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In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 3919-3919

Abstract: Introduction The prognosis for patients with high tumor burden follicular lymphoma (FL) continues to improve in the modern immunochemotherapy era. However there is still a subgroup of 20% of patients who progress within 2 years of first line R-CHOP, (rituximab, doxorubicin, vincristine, prednisone) and experience a poor outcome (Casulo JCO 2015). To date, early identification of these high risk patients has been unsatisfactory. FDG-PET-CT (PET) is now the recommended imaging technique for staging and response assessment in FL and central scan review in a pooled analysis from three prospective studies has shown that post induction PET identifies a population with a high risk of death (Trotman, Lancet Haematol 2014). From this new pooled analysis we aimed to determine the prognostic impact of the total metabolic tumour volume (TMTV) measured on baseline PET and its added value to existing clinical prognostic indexes. Material and Methods 161 FL patients who had measurable quantitative data on baseline PET were selected from PET-FL, n=84 (Dupuis, JCO 2012), PRIMA, n=36 (Trotman, JCO 2011) and FOLL05 studies, n=41 (Luminari, Ann Oncol 2014). All met criteria for treatment of symptomatic high tumour burden or advanced stage disease. They received R-CHOP (80%), R-CVP (17%) or R-FM (4%) induction therapy with 24% receiving Rituximab maintenance. TMTV was computed on baseline PET by summing the metabolic volumes of all nodal and extranodal lesions using the established 41% SUVmax thresholding method (Meignan, Eur J Nucl Med Mol Imaging 2013). Optimal cut-points for binary outcomes were determined using X-tile® and ROC analysis. Prognostic value was assessed using univariate analysis and Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) and compared to other prognostic factors. Results 156 patients with available survival data were analyzed. Median age was 56 years; 92% were stage III/IV; 38% had FLIPI 3-5; and 29% had FLIPI2 3-5. Median SUVmax was 10 (Q1-Q3: 7-14). Median TMTV was 260 cm3 (Q1-Q3: 131-513 cm3). With a median follow-up of 64 months, 5-yr PFS and OS were 56% and 92% respectively in the whole population. Using a cut-off of 510 cm3, 39 patients (25%) had a high TMTV ( 〉 510cm3). Patients with high TMTV ( 〉 510cm3) had a significantly shorter PFS (Figure 1) and OS (Figure 2) than those with low TMTV (≤510cm3), (5-yrs PFS was 37% vs 62% p=.0007, HR=2.3 and 5-yr OS 83% vs 95% p=.0045, HR=4.1). Median PFS was not reached for patients with low TMTV vs. 34.8 months for patients with high TMTV. Beta2 microglobulin (Β2Μ) 〉 ULN and FLIPI2 3-5 were also predicted factor of poor PFS, whereas FLIPI and LDH were not. When combined, FLIPI2 and TMTV had a significant impact on PFS and OS . The 5-yr PFS was 67%, 45% and 27% respectively for patients with: low TMTV and FLIPI2 0-2, high TMTV or FLIPI2 3-5, and high TMTV and FLIPI2 3-5. Incorporating TMTV 〉 510cm3 into the FLIPI2 instead of the longest diameter of the largest lymph node 〉 6cm improved results for PFS and OS. Patients with 3-5 factors with this revised index had a significantly worse outcome than patients with 0-2 factors (5yr PFS 38% vs 66%, p=0.001, HR=2.62, 5yr OS 84% vs 97%, HR=4.98, p=0.013). Conclusions In this pooled analysis from three prospective studies baselineTMTV is a strong predictor of outcome in high tumor burden FL. It adds value to existing pre-treatment prognostic indices in identifying a population for whom FL can no longer be characterized as indolent. The prognostic value of TMTV in stratifying patient outcomes needs to be validated in other populations treated with both R-CHOP +/- maintenance and R-Bendamustine. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Dupuis: ABBVIE: Membership on an entity's Board of Directors or advisory committees; ROCHE: Speakers Bureau. Haioun:Roche: Honoraria. Salles:Celgene Corporation; Roche and Gilead Sciences: Research Funding; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche: Speakers Bureau. 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.V126.23.3919.3919

