Kooperativer Bibliotheksverbund

In: The British Journal of Radiology, British Institute of Radiology, Vol. 94, No. 1123 ( 2021-07-01), p. 20210012-

Abstract: To investigate the efficacy of a schedule of low-dose radiotherapy (LDRT) with 4 Gy (2 Gy x 2) in a cohort of unselected MALT or MZL patients. Methods: We retrospectively collected all patients receiving LDRT, either for cure or palliation, for a stage I–IV histologically proven MALT or MZL between 2016 and 2020. Response to LDRT was evaluated with the Lugano criteria. Local control (LC), distant relapse-free survival (DRFS), progression-free survival (PFS) and overall survival (OS) were stratified for treatment intent (curative vs palliative) and estimated by the Kaplan-Meier product-limit. Results: Among 45 consecutively enrolled patients with a median age of 68 years (range 22–86), 26 (58%) were female. Thirty-one patients (69%) with a stage I–II disease received LDRT as first line therapy and with a curative intent. Overall response rate was 93%, with no significant difference among curative and palliative intent. With a median follow-up of 18 months, LC, DRFS, PFS and OS at 2 years were 93, 92, 76 and 91%, respectively, in the overall population. Patients receiving curative LDRT had a better PFS at 2 years (85% vs 54%, p 〈 0.01) compared to patients receiving palliative treatment. LDRT was well tolerated in all patients, without any significant acute or chronic side-effect. Conclusions: LDRT is effective and well tolerated in patients affected with MALT or nodal MZL, achieving high response rates and durable remission at 2 years. Advances in knowledge: This study shows the efficacy of LDRT in the treatment of MALT and MZL.

Type of Medium: Online Resource

ISSN: 0007-1285 , 1748-880X

URL: Article

DOI: 10.1259/bjr.20210012

Language: English

Publisher: British Institute of Radiology

Publication Date: 2021

detail.hit.zdb_id: 1468548-6

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 15_suppl ( 2014-05-20), p. 8530-8530

