti-CD52 antibody used to treat B and T-cell disorders. CD52 is widely expressed on bone marrow lymphoplasmacytic cells and growth supporting mast cells in patients with lymphoplasmacytic lymphoma (LPL), including Waldenstrom’s macroglobulinemia (WM). We therefore examined the activity of alemtuzumab in LPL. Methods: 28 patients with LPL, including 27 WM patients were enrolled in this multicenter study. 23 patients were previously treated. Median age was 60 (range 33–75 years), median prior therapies was 2 (range 0–5), and median time from diagnosis was 2.9 (range 0.1–9.0 years). Baseline median bone marrow involvement was 30% (range 5–90%), median serum IgM was 3510 (range 622–12,000 mg/dL) and hematocrit was 35.1 (range 24.4–42.8%). Patients received 3 test doses of alemtuzumab (3, 10, and 30mg IV) followed by 30 mg TIW for up to 12 weeks. All patients received acyclovir and bactrim or equivalent prophylaxis. Results: Twenty-five patients are evaluable for response. 24/25 patients demonstrated a decrease in serum IgM levels (median change -40.5%), for an overall response rate of 76%, which included 8 (32%) partial responders (≤50% decrease in serum IgM), and 11 (44%) minor responders (≥25% decrease in serum IgM). Hematological toxicities were common among previously treated (but not untreated) patients and included G3/4 neutropenia 39%; thrombocytopenia 18%; anemia 7%. G3/4 non-hematological toxicity for all patients included dermatitis 11%; fatigue 7%; and infection 7%. CMV reactivation and infection was commonly seen among previously treated patients and may have been etiological for one death on study. Two other patients also succumbed on study, one related in part to drug therapy for CMV infection and another due to complications of therapy induced thrombocytopenia and Von Willebrand disease. With a median follow-up of 8.5+ months, 11/19 responding patients remain free of progression. Conclusions: Alemtuzumab is highly active in patients with LPL. Hematological and non-hematological toxicities, including CMV reactivation and infection are common among previously treated patients. Further exploration of this agent in LPL, including upfront therapy is warranted.

No significant financial relationships to disclose.
Very long term outcome of patients with gastric marginal zone B cell lymphoma of mucosa associated tissue (MALT) following Helicobacter pylori (Hp) eradication therapy
Authors: Chini C. , Proserpio I. , Giudici M. E. , Pinotti G. , Pozzi B. , Capella C.
Published: March 2020

7531

Background: Hp infection plays a decisive role in the pathogenesis of low-grade gastric MALT lymphoma and eradication therapy has become a widely accepted initial treatment of stage I disease. The aim of this study was to evaluate the long term outcome of patients (pts) with localized gastric MALT lymphoma exclusively treated with Hp eradication therapy. Methods: a prospective series of 62 newly diagnosed IE gastric MALT lymphoma pts (29M/33F) with median age of 63 years (range 27–87), referred to our department from June 1991 to January 2004 were evaluable for the study. Diagnosis was histologically proved and Hp status was evaluated. Staging was performed according to the modified Ann Arbor system. All pts received the triple eradicating therapy (OMC: omeprazole 20 mg bid, metronidazole 400 mg bid and clarithromycin 500 mg bid or OAC: omeprazole 20 mg bid, amoxycillin 1,000 mg bid and clarithromycin 500 mg bid) for one week. Response, evaluated every 6 months with multiple biopsies, was graded according to the Wotherspoon’s histologic scoring system. Results: Hp was eradicated in all patients, but 8 pts required a second line antibiotic therapy; symptoms disappeared or markedly diminished and endoscopic features improved in all pts. Histological remission (score 0–2) was observed in 57 pts (91.9%) after a median time of 6 months (range 2–72); 5 pts (8.1%) who failed to respond were referred to other treatments. With a median follow-up time of 76 months (range 12–162) the histological remission persists in 27/57 pts (47,4%); 21/57 pts (36.8%) have a continuous histological score fluctuation (from 0 to 4); 8/57 (14%) pts had an histological relapse (score 5) after a median time of 12 months (range 6–48) without Hp reinfection and 6 of them had a second spontaneous histological remission. The OS at 76 months is 93%. Only one patient died for an high grade gastric MALT lymphoma transformation. Conclusion: the majority of pts with gastric MALT lymphoma have a favourable long term outcome, independently of the pathological remission; eradication therapy may offer a real chance of cure. Watch and wait policy in agreement pts who failed to respond could be considered an option outside of clinical trial.