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 992-992

Abstract: F-18-fluorodeoxyglucose positron emission tomography integrated with computed tomography (FDG-PET/CT) enables to detect with relatively high sensitivity and specificity myeloma bone disease and extramedullary sites of metabolically active clonal plasma cells. FDG-PET/CT has also been used to assess and monitor the metabolic response to therapy and to predict the prognosis. One of the major limitation of PET/CT is the lack of standardized image criteria and of inter-observer reproducibility in interpreting the results. Aim of the present sub-study was to prospectively evaluate FDG-PET/CT at diagnosis, after 4 cycles of induction therapy and prior to maintenance therapy in a sub-group of patients enrolled into EMN02/HO95 MM international phase III trial. In particular, the two primary end-points were firstly to assess the prognostic significance of PET/CT at diagnosis and after therapy and secondly to standardize PET/CT evaluation by centralized imaging and revision and definition of criteria for interpretation. Seven hundred and 18 patients with newly diagnosed transplant-eligible symptomatic MM have been prospectively randomized in Italy from February 2011 through April 2014 to receive 4 cycles of bortezomib-melphalan-prednisone (VMP) vs high-dose melphalan and single or double autologous stem cell transplantation (ASCT) as intensification following induction with bortezomib-cyclophosphamide-dexamethasone (VCD). Consolidation therapy with bortezomib-lenalidomide-dexamethasone vs no consolidation was planned after VMP or ASCT(s), followed by lenalidomide maintenance until progression or toxicity. One hundred and three patients were included in the PET/CT imaging sub-study, and followed for a median of 24 months. By study design, PET/CT was performed and analysed in each of the 8 participating centres at baseline, after induction therapy and prior to the start of maintenance (EOT). Each PET scan was a posteriori re-interpreted in a blinded independent central review process, managed by WIDEN®, by a panel of 5 expert nuclear medicine physicians. They described the following characteristics: bone marrow metabolic state (BM), number (Fx) and score (Fs) of focal PET positive lesions, osteolysis (Lx), presence and site of extramedullary disease (EM), and fractures(Fr), according to the IMPeTUs criteria (Nanni et al, EJNM 2015). Moreover, a global score (GS), from 1 to 5, was given to each patient, considering the highest score among BM, Fx, Fs and EM. Concordance among reviewers on different metrics was calculated using Krippendorf's alpha (AK) coefficient Baseline characteristics of the patients were the following: median age 58 years, ISS and R-ISS stage III 15% and 10%, high-risk cytogenetics (t(4;14) ± del(17p) ±del (1p)±1q gain detected by FISH) 42%. At baseline, 78% of the patients had FLs, with a median SUVmax of 6.0. The percentages of PET positive patients for the different characteristics are summarized in table 1. The agreement among reviewer was good for BM (AK=0.49), Fx (AK=0.65), Fs (AK=0.62), Lx (AK=0.62) and EM (AK=0.40). Of all parameters, only Fx ≥ 4 was associated with worse PFS and OS (P = 0.06) Following 4 cycles of VCD, PET/CT remained positive in 59% of the patients, with a median SUVmax of 3.7. Of all parameters, only Fs ≥ 4 was predictive of worse OS (P= 0.05). Prior to maintenance therapy, PET/CT remained positive in 34% of the patients, with a median SUVmax of 3.4. Normal PET/CT findings before maintenance (66%) were associated with a significant improvement in PFS, in particular the following: presence of FLs (P=0.03), Fx ≥ 4 (P=0.001), Fs ≥2 (P=0.03), 3 (P=0.03) and 4 (P=0.006) and SUVmax ≥ 3.4 (p=0.002). GS was also predictive for PFS if ≥ 3 (P=0.033), 4 (P=0.0001) and 5 (P=0.004). The same parameters were also predictive for OS. The prognostic relevance of pre-maintenance PET/CT was retained across the randomization arm (VMP or ASCT), in terms of PFS and OS. In conclusion, PET/CT was confirmed to be a reliable predictor of outcome in newly diagnosed transplant eligible MM patients, whatever the treatment. Normalization of PET/CT before maintenance was associated with a significant improvement for PFS and OS. FDG-PET/CT is by now the preferred imaging technique for evaluating and monitoring response to therapy. Acknowledgments: this study was partially supported by a grant to Elena Zamagni from Fondazione del Monte di Bologna e Ravenna Table 1 Table 1. Disclosures Gay: Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees. Larocca:Bristol-Myers Squibb: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Sonneveld:Celgene: Other: Advisory board, Research Funding; Onyx: Other: Advisory board, Research Funding; Millennium: Other: Advisory board, Research Funding; Janssen-Cilag: Other: Advisory board, Research Funding. Cavo:Amgen: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.992.992