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/jco.2014.32.15_suppl.8530

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2014

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 16-17

Abstract: Background and Aims. Prediction of treatment efficacy is an active and growing field of pharmacology. In the Fondazione Italiana Linfomi (FIL) MCL0208 phase III trial (NCT02354313), a 24 months lenalidomide maintenance (LM, 15 mg days 1-21 every 28 days) after high-dose immuno-chemotherapy followed by autologous transplantation (ASCT) in 300 frontline mantle cell lymphoma (MCL) patients showed substantial clinical activity in terms of Progression-Free Survival (PFS) vs observation (OBS). However, this benefit seemed not uniform across patient series. To deeper investigate the differential pattern of response to lenalidomide, a wide analysis of the host pharmacogenomics (PG) background was planned, in order to dissect whether specific germline polymorphisms of transmembrane transporters, metabolic enzymes or cell surface receptors (ABCB1, ABCG2, VEGFA, FCGR2A, NCF4, GSTP1, CRBN) might predict the drug efficacy. Actually, several single nucleotide polymorphisms (SNPs) of ABCB1 exert an effect on substrate affinity of lenalidomide for the transmembrane transporter. Moreover, VEGFA is involved in the anti-angiogenic activity of lenalidomide and might eventually upregulate ABCB1 expression, too. Patients and methods. Genotypes for SNPs were obtained through allele-specific (ASO) probes on germline DNA from peripheral blood. Minor allele frequencies (MAFs) were obtained and the Hardy-Weinberg equilibrium (HWE) was checked. Genotypes were used to infer individual haplotypes by Arlequin and Haploview softwares. Minimal residual disease (MRD) was assessed with ASO primers on either IGH or BCL-1/IGH rearrangements by RQ-PCR in bone marrow samples. TP53 disruption was identified by NGS targeting resequencing and copy number variation analysis. Clinical-biological correlations were screened by automated machine learning methods and validated by both Kaplan-Meier at univariate level and Cox models for multivariate analysis (MV). A logistic regression was implemented to investigate correlations between polymorphisms and MRD kinetics. Results. 278 out of 300 patients (93%) were fully genotyped. The MAF values of the SNPs were very similar to published data and the HWE was confirmed. Most notably, ABCB1 c.2677G & gt;T/A(W) and VEGFA c.2055A & gt;C were significantly associated to outcome and are thus described in this abstract. In the case of ABCB1, the three loci were in strong linkage disequilibrium (p & lt;0.001). 31% of patients were homozygous for ABCB1 wild type alleles (GG, "WT"), 53% heterozygous (GW, "HET") and 16% polymorphic on both chromosomes (WW, "POL"). 20% were VEGFA WT (AA), 47% HET (AC) and 33% POL (CC). PG did not impact on induction therapy and randomization rates of this trial, as superimposable polymorphism frequencies were described between the enrolled and randomized population. Conversely, both ABCB1 HET and POL and VEGFA HET/POL associated with higher MRD clearance rates vs WT after 6 months of LM (93% vs 71% and 91% vs 67%, respectively). Interestingly, the risk of MRD reappearance during LM was 86% lower for patients harboring either polymorphism vs WT (odds ratio 0.14, 95% CI 0.02-0.99; p & lt;0.05). Actually, ABCB1 HET/POL predicted for a more favorable PFS vs WT in LM (3yPFS 85% vs 69% p & lt;0.05, Fig.1A), as well as VEGFA HET/POL (3yPFS 85% vs 59% p & lt;0.01, Fig.1B). The two polymorphisms co-occurred in 57% of patients, being 12% ABCB1 HET/POL only, 23% VEGFA HET/POL and 8% ABCB1/VEGFA WT. Interestingly, patients with either polymorphism had superimposable outcome to patients in whom both co-occurred (Fig.1C). Finally, MV showed that either polymorphism was protective for PFS among randomized patients (HR=0.42; 95% CI 0.20-0.85; p & lt;0.05). According to this hypothesis, among the 17 ABCB1/VEGFA WT patients LM did not improved PFS vs OBS (Fig.1D), independently from TP53 disruption. Conclusions. The first PG data on LM after ASCT in MCL suggested that: 1) ABCB1 and VEGFA polymorphisms did not impact on the chemotherapeutic efficacy of FIL-MCL0208 trial; 2) both polymorphisms favored sustained MRD clearance during LM; 3) either polymorphism conferred a survival advantage during LM. Taken together, these observations hint that a variable excretion of lenalidomide through ABCB1 (heralded by SNPs), as well as an altered VEGFA pathway, could predict treatment efficacy. This observation might be very useful in the future to tailor lenalidomide therapy to MCL patients. Disclosures Ferrero: Servier: Speakers Bureau; Gilead: Research Funding, Speakers Bureau; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Boccomini:SC Ematologia, ASOU Città della Salute e della Scienza di Torino, Turin, Italy: Current Employment. Maria:Roche: Consultancy, Other: travel, accomodations, expenses; Abbvie: Consultancy, Other: travel, accomodations, expenses; BMS: Consultancy; MSD: Consultancy; Janssen: Consultancy, Other: travel, accomodations, expenses; Gilead: Consultancy, Other: travel, accomodations, expenses, Research Funding. Ferreri:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Hutchinson: Research Funding; BMS: Research Funding. Palumbo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. OffLabel Disclosure: Lenalidomide maintenance in mantle cell lymphoma