No significant financial relationships to disclose.
Bortezomib is active in Waldenstrom’s Macroglobulinemia (WM)—Results of a National Cancer Institute of Canada (NCIC) phase II study in previously untreated or treated WM
Authors: Chen C. I. , Kouroukis T. , White D. , Voralia M. , Stadtmauer E. , Wright J. , Powers J. , Eisenhauer E.
Published: March 2020

7543

Background: WM is a B cell lymphoma characterized by a serum monoclonal IgM and marrow infiltration by lymphoplasmacytoid cells. Bortezomib is a proteasome inhibitor active in myeloma and other hematologic malignancies. In this 2-stage study, 27 WM pts received single agent bortezomib with RR as primary endpoint. Methods: Eligibility: symptomatic WM (Hb <110 g/L; lymphadenopathy; organomegaly; or hyperviscosity); ≤2 prior chemo regimens (± rituximab). Bortezomib 1.3 mg/m2 IV given d1, 4, 8, 11 on a 21d cycle until PD or 2 cycles beyond CR/SD. Nodal disease was included in response criteria (2nd International WM Workshop). Results: Median age 65 (46–87), M:F 14:13, no prior therapy 11 (44%). At entry, median IgM 38 g/L (11.2–83.3); median Hb 108 g/L (63–142); 18 (66%) with nodal disease on CT. At a median of 6 cycles (2–35), 11/27 (41%) patients had ≥50% decrease in IgM alone plus 10 (37%) minor responses (25–49% decrease). Using IgM + nodal criteria: 1 CR, 5 PR (≥50% decrease in IgM and bidimensional disease), 20 SD, 1 PD = overall RR 22% (95% CI 8.6–42.2%). IgM responses were prompt (median 2 cycles; range 1–8) with nodal responses lagging (median 4 cycles). Hb increased by ≥10g/L in 18 pts (66%). Bortezomib was well-tolerated with most non-hematologic toxicities Gr 1–2: fatigue (74%), nausea (63%), myalgias (51%), non-neutropenic infections (48%), diarrhea (44%), constipation (44%). 18 pts (66%) developed neuropathy (sensory): typical onset 2–4 cycles; Gr 3 in 5 pts; 15/18 (83%) improving ≥1 grade (11 complete) in 2–13 mo. Gr 3 myalgias in 2 pts resolved in <1 mo. Gr 3–4 thrombocytopenia (30%) and neutropenia (18%) led to 12 missed doses, 1 dose reduction. Conclusions: Bortezomib is active in WM with 78% pts with ≥25% fall in IgM, 41% with IgM response criteria of ≥50% decrease, 22% with composite nodal/IgM responses. Despite prompt IgM and hematologic improvement, decrease in nodal disease is slow, reflected in overall responses lower than IgM alone. Although bortezomib is generally well-tolerated, neuropathy is common but reversible. Bortezomib combinations with conventional cytotoxic or targeted agents warrant further study in WM. This is a NCIC CTG study with a grant from NCIC and funds from Canadian Cancer Society.

[Table: see text]
Chlamydia psittaci (Cp)-eradicating therapy with doxycycline is an active treatment against ocular adnexa MALT lymphoma (OAML): Final results of a multicentre prospective trial
Authors: Ferreri A. J. , Ponzoni M. , Guidoboni M. , Cortelazzo S. , Demeter J. , Zallio F. , Palmas A. , Politi L. , Doglioni C. , Dolcetti R.
Published: March 2020