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 811-811

Abstract: Introduction. The administration of immuno-chemotherapy (ICT) followed by rituximab maintenance (RM) is the recommended approach for the front-line therapy of high tumor burden follicular lymphoma (HTB-FL) patients. Among available ICT regimens, RB (Rituximab-bendamustine) and R-CHOP regimen, are preferred options with high, similar efficacy. Regarding RM, its use is strongly supported after R-CHOP by the results of the PRIMA randomized trial; conversely, no prospective data are available to confirm the efficacy of RM in patients initially treated with RB. The FOLL12 trial was conducted to try to demonstrate that a response adapted post induction management of patients with HTB-FL could be as effective as standard RM in terms of Progression Free Survival (PFS). The trial actually showed the better efficacy of standard RM compared to the experimental approach thus providing indirect confirmation of the efficacy of RM after ICT, 10 years after the PRIMA trial. We here analyse the impact of initial ICT in the FOLL12 study that left treatment choice between RB and R-CHOP at physician discretion and on an individual patient basis. Methods. FOLL12 is a multicenter, randomized, phase III trial that compared standard RM vs. a response adapted post induction management in treatment naïve adult patients with grade 1-3a, stage II-IV and a HTB-FL. All patients received induction immunochemotherapy with 6 cycles of either R-CHOP or R-Bendamustine both followed by two additional doses of rituximab. Choice of ICT was at the physicians' discretion. After ICT, patients in the standard arm received bimonthly rituximab for up to two years. Patients in the experimental arm were managed according to centrally reviewed metabolic and molecular response. Patients achieving complete metabolic (CMR) and molecular response were managed with observation only, those in CMR with molecular persistence received 4 weekly rituximab doses. Patients not achieving CMR were treated with radioimmunotherapy with ibritumomab tiuxetan followed by standard RM. Primary study endpoint was 3 years progression free survival (PFS). Results. A total of 786 eligible patients were enrolled and 1:1 randomized either to standard or experimental arm. By backbone therapy, 341 patients received RB and 445 received RCHOP induction immunochemotherapy. RB was more frequently prescribed in older and female patients (OR 1.6, p=0.001) whereas RCHOP was preferred in patients with bulky disease ( & gt;6cm) and grade 3a histology (OR 0.65, p=0.013). The median follow-up of the analysis was 56 months (range 1-71). In the non-randomized comparison between RB and RCHOP, no difference in terms of PFS was observed between the two regimens (HR for RB 1.07, 95%CI 0.83-1.38, p=0.597, Figure 1). Standard maintenance arm was more effective than experimental arm both in patients initially treated with RCHOP and in those treated with RB (HR RCHOP 1.61, 95% CI 1.16-2.25; HR RB 1.89, 95% CI 1.27-2.82). An unequal interaction between RB and RCHOP and post-induction therapy was observed for sex and for bone marrow involvement. Considering grade 3 to 5 adverse events (AEs), neutropenia was less frequently observed in RB (35.7%) compared to RCHOP (46.2%). Among extra-hematological AEs, higher frequency of grade 3-4 infections and of cutaneous toxicity were observed in RB treated patients (3.8% vs. 1.2% and 2.4% vs. 0.2%). Overall, 54 second malignancies (SM) have been observed including 23 hematologic malignancies and 31 solid cancers. Cumulative incidence of secondary cancer (excluding non melanoma skin cancers) at 3 and 5 years was 3.7% (95%CI 2.4-5.3%) and 8.1% (95%CI 5.8-10.9%). Conclusion. The current update of the FOLL12 trial demonstrated superiority of standard RM compared to the response adapted post induction management irrespective of prescribed regimen thus proving a first prospective non-randomized evidence of RM efficacy in patients with high tumor burden follicular lymphoma patients treated with RB. Both R-CHOP and RB were associated with a similar efficacy profile. Figure 1. Progression free survival for the standard maintenance arm (A) versus response oriented experimental arm (B) of the FOLL12 trial in patients treated with R-CHOP or R-Bendamustine (RB). Figure 1 Figure 1. Disclosures Luminari: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Janssen: Other: Travel, Accomodations, Expenses; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy; GENELAB SRL: Consultancy; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees. Tucci: janssen: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Ferrero: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Morphosys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Clinigen: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau. Arcaini: Gilead Sciences: Research Funding; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Celgene: Speakers Bureau; Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses. Pulsoni: Roche: Consultancy, Speakers Bureau; Takeda, Pfizer, Sandoz, Merk: Consultancy; Gilead, Bristol: Speakers Bureau. Musuraca: Janssen, Roche, Incyte: Honoraria; Janssen, Roche, Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen, Incyte, Roche: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-148581