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-134875

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1607-1607

Abstract: BACKGROUND: Standard rituximab plus chemotherapy salvage treatment has shown moderate activity in patients with relapsed/refractory Waldenström's macroglobulinemia (RR-WM), with 18-months progression free survival (18-PFS) of about 50%. On behalf of the Fondazione Italiana Linfomi (F.I.L.) we designed a multicenter phase II study to assess the efficacy of a combination of bendamustine, rituximab and bortezomib (BRB) in improving these results. METHODS and PATIENTS: This single-arm phase II study tested the hypothesis that 18-PFS is at least 65%. The required sample size was 38 patients (alpha=0.10; beta=0.25; minimum follow up=24 months). Treatment plan was: rituximab 375 mg/m2 intravenously on day 1 followed by intravenously bendamustine 90 mg/m2 on day 1 and 2 and subcutaneous bortezomib 1.3 mg/m2 on day 1, 8, 15 and 22, every 28 days for 6 months. Patients with RR-WM after first line of therapy were enrolled in 18 F.I.L. centers, from October 2014 to November 2017. In the last 23 patients MYD88L265Pwas tested by the recently described droplet digital PCR (ddPCR) assay both on bone marrow (BM) and peripheral blood (PB) samples, both at baseline (as mutational screening) and at the end of treatment (for minimal residual disease purposes, MRD). RESULTS: At the time of analysis, 29 patients completed the six cycles of therapy, six patients stopped therapy for toxicity, two patients died and one had just finished therapy and was not yet evaluated. 18-PFS was 84% (95%CI: 61-94%), with two progressions and two deaths without evidence of progression (one cerebrovascular accident during the fifth cycle and one pulmonary embolism at three months follow up). On an intention-to-treat analysis (N=37), overall response rate was 70%, (N=26) including 4 (11%) complete, 11 (30%) very good partial, 10 (27%) partial responses and 1 (3%) minimal response according to IWM response criteria. Overall, treatment was well tolerated, the most common adverse events of any grade included 13 patients (34%) experiencing grade 3-4 neutropenia, especially in cycle 4 (leading in four cases to treatment discontinuation). Peripheral nervous system toxicity was observed in five patients (13%; 4 of grade 1-2 and 1 of grade 3-4), with no discontinuations. Serious adverse events were observed only in three patients, mainly rash, all resolved. All the 23 patients assessed for MYD88L265Pat baseline scored positive in BM, while only 18/23 (78%) in PB, prospectively confirming the risk of false negative results when only PB of rituximab pre-treated patients is analyzed. Among the 21 patients monitored for MRD after treatment 5 scored MRD negative in BM and 13 in PB, highlighting the deep activity of the BRB regimen in clearing the disease. CONCLUSIONS: Among patients with RR-WM after first line of therapy, BRB regimen is a well-tolerated salvage treatment, resulting in high rates of PFS at 18 months. Moreover, the deep anti-tumor activity of this regimen is highlighted by the promising rates of both clinical and molecular responses. More complete and mature results will be presented during the meeting. (ClinicalTrials.gov number: NCT02371148). Disclosures Gaidano: AbbVie: Consultancy, Honoraria; Morphosys: Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Vitolo:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Gilead: Speakers Bureau; Sandoz: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-114023

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 2720-2720

Abstract: Abstract 2720 Introduction: Bendamustine is a promising agent that has been showed high efficacy in combination with Rituximab in indolent lymphomas; however experiences on its use in combination with other cytotoxic agents are scant, particularly in FL. A previous FIL trial showed that a brief R-FND induction chemoimmunotherapy with only 4 courses of R-chemotherapy followed by 4 rituximab doses as consolidation can achieve high CR and PFS rates in FL patients, supporting the feasibility of this regimen in the elderly (Vitolo et al, ASH 2011). These promising results prompted FIL to investigate safety and efficacy of a similar combined brief regimen substituting Bendamustine for Fludarabine aimed at reducing toxicity and maintaining efficacy. Patients and methods: From September 2009 to November 2011, 76 elderly patients (age 65–80) with advanced stage FL at diagnosis were enrolled. Inclusion criteria were: untreated grade I, II and IIIa FL; advanced disease requiring treatment (stage III/IV) or stage II including at least one of the following conditions: bulky disease ( 〉 7 cm), active disease with rapid lymph node progression, lactate dehydrogenase or β2 microglobulin above normal, systemic symptoms and extranodal involvement. A comprehensive geriatric assessment (ADL, I-ADL, CIRS) was also performed at diagnosis and only “FIT” patients were enrolled into the study. Treatment plan was: 4 monthly courses of R-BM (375 mg/m2 Rituximab day 1, 90 mg/m2 Bendamustine days 1–2, 8 mg/m2 Mitoxantrone day 1), followed by consolidation with 4 weekly Rituximab infusions. Polymerase chain reaction (PCR) for BCL2/IgH rearrangement was performed on bone marrow samples at diagnosis, after R-BM and after consolidation. Results: At the time of analysis, 69/76 patients are evaluable for clinical characteristics, response to treatment and toxicity. Median age was 71 years (range 65–80); 26 males, 43 females; WHO grading was as follow: I 16%, II 55% and IIIa 29%; 19% had advanced stage II disease, 27% stage III and 54% stage IV; 49% had BM involvement, 19% B symptoms and 7% leukemic dissemination; 58% patients had no comorbidity, 20% one and 22% two or more comorbidities. According to FLIPI patients were: 12% at low, 30% at intermediate and 58% at high risk. PCR analysis was carried out in 64 patients at diagnosis: 58% were Bcl-2 positive. Sixty three patients completed the planned treatment and the whole program was completed according to the planned time in 60/63 patients. Six patients did not complete the treatment: 1 for progressive disease, 4 for adverse events (2 haematological toxicity with prolonged neutropenia; 1 CMV colitis and 1 for infection and concomitant worsening of pre-existing oral pemfigo) and 1 patient for worsening of performance status. Overall response after R-BM + Rituximab was observed in 64 (96%) patients with 52 (75%) patients in complete remission and 12 (18%) in partial remission (PR). Response to 4 cycles of R-BM was as follow: 27 (39%) in CR, 37 (54%) in PR and 5 (7%) patients in stable (SD) or progressive disease. Of the 40 patients in PR or SD after 4 R-BM, 26 (65%) converted to CR following further Rituximab consolidation. At the time of this analysis, of the 37 patients Bcl-2 rearranged at diagnosis, 19 (51%) were evaluable for molecular response during and after treatment. PCR negativity was achieved in 16/19 (84%) patients after R-BM and in 18/19 (95%) patients at the end of treatment. A total of 521 courses of R-BM and Rituximab were given. The most frequent severe toxicity (CTC grade 3–4) was neutropenia reported in 18% of the courses; nevertheless only four serious infections were recorded (all due to bacterial agents). Pulmonary and cardiac toxicities were 〈 1%. Two deaths were recorded: one due to lymphoma after second line treatment and one due to hepatic carcinoma occurred 3 months after completion of therapy. Conclusions: A brief course of chemo-immunotherapy R-BM followed by Rituximab consolidation is safe and effective with a high CR rate in elderly patients with untreated advanced stage FL. Planned future analysis of the entire study will give further information on late toxicity and outcome. Disclosures: Off Label Use: In Europe use of Bendamustine in first-line treatment of follicular lymphoma is off-label. Drug was provided free by Mundipharma. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.2720.2720