7559

Background: An association between OAML and Cp infection has been reported. Preliminary data suggest that patients (pts) with Cp-related OAML could achieve lymphoma regression after eradicating therapy with doxycycline, while data on the activity of this strategy in Cp-negative OAML are not available. Methods: In this multicentre prospective trial, 27 consecutive pts with OAML and measurable disease, at diagnosis (n = 15) or relapse, were treated with doxycycline 100 mg, bid orally, for 3 weeks. Objective response was the primary endpoint. The presence of Cp DNA in lymphoma samples was evaluated by TETR-PCR. Results: Tolerability was excellent in all pts but one. At a median follow-up of 13 mo. (range 3–45), response was complete (CR) in 6 pts and partial in 7 (ORR = 48%; 95% CI:30%-66%); three pts had a response <50%, 9 had stable disease (3–13 mo.), two had progressive disease. Response was slow; 5 pts achieved the best response only after one year of follow-up (median time to the best response: 6 mo.). TETR-PCR resulted positive in 11 (41%) pts and negative in 16. Lymphoma regression was observed in both PCR-positive and -negative pts (64% vs. 38%; p = 0.25), with a CR rate of 36% and 13% (p = 0.18), respectively. Response rate was similar between pts with conjunctival and intra-orbital lymphomas (43% vs. 54%, p = 0.71). The three pts with regional lymphadenopathies and three of the 5 pts with bilateral OAL achieved objective response (4 CRs), which lasted 3+, 13+, 16+, 22+, 26+, and 37 mo. In relapsed pts, objective response was observed in 3 of 5 previously irradiated pts and in 5 of 7 non-irradiated pts (p = 0.99). Twenty pts are failure-free, with a 2-yr FFS of 66±12%. Conclusions: Doxycycline is a fast, cheap and safe therapy, able to induce durable regression in 64% of Cp-related OAML. This antibiotic is a valid alternative against OAML, even in pts with multiple failures, involving previously irradiated areas or regional lymph nodes. We report for the first time responses also in PCR-negative OAML; this finding stimulates the development of more sensitive and specific methods for Cp detection and the study of potential associations with other infectious agents responsive to doxycycline.

No significant financial relationships to disclose.
Sequential radioimmunotherapy with tositumomab/Iodine I131 tositumomab followed by CHOP for mantle cell lymphoma demonstrates RIT can induce molecular remissions
Authors: Zelenetz A. D. , Noy A. , Pandit-Taskar N. , Scordo M. , Rijo I. , Zhou Y. , O’Donoghue J. A. , Divgi C.
Published: March 2020

7560

Background: Mantle cell lymphoma remains a clinical challenge particularly for pts not candidates for consolidation with ASCT or treatment with leukemia induction regimens. Methods: We investigated sequential radioimmunotherapy (RIT) cytoreduction with tositumomab/Iodine I131 tositumomab followed by CHOP chemotherapy as initial therapy for patients either ineligible for or unwilling to undergo high dose therapy and stem cell transplantation. In addition, pts had to have less than 25% of the intratrabecular bone marrow space involved with lymphoma. Results: Twenty-five patients (pts) were enrolled but only 24 were treated with the therapeutic dose of RIT because a manufacturing problem prevented the treatment of one patient. The median age was 66 (45–80), there were 23 men and 2 women. All patients had advanced stage (III/IV) disease and bone marrow was involved in 48% and the GI tract was involved in 48% of the patients. The overall response rate (ORR) to RIT was 83% (CR/CRu 46%; PR 38%). Two pts withdrew consent following the RIT (and are censored from that point); 1 pt with disease progression requiring alternative therapy is included in EFS and OS analyses. Twenty-one pts proceeded to the CHOP consolidation and 19 completed planned therapy (1 pt died of a CVA; 1 pt chose not to complete chemotherapy after two cycles of CHOP). At the completion of delivered therapy the ORR was 86% (CR/CRu 67%, PR 19%). The median follow up is 2.1 years (0.7 to 4.2). The median EFS was 1.4 years though there have been no events beyond 1.7 years with 7 pts at risk; median OS has not been reached (92% at 2.1 years). Minimal residual disease (MRD) was evaluated with a clonotypic PCR (cPCR) capable of detecting about 1:105 tumor cells; this assay was informative in 17 pts. Following induction with RIT 6 pts (46%) were molecularly negative in blood and bone marrow. Despite the increase in clinical CR following CHOP consolidation, no additional pts became molecularly negative. Conclusions: RIT with tositumomab/iodine I131 tositumomab is a very active agent in the treatment of MCL; unfortunately, MRD is not effectively eliminated by subsequent CHOP chemotherapy. We are planning to explore chemotherapy induction followed by RIT.

[Table: see text]