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 130, No. Suppl_1 ( 2017-12-07), p. 736-736

Abstract: Background: About 15-20% of patients with early-stage unfavorable Hodgkin lymphoma (HL) relapse or are refractory to first-line treatment with combined modality therapies. Early assessment of metabolic response after 2 cycles of ABVD has been shown to be an accurate predictor of progression-free survival and overall survival. Brentuximab vedotin (BV) in combination with AVD chemotherapy (BV-AVD) has demonstrated a promising efficacy with a favorable safety profile in a phase I trial for treatment-naive patients (Younes A. et al, Lancet Oncol 2013). Based on these results, we conducted a randomized, multicentric, phase II trial in order to improve the PET response rate after 2 cycles with BV-AVD regimen for previously untreated, early-stage unfavorable Hodgkin lymphoma. Methods: Patients with previously untreated, stage I/II, HL and unfavorable EORTC/LYSA criteria (defined with at least one of the following: age ≥ 50 y, bulky mediastinal mass with mediastinum / thorax ratio ≥ 0.35, number of involved nodal areas ≥ 4, ESR ≥ 50mm/h or ≥ 30mm/h with B symptoms) were enrolled at the time of diagnosis. Patients were randomly assigned in a 2:1 ratio to receive 4 cycles of BV-AVD (experimental arm) or ABVD (standard arm), followed by 30Gy involved node radiation therapy (INRT). The primary objective was to evaluate the efficacy of the BV-AVD regimen, as measured by negative-PET rate after 2 cycles based on central review. PET was interpreted according to the Deauville 5-point scale with negative PET defined as Deauville 1-3. Patients with missing PET evaluation, whatever the reason, were considered as non-responders. The statistical hypothesis was based on an increase of 10% (from 75% to 85%) of the PET negativity rate after 2 cycles in the experimental arm. The standard arm was added in order to ensure that the hypothesis taken in the sample size evaluation (negative-PET rate after 2 cycles of ABVD ≤ 75%) was verified. If ≥ 93 patients out of 113 evaluable patients had negative-PET, the hypothesis that the negative-PET rate ≤ 75% in the experimental arm would be rejected. This planned analysis of the primary endpoint was performed by intention to treat (ClinicalTrials.gov registration: NCT02292979). Results: From March 2015 to October 2016, 170 patients were included, 113 were randomized in the BV-AVD arm and 57 in the ABVD arm. Median age at randomization was 29 y (range 18-60) and 51% were female. The median number of involved nodal areas was 3 and 92% of the patients were Ann Arbor stage II, 57% had a bulky disease and 40% had B symptoms. After 2 cycles of treatment, 93/113 patients (82.3%, 95% CI 75.3-88.0) and 43/57 (75.4%, 95% CI 64.3-84.5) achieved a negative-PET based on central review in the experimental and standard arms, respectively. With the lower bound of the 95% confidence interval superior to 75% in the experimental arm, the primary objective can be considered to be met. During the first 2 cycles, grade 3-4 adverse events (AEs) were documented in 74% of the patients in the BV-AVD arm and 56% in the ABVD arm. The most frequent grade 3-4 AEs in the experimental arm were neutropenia (64%), leucopenia (31%), gastro-intestinal disorders (8%), febrile neutropenia (7%), transaminases increased (4%) and infections (4%). Only 2 patients (2%) have developed a grade 3-4 peripheral neuropathy after the first 2 cycles of BV-AVD. No pulmonary toxicity has been observed. Grade 3-4 serious AEs (SAEs) were documented in 19% of the patients in the experimental arm (treatment-related SAEs in 17%) and 7% in the standard arm. SAEs have led to permanent BV discontinuation in 7/113 (6%) patients during the first 2 cycles. Reasons for permanent BV discontinuation were loss of weight, hyponatremia, febrile neutropenia, epileptic seizure, peripheral neuropathy, hepatitis and cutaneous rash. Conclusion: This randomized, multicentric, open-label phase II trial aimed to evaluate the efficacy of BV in combination with AVD chemotherapy based on PET response after 2 cycles for previously untreated, unfavorable early-stage HL. The primary objective was met with an improvement of the negative-PET rate with BV-AVD regimen. This first analysis highlighted an increased toxicity with BV-AVD regimen compared to ABVD, with a higher rate of grade 3-4 AEs and SAEs during the first 2 cycles of treatment. Disclosures Fornecker: BMS: Honoraria; Servier: Honoraria; Gilead: Honoraria; Roche: Honoraria; Takeda: Honoraria. Aurer: takeda: Honoraria, Research Funding. Bonnet: Takeda: Other: advisory board. Perrot: Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Amgen: Honoraria. Specht: Takeda: Other: advisory board. Touati: Takeda: Honoraria. Stamatoullas: Takeda: Consultancy; Celgene Corporation: Honoraria. Lugtenburg: Takeda: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Servier: Honoraria; Celgene: Honoraria; BMS: Honoraria; Sandoz: Honoraria. Federico: takeda: Honoraria, Research Funding. Andre: Takeda: Honoraria, Other: Advisory board, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V130.Suppl_1.736.736