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 1320-1320

Abstract: Introduction: Elderly patients (pts) with FL do worse than younger ones and the aim of the treatment is usually palliation rather than cure. In order to outline a treatment plan specifically devised for elderly pts with a reduced amount of chemotherapy, we investigated the efficacy and safety of a brief chemo-immunotherapy FND plus Rituximab. Patients and methods: from March 1999 to March 2003, 80 elderly pts (age 〉 60) with advanced stage FL at diagnosis were enrolled. Treatment plan was: 4 courses of FND (Fludarabine 25 mg/m2 days 1–3, Mitoxantrone 10 mg/m2 day 1 and Dexamethasone 20 mg days 1–3) followed by 4 Rituximab infusions at 375 mg/m2/week; pts in partial remission received 2 further FND and 2 Rituximab infusions. PCR molecular monitoring for the presence of IgH/Bcl2 and/or Ig heavy chain gene rearrangement was performed at the beginning of the treatment, after FND, after Rituximab and during follow-up time on bone marrow (BM) samples. Results: median age was 66 (range 60–78); 42 males and 38 females; 16% had stage II, 12% stage III and 72% stage IV disease; 61% had BM involvement; 41% had bulky disease and 24% were at high risk according to IPI score. PCR molecular analysis was performed in 46 pts at diagnosis: 63% were Bcl2 rearranged and 37% were not; IgH rearrangement was detected in 24% of Bcl2 negative pts. Up to date, 70 pts are evaluable. Overall response at the end of treatment was achieved in 63 pts (90%) with 58 pts (83%) in complete remission (CR) and 5 pts (7%) in partial remission (PR). Six pts (9%) did not respond and one patient (1%) died of neutropenic sepsis during a FND course. The addition of Rituximab allowed to increase CR rate from 44% (31 pts) after FND to 83% (58 pts); 73% of responding pts did so with a brief treatment program (4 FND + 4 Rituximab). Patients with adverse prognostic features at diagnosis responded as well as those with more favorable ones with no significant differences in CR rates: BM+ 89%, BM- 79%; low IPI 83%, high IPI 82%; Bulky+ 85%, Bulky- 79%; stage II 90%, III 87%, IV 84%. A thorough molecular analysis is ongoing; to date a molecular marker was detectable in 26 pts. After FND 9/26 pts (35%) did not show anymore BM molecular disease, while PCR negativity was achieved in 23/26 pts (88%) after Rituximab treatment. With a median follow-up of 30 months, 3-yr failure free survival was 50% for the whole series of pts. Failures were observed more frequently in PCR+ pts: all 3 PCR+ pts failed compared to only 7/23 PCR- pts (p=.01). The toxicity was mild with grade 3–4 neutropenia reported in 22% of FND courses, but only 3 pts developed grade 3–4 infections. The whole program was performed in an outpatient setting. Rituximab toxicity was as expected. Conclusions: a brief course of chemo-immunotherapy is able to achieve high clinical and molecular response rates in elderly pts with low toxicity. The sequential use of FND and Rituximab induces a CR rate 〉 80% also in unfavorable subsets of pts. The achievement of PCR negative status correlates with a lower risk of failure.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V104.11.1320.1320