Language: English

Publisher: American Society of Hematology

Publication Date: 2017

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 184-184

Abstract: Objective: Baseline quantitative PET parameters measuring tumour burden and metabolism are proposed as early prognosticators of outcome in different lymphoma subtypes. It has been shown that in advanced stage Hodgkin lymphoma (HL) and Primary mediastinal B cell lymphoma, total metabolic tumor volume (TMTV) or total lesion glycolysis (TLG) predicted outcome better than the bulk. From the H10 EORTC/LYSA/FIL randomized intergroup trial (NCT00433433) including patients with supradiaphragmatic stage I/II, histologically proven classical HL, we investigated the prognostic value of quantitative PET metrics measured on baseline FDG PET/CT in the unfavorable group of the standard arm. Methods: One hundred and fifty patients were randomly selected from the 352 patients recruited by the LYSA centers, in the unfavorable group (≥ 4 nodal areas or age ≥ 50 yrs or mediastinal thoracic (MT) ratio ≥ 0.35 or erythrocyte sedimentation rate (ESR) ≥ 50 (without B-symptoms) or ESR ≥ 30 (with B-symptoms)) of the standard arm of the H10 trial. Only patients who had baseline PET/CT with fused images available were analyzed. Standard treatment was 4 cycles of ABVD completed by involved-node radiotherapy. All patients had an interim PET performed after 2 ABVD cycles (PET2). Baseline TMTV was computed using the 41% and 25% SUVmax thresholding methods; SUVmax, TLG41%, TLG25% were calculated. PET2 was centrally reviewed reported. Optimal quantitative parameters cut-off to predict PFS and OS were determined by ROC curves, and Kaplan Meier (KM) curves were obtained. Multivariate analyses were performed using a Cox model. Results: 128 patients with a median age of 32 years were analyzed: 54 (42%) had B symptoms, 74 (58%) had ESR 〉 40 (ROC optimal cut off), 48 (37%) mediastinal bulk as defined above. Median TMTV41%, TMTV25%, SUVmaxand TLG41%, TLG25%were 81 cm3 (25th-75thpercentiles 44-145 cm3), 194 cm3 (112-323), 11 (8-14), 407 cm3 (221-475) and 731 cm3 430-1321) respectively. After a median follow-up of 5 years, the 5y-PFS was 84% and the 5y-OS was 92%. The strongest PET quantitative parameter to predict outcome was the TLG41% (p=0.0006 HR=6.5 for PFS with a cut off of 420 cm3, p=0.025 HR=7.7 for OS with a cut off of 584 cm3). Patients with a high TLG41% had a 5y-PFS of 76% vs 92% (95%CI 71-81; 88-96) and a 5y-OS of 88% vs 96% (95%CI 83-92; 92-100) for those with the lower TLG41% respectively. Similar results were found using 25% SUVmax threshold (p=0.0005 HR=4.7 for PFS, p=0.0032 HR=7.9 for OS). TMTV41% higher than 149 cm3 cut off was associated with a worse PFS (p=0.0099, HR=3.26) and OS (p=0.022, HR=4.8) but with a lower significance level. A SUVmax greater than 14 was also associated with a worse PFS (p=0.018 HR=3.0) with a 5y-PFS of 74% vs 86% but not with OS. In multivariate analysis testing TLG41% and SUVmax or TLG41%and TMTV41%, only TLG41% remained significant (p=0.0096 and p=0.015 for PFS and OS respectively). B symptoms and ESR 〉 40 were predictive of PFS (p=0.0077 HR=3.7 and p=0.0062 HR=6.07 respectively) but not of OS. MT ratio was predictive of neither PFS nor OS (p=0.49, p=0.20). In multivariate analysis, B symptoms, ESR 〉 40 and TLG41% remained significant independent predictors of PFS (p=0.038; p=0.034; p=0.014 respectively). For the 124 patients with a centralized reading available, a positive PET after two cycles (PET2 +) using IHP criteria (n=29) was associated with a worse PFS (p=0.0006). In multivariate analysis testing TLG41% and interim PET, they both remained independent prognosticators (p=0.014 and p=0.025 respectively). Interestingly combining TLG41% and interim PET brings out 3 distinctive prognostic categories (p 〈 0.0001): negative PET2 and low TLG41% with good outcome (5y-PFS=92%, n=60); positive PET2 and high TLG41% with bad outcome (5y-PFS=57%, n=21) and an intermediate category (5y-PFS=88%, n=43) cf. KM curve. No progression was observed in the 8 patients with a positive interim PET but a low baseline TLG41%, suggesting that TLG41% results may reduce the numbers of false positive PET2 patients. Conclusion: Quantitative PET parameters improve patient risk stratification at staging. The study data suggest that TLG is an independent prognosticator of outcome and seems particularly interesting in early stage HL patients, to identify in conjunction with the early PET response, those patients who require treatment intensification. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.184.184

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2636-2636

Abstract: Abstract 2636 Background and objectives: Quality of response assessed with [18F]fluorodeoxyglucose - Positron Emission Tomography (FDG-PET) is confirmed as a strong independent prognostic factor in patients with Hodgkin lymphoma and Diffuse Large B-Cell Lymphoma. Recently the prognostic role of response assessment with PET was also shown in patients with Follicular Lymphoma (FL) (Trotman et al JCO 2011). We conducted a retrospective analysis to investigate the role of FDG-PET after immunochemotherapy in FL. Patients and methods: The study was designed as a retrospective unplanned analysis of newly diagnosed FL patients randomized among R-CVP, R-CHOP, R-FM in the FOLL05 clinical trial (NCT00774826). To be included in the study patients should have confirmed eligibility for the FOLL05 trial, have available data on clinical presentation, treatment details and results, and on follow-up. As mandatory patients should have undergone staging and restaging at the end of treatment with FDG-PET. Local PET interpretation was used to identify clearly positive and clearly negative cases. For this phase of the study uncertain cases were not analyzed for study endpoints: centralized review is ongoing. Contrast enhanced computed tomography (CECT) scans were also collected to confirm quality of response: in particular a cut off of 1.5 cm for the maximum transverse diameter of residual lymph nodes was considered to separate Complete vs. Partial remissions according to International Workshop Criteria (IWC) (Cheson et al JCO 1999). The primary study endpoint was Progression Free Survival. Results: Among 534 patients enrolled in the FOLL05 trial, 114 cases fulfilled eligibility criteria for this study. Baseline patients characteristics did not differ from the overall FOLL05 patient population. In particular FLIPI was 0–1 in 23%, 2 in 42% and 3–5 in 35%. First-line immunochemotherapy, included R-CHOP (36 pts.), R-CVP (33), and R-FM (45). No maintenance therapy with Rituximab was given. Overall response rate at the end of therapy, defined according to IWC, was 97% including a 78% complete remissions (CR) rate. Baseline PET scan was positive in all patients. In 16 cases an interim PET was also available and resulted clearly positive in 6 patients (38%). At the end of treatment 10 cases had inconclusive final PET results and were excluded from subsequent analyses; a clearly positive PET scan was recorded in 26 out of the remaining 104 (25%). In univariate logistic analysis number of nodal sites ( 〉 4) was predictive of final positive PET. Although a trend towards a higher rate of PET positive scans was observed with increasing FLIPI and FLIPI2 this difference was not statistically significant. The rate of patients with negative final PET was 81%, 57%, and 60% for those in CR, PR, and less than PR (Fisher exact test: P=0.021). Assessing response with International Harmonization Project (IHP) criteria (Cheson et al JCO 2007), that also consider PET, 14/74 (19%) of patients previously defined in CR according to IWC were changed to PR and 13/23 (57%) of those in PR were switched to CR. The CR rate changed from 78% to 75% with an agreement rate of 70% between IWC and IHP. With a median follow up of 28 months (range 9–56), 3 year PFS was 68% (95% IC 54%–79%). In univariate analysis a shorter 3yr PFS was observed in post-treatment PET+ vs. PET- patients: 48% vs 84% (log rank p=0.036, HR 2.34, 95% CI 1.03–5.3). A positive final PET was confirmed as a poor prognostic factor when adjusted by FLIPI and FLIPI2 (HR 2.33 P=0.048, and HR 2.41 P=0.039, respectively). Prognostic role of final PET was not affected by treatment arm or by any of analyzed prognostic factors. Finally a trend toward a prolonged duration