Language: English

Publisher: American Society of Hematology

Publication Date: 2004

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 2828-2828

Abstract: Introduction: The clinical course of MCL is characterized by a continuous pattern of relapse and a poor long term outcome with a median Overall Survival (OS) of four years and a 15% of long term survivors. Recently a new clinical prognostic score (MIPI), including performance status, age, LDH level and leukocyte count has been reported. This score allows a more reliable estimation of individual clinical course. We retrospectively applied the MIPI score to patients with MCL. Patients and methods: Between 1999 and 2007, 40 patients with MCL diagnosed and treated in a single institution entered into the study. Clinical characteristics were as follows: median age 56 years (range 37–81), 80% male; 82% stage IV; 78% bone marrow involvement and 15% MCL with blastoid variant. First line treatments were: high dose chemoimmunotherapy including Rituximab (R) with autologous stem cell transplantation (R-HDC) in 26 patients and Rituximab-CHOP like chemotherapy (R-CHOP) in 14. Crude Kaplan-Meier OS and progression-free survival (PFS) curves were estimated both overall and stratified by MIPI and International Prognostic Index (IPI) score. Differences between curves were tested using the 2-tailed log-rank test. In order to quantify the predictive discrimination of MIPI and IPI scores, univariate logistic models (with death and progression event as binary outcomes) were fitted and the area under the receiver operating characteristic (ROC) curves (c index) was estimated. Results: According to MIPI score 17 patients (43%) were at low risk (LR, score 0–3), 13 patients (32%) at intermediate risk (IR, score 4–5) and 10 patients (25%) at high risk (HR, score & gt;5). According to IPI score 14 patients (35%) were at low risk (LR), 16 patients (40%) at low-intermediate risk (LIR) and 10 patients (25%) at intermediate-high and high risk (IH-HR). At the end of the treatment, 30 patients achieved a CR, five a PR and five did not respond. Relapses occurred in 17 patients and seven of them died of lymphoma. With a median follow-up (FU) of 29 months, OS was 85% (95% CI: 66%–93%); with a median FU of 21 months, PFS was 70% (95% CI: 51%–83%). Twenty-nine months OS rates for MIPI score were: LR 100%, IR 81%, HR 66% respectively (p=.07) and for IPI score were: LR 92%, LIR 94%, IH-HR 65% respectively (p=.09). Twenty-one months PFS rates for MIPI score were: LR 92%, IR 59%, HR 45% respectively (p=.006) and for IPI score were: LR 73%, LIR 87%, IH-HR 44% respectively (p=.09). MIPI score was more predictive than IPI score for the death event and for the progression event: the c index was 74% and 73% for MIPI compared to 72% and 69% for IPI respectively. In a subgroup analysis performed on 26 R-HDC patients, OS and PFS rates stratified for MIPI were: for OS, LR 100% vs IR 80% vs HR 69% (p=.4) and for PFS, LR 91% vs IR 80% vs HR 57% (p=.04) respectively. Discussion: in our retrospective series of patients, MIPI prognostic score discriminates among patients with different PFS. Relapses remain the most important issue for all patients affected by MCL, namely in HR group according to MIPI. New therapeutic strategies are warranted to improve the prognosis of MCL.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.2828.2828