of remission was observed for patients who achieved a PET negative CR, compared with PET+ CRs and and both PET+/− PRs. Conclusions: This FOLL05 ancillary study confirms that post-treatment PET-CT can modify response allocation and is a predictor of PFS after first line immunochemotherapy in patients with FL. If the prognostic role of PET assessment of response will be confirmed in a larger series and in prospective studies a response adapted treatment strategy could be tested also in FL. Disclosures: Di Raimondo: Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.2636.2636

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 975-975

Abstract: Hodgkin’s lymphoma (HL) is generally treated according to stage and risk profile. A tailored therapy decrease the risk of secondary malignancies which exceeds 10% in several historical series in patients with early stage disease. Anatomic imaging modalities, particularly computed tomography (CT), allow to good morphological imaging but lack sensitivity and specificity because the definition of lymph node involvement is based on size criteria. During the last decade FDG-PET has been introduced for noninvasive staging of lymphoma. Herein we propose a prospective multicentric study with the aim to assess the impact of FDG-PET on the staging of pts with diagnosis of HL. A total of 135 consecutive pts coming from five Italian hematological Institutions underwent a FDG-PET scan in addition to conventional staging procedures, which include physical examination, laboratory data, bone marrow biopsy and imaging of the neck, thorax and abdomen using CT scan. All pts with disconcordant results were carefully evaluated with CT or NMR or ultrasound before starting, during and at the end of therapy. Pts characteristics: 70 male and 65 female, 106 (78.5%) with diagnosis of nodular sclerosis classical HL, 16 (12%) mixed cellularity classical HL, 8 (6%) lymphocyte-rich classical HL, 1 (0.5%) lymphocyte-depleted classical HL and 4 (3%) non specified HL. Standard staging procedures led to: 12 (9%) pts were stage I, 82 (61%) stage II, 26 (19%) stage III and 15 (11%) stage IV. FDG-PET and CT were concordant in 114 out 135 pts (84%). FDG-PET allowed to identify in 30 out 114 concordant stage more nodal (27 pts) or extranodal (3 pts: two spleen and one liver) involvement in comparison with CT imaging. In five out 114 concordant stage CT showed one more involved site in comparison with FDG-PET. FDG-PET results suggested an upstage in 17 pts (12,5%) and a downstage in 4 pts (3%). In these four pts FDG-PET did not confirm one nodal involvement and 3 extranodal involvement identified by CT (1 in the spleen, 1 in the liver and 1 in the lung). All these abnormal uptake sites were confirmed with other instrumental tests, we check after two or three cycles of chemotherapy and, after an accurate re-evaluation, they disappeared. Eleven pts (7%) with localized disease (I–II) at standard staging changed in an advanced stage as a result of the FDG-PET scan: four pts shifted from II to IV stage and seven pts from II to III stage. All pts with an upstaging PET were carefully analysed to confirm or not the PET positivity and in five out 17 of these pts the information provided by FDG-PET led to a change in the therapeutic options in particular for the extent of the radiation fields. In conclusion our data confirm that conventional staging system has an high sensibility nevertheless in this large cohort of pts FDG-PET is a relevant noninvasive method that supplements conventional procedures and therefore should be used in combination with conventional diagnostics to stage HL particularly in pts with early stage, where a change in staging could modify disease management.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V106.11.975.975