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 41-42

Abstract: Background: Approximately 40% of patients (pts) with non-Hodgkin lymphoma (NHL) have disease that will relapse or is refractory to chemotherapy and/or immunotherapies; management of these pts remains a challenge. Although follicular lymphoma (FL) generally responds well to first-line treatment (tx), this disease is characterized by frequent relapses with shorter intervals between tx lines. Pts with early relapse (ER) (progressive disease & lt;2 y after initial diagnosis) and those who are double-refractory (DR) to both rituximab and chemotherapy, have particularly poor outcomes. Avadomide (CC-122) is a small molecule oral agent that induces cereblon-mediated degradation of the transcription factors Ikaros and Aiolos and promotes antilymphoma activity. Results from the dose-escalation part of the CC-122-NHL-001 study demonstrated preliminary antitumor activity of avadomide in combination with obinutuzumab in pts with relapsed and/or refractory (R/R) FL. Here, we report long-term safety and efficacy results from the dose-escalation and dose-expansion parts of the CC-122-NHL-001 study in pts with R/R FL. Methods: CC-122-NHL-001 (NCT02417285) is an ongoing, open-label, phase 1b study of avadomide in combination with obinutuzumab conducted at 8 sites in 3 European countries with dose-escalation and dose-expansion parts in R/R FL. Eligible pts (age ≥18 y) had histologically confirmed, CD20-positive R/R NHL. Pts with FL (grade 1, 2, or 3a) had ≥1 prior standard regimen. Avadomide active ingredient in capsule (1.0-4.0 mg) or formulated capsules (3.0 or 4.0 mg) was administered orally once daily on days 1-5 followed by 2 days off (5/7-day schedule) every week of each 28-day cycle. Obinutuzumab 1000 mg was given intravenously on days 2, 8, and 15 of cycle 1 and on day 1 of cycles 2-8. Primary objectives were to determine the safety and tolerability of the combination, including the non-tolerated dose, maximum tolerated dose, and recommended phase 2 dose (RP2D). Response was assessed using Cheson 2007 criteria every 2 cycles to cycle 6, then every 3 cycles to cycle 12, and every 6 cycles thereafter. Median duration of response (mDOR) and median progression-free survival (mPFS) were assessed by Kaplan-Meier estimates. Results: As of January 10, 2020, 73 pts with R/R NHL were enrolled and treated, including 19 with R/R diffuse large B-cell lymphoma, 1 with marginal zone lymphoma, and 53 with R/R FL; all 35 pts in the dose-expansion part of the study had R/R FL. The median age among treated pts was 61 y (range, 26-83), the median number of prior antilymphoma therapies was 3 (range 1-11), and 26 pts (36%) had prior autologous stem cell transplantation. As of July 14, 2020, tx was ongoing in 3/38 pts (8%) in dose-escalation (all ongoing in cycle & gt;24, 1 pt ongoing in cycle & gt;40). In the dose-expansion, tx was ongoing in 15/35 pts (43%); of these pts, all were ongoing in cycle & gt;21 and 1 was ongoing in cycle 30. The RP2D of avadomide was established as 3.0 mg formulated capsule. In the expansion part of the study, pts received a median of 15 tx cycles (range, 1-33), and median tx duration was 60 wk (range, 1-132). The most common (≥10%) grade 3/4 TEAEs were neutropenia, reported in 19 pts (54%) and thrombocytopenia, reported in 7 pts (20%). Sixteen pts (46%) had a serious TEAE; only pyrexia (11%) and sepsis (9%) occurred in & gt;2 pts. The objective response rate (ORR) among the 35 pts with R/R FL in the dose-expansion part of the study was 71%, including 40% with a complete response (CR). The mDOR was 14.6 mo (95% CI, 14.6-not estimable [NE]), and mPFS was 16.4 mo (95% CI, 8.3-NE). The median duration of PFS follow-up in dose-expansion was 14.4 mo (range, 0.8-30.3). Two pts had CRs lasting 13.7 mo and 15.3 mo before discontinuation owing to receiving allogeneic stem cell transplantation. Response rates were similar among all 53 R/R FL pts in both parts of the study (dose escalation and dose expansion) and in high-risk (ER and/or DR) FL pts (Table). Conclusions: Long-term follow-up results demonstrate that avadomide plus obinutuzumab has a manageable safety profile and durable responses in patients with R/R FL. The antitumor activity of cereblon modulators plus next-generation anti-CD20 antibodies in heavily pretreated R/R NHL warrants further investigation as a novel chemotherapy-free option. Disclosures Michot: Genentech: Research Funding; Abbvie: Research Funding; Forma: Research Funding; Eisai: Research Funding; Debiopharm: Research Funding; Daiichi Sankyo: Research Funding; Kyowa: Research Funding; AstraZeneca: Other, Research Funding; Gustave Roussy: Honoraria, Other: Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 bio, Research Funding; Janssen: Other, Research Funding; Celgene: Other; Mundi Pharma: Other; Eos: Research Funding; AZD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Medimmune: Research Funding; Lytix Biopharma: Research Funding; Lysarc: Research Funding; Lilly: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Argen-x: Research Funding; Amgen: Research Funding; Agios: Research Funding; Xencor: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other; Exelixis: Research Funding. Doorduijn:Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Boccomini:SC Ematologia, ASOU Città della Salute e della Scienza di Torino, Turin, Italy: Current Employment. Kersten:Takeda: Research Funding; Miltenyi Biotech: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen/Cilag: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); MSD: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Kite/Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Chiappella:Servier: Honoraria; Takeda: Honoraria; Roche: Honoraria; Janssen: Honoraria; Gilead-Kite: Honoraria; Celgene: Honoraria; Iqone: Honoraria. Zinzani:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salles:Abbvie, Autolus, BMS/Celgene, Debiopharm, Genmab, Kite/Gilead, Epizyme, Janssen, Karyopharm, Morphosys, Novartis, F. Hoffmann-La Roche, Takeda: Consultancy; Abbvie, Amgen, Celgene, Gilead, Janssen, Kite, Morphosys, Novartis, Roche, Takeda: Other: Participation to educational events; Abbvie, Autolus, BMS/Celgene, Debiopharm, Genmab, Kite/Gilead, Epizyme, Janssen, Karyopharm, Morphosys, Novartis, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie, Amgen, Celgene, Gilead, Janssen, Kite, Morphosys, Novartis, F. Hoffmann-La Roche, Takeda: Honoraria. Hentrup:Neuronetics, Inc: Current equity holder in publicly-traded company, Ended employment in the past 24 months; BMS Consultant: Current Employment. Rhee:I own stocks for publicly-traded companies: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current Employment. Hagner:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Klein:Roche: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Pourdehnad:Celgene: Ended employment in the past 24 months, Patents & Royalties: Various CC-122 patents; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: Various CC-122 patents. Hege:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Patents & Royalties: numerous, Research Funding; Celgene (acquired by Bristol Myers Squibb): Ended employment in the past 24 months; Mersana Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Arcus Biosciences (Former Board of Directors): Divested equity in a private or publicly-traded company in the past 24 months. Dobmeyer:BMS: Consultancy. Nikolova:Celgene, A Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Ribrag:nanostring: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; gustave roussy comprehensive cancer center: Current Employment; servier: Consultancy; pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; argenX: Research Funding; epizyme (EPZ): Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; EPZ: Honoraria, Membership on an entity's Board of Directors or advisory committees; AZD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This is a phase I study evaluating the safety and efficacy of avadomide in combination with obinutuzumab in patients with R/R B-cell NHL. Avadomide is an investigational agent and has not yet been approved in the US.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-134949

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4295-4295

Abstract: FDG PET/CT (PET) is commonly used in the management of patients with lymphomas and is recommended for both initial staging and response assessment after treatment in patients with diffuse large B-cell lymphoma and Hodgkin lymphoma. In follicular lymphoma (FL), PET proved to be more accurate than conventional imaging for initial staging and for restaging and a positive PET after induction treatment (piPET) has been recently confirmed as a negative prognostic factor for progression Free Survival (PFS). So far however a clear definition and standardization of how the assessment of piPET must be done is lacking. In this work we tested the 5 point Deauville scale (5PS), applied by an expert panel to piPET to determine if it could be a reliable and accurate tool to support the prognostic role of piPET in patients with FL. Patients and Methods This study was conducted on patients with advanced stage untreated FL enrolled in the FOLL05 randomized trial for whom pi- and baseline PET were available in DICOM format. Scans were then interpreted using visual assessment with the Deauville 5-point scale by an international expert panel (EP). Two EP readers scored piPET independently and a third one was asked to resolve the discrepancies. Binary (+ve vs –ve) and overall concordance rates were calculated using k Cohen’s and Fleiss’s kappa coefficients, respectively using the scores obtained on independent reading. Central review results were correlated with patients features, and with patients outcome using PFS as principal endpoint. Results Among 534 patients randomized to the FOLL05 trial we could retrieve a digital PET-DICOM file in 121 patients; 31 patients were excluded for poor quality of the images with a total of 90 pts available for the central review. Median age was 54 (range 36 to 75), 80 (89%) had stage III-IV, 33.3% had high risk FLIPI (score 3-5). After review two different cutoffs were used to classify piPET as +ve or –ve. Using a cut off at 3, rate of +ve piPET was (18%) with a low Cohen’s K index of 0.23. Using a cutoff at 4 +ve piPET rate was 11% but Cohen’s K index improved to 0.62. Using the cut-off at 3 and at 4 concordance rate was 81%, and 94.5% respectively. When 5PS results were correlated with patients features no correlation was shown. Overall at time of current analysis and with a median follow-up of 25.9 months 56 pts (62%) were in continuous CR and 34 (38%) had progressed or relapsed. Overall Results of the 5PS were confirmed to be predictive of PFS (Log rank = 9, P 〈 0.05). The 3-year PFS of piPET -ve and piPET +ve pts with score 3-5 as positive was 38% and 72%, respectively; PPV and NPV were 0.29 and 0.68, respectively. The 3-year PFS of piPET -ve and piPET +ve pts with score 4-5 as positive was 20% and 71%, respectively; PPV and NPV were 0.24 and 0.68, respectively. Looking at single 5PS scores the best discrimination for PFS was observed for scores 4 and 5. Conclusions The central review of FDG-PET scans using the 5PS confirmed that a qualitative assessment of response is feasible also for patients with FL. With the qualitative assessment of response the prognostic role of piPET had the best ratio between reproducibility and clinical informative power using a cut off at 4. These results confirm piPET-response as relevant prognostic factor for patients with FL, and warrants the adoption of the 5PS in future studies. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.4295.4295

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 3934-3934

Abstract: Background and rationale. Recent studies show that the risk of VTE in NHL pts is similar to that observed in high risk solid tumors (i.e. pancreatic, ovarian cancer). VTE in NHL occurs in most cases within three months from diagnosis and can have substantial impact on treatment delivery and outcome as well as on quality of life. However few data are available on potential predictors. To better clarify the epidemiology of early (within six months from treatment start) VTE in NHL we conducted a pooled data analysis of 12 clinical trials from FIL. Our analysis included basic demographic features, lymphoma-related characteristics as well the Khorana score (based on histology, BMI, platelets WBC and HB counts) which is extensively used in solid tumors to predict VTE risk. Patients and methods. From Jan. 2010 to Dec. 2014, all pts with B-cell NHL enrolled in prospective clinical trials from FIL for frontline treatment were included. For 9 studies study period included the entire trial population was included. The analyses were conducted based on CRFs as well as pharmacovigilance reports. VTE definition and grading was stated according to standard criteria of toxicity (CTCAE V4.0). Cumulative incidence of VTE from the study enrollment was estimated using the method described by Gooley et al. accounting for death from any causes as a competing risk. The Fine & Gray survival model was used to identify predictors of VTE among NHL pts. Factors predicting the grade of VTE were investigated using an ordinal logistic regression model. This pooled data analysis was approved by local IRB. Results. Overall,1717 patients belonging to 12 studies were evaluated. Eight were phase I/II or II (25% of pts) and 4 phase III (75% of pts). M/F ratio was 1.41, Median age was 57, (IQ range (IQR) 49-66). Histologies were: DLCL-B 34%, FL 41%, MCL 18%, other 6%. Median BMI was 25 (IQR 22-28). Median Hb, WBC and platelets counts were 13g/dl) (IQR 11.5-14.2), 7,1*10^9/l (IQR 5.6-10.3), 224*10^9/l (IQR 169-298), respectively. 1189 pts were evaluable Khorana score: 58% low risk, 30% intermediate risk, 12% were high risk. Human erytropoetin support was given to 9% of patients. All pts received Rituximab. Planned therapeutic programs included ASCT in 27% of pts, conventional chemotherapy in 67% a conventional chemotherapy plus lenalidomide in 6%. Overall 59 any grade VTE episodes occurred in 51 pts (2.9%), including 21 grade III-IV VTE (18 pts). None was fatal. Median time from study enrolment to VTE was 63 days (IQR: 35-110). Considering death as a competitive event the 6 months cumulative incidence of VTE was 2,2% in low risk Khorana score, 4.5% (95%IC: 2.3-6.7) in intermediate and 6.6% (95%IC: 2.4-10.8) in high risk (p=0.012) (figure 1). Khorana score was predictive also for grade III-IV events as they were 0,7% (95%IC:0.1-1.4) in low risk and 2.0% (95%IC:0.8-3.3) in intermediate-high risk (p=0.048). The result were similar also after excluding lenalidomide containing studies. The Fine and Gray multivariate analyses, adjusted for age and stage, showed that Khorana score (intermediate risk adjHR=1.96; 95%IC: 0.84-4.56 and high risk adjHR=3.81; 95%IC: 1.51-9.58) and DLCL-B histotype (adjHR=2.58; 95%IC: 1.01-6.55) were independently associated to an increased risk of VTE. Moreover an ordinal logistical regression model indicated that the increase of one point in the Khorana score resulted in an increased risk of VTE (OR=1.85; 95%CI: 1.23-2.79). Conclusions: our results suggest that DLCL-B hystotype and Khorana score are predictors of VTE in NHL. The latter might become a simple and effective tool to assess the risk of VTE in NHL. Prospective validation including also patients not eligible for clinical trials is needed. Figure 1. Figure 1. Disclosures Off Label Use: This is a metaanalysis on 12 prospective trials which employed several different experimental agents. All experimental agent will be disclosed to the audience. Luminari:Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.3934.3934

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7