Language: English

Publisher: American Society of Hematology

Publication Date: 2005

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 2 ( 2023-01-10), p. 327-335

Abstract: The prognosis of patients with early-stage unfavorable Hodgkin lymphoma remains unsatisfactory. We assessed the efficacy and safety of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (BV-AVD) in previously untreated, early-stage unfavorable Hodgkin lymphoma (ClinicalTrials.gov identifier: NCT02292979 ). METHODS BREACH is a multicenter, randomized, open-label, phase II trial. Eligible patients were age 18-60 years with ≥ 1 unfavorable EORTC/LYSA criterion. Patients were randomly assigned (2:1) to four cycles of BV-AVD or standard doxorubicin, bleomycin, vincristine, and dacarbazine (ABVD), followed by 30 Gy involved node radiotherapy. The primary end point was the positron emission tomography (PET) response rate after two cycles by expert independent review using the Deauville score. The study was designed to test if the PET-negative rate after two cycles of BV-AVD was superior to 75%. We hypothesized a 10% increase in the PET-negative rate after two cycles of BV-AVD. RESULTS Between March 2015 and October 2016, 170 patients were enrolled. After two cycles, the primary end point of the study was met: 93 (82.3%; 90% CI, 75.3 to 88.0) of 113 patients in the BV-AVD arm were PET-negative (Deauville score 1-3) compared with 43 (75.4%; 90% CI, 64.3% to 84.5%) of 57 in the ABVD arm. The 2-year progression-free survival (PFS) was 97.3% (95% CI, 91.9 to 99.1) and 92.6% (95% CI, 81.4% to 97.2%) in the BV-AVD and ABVD arms, respectively. High total metabolic tumor volume was associated with a significantly shorter PFS (hazard ratio, 17.9; 95% CI, 2.2 to 145.5; P 〈 .001). For patients with high total metabolic tumor volume, the 2-year PFS rate was 90.9% (95% CI, 74.4 to 97.0) and 70.7% (95% CI, 39.4% to 87.9%) in the BV-AVD and ABVD arms, respectively. CONCLUSION BV-AVD demonstrated an improvement in the PET-negative rate compared with ABVD after two cycles.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.21.01281

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2023

detail.hit.zdb_id: 2005181-5

In: European Journal of Nuclear Medicine and Molecular Imaging, Springer Science and Business Media LLC, Vol. 39, No. 4 ( 2012-4), p. 569-580

Type of Medium: Online Resource

ISSN: 1619-7070 , 1619-7089

URL: Article

DOI: 10.1007/s00259-011-2031-6

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2012

detail.hit.zdb_id: 2098375-X

In: Arthritis & Rheumatism, Wiley, Vol. 65, No. 9 ( 2013-09), p. 2469-2475

Abstract: Chronic periaortitis (CP) usually responds to glucocorticoids, but some patients have glucocorticoid‐refractory disease or contraindications to glucocorticoid therapy. This study was undertaken to evaluate treatment with the anti–interleukin‐6 receptor (anti–IL‐6R) antibody tocilizumab in 2 patients with CP, one with refractory disease and the other with contraindications to glucocorticoids, and to assess IL‐6 levels in an additional cohort of patients with CP. Methods Both patients were given intravenous tocilizumab (8 mg/kg) once every 4 weeks for 6 months. Serum IL‐6 was measured in 22 patients with active CP and 16 healthy controls. Tissue IL‐6 expression was assessed by confocal microscopy in biopsy specimens obtained from 6 patients with CP. Results In the first patient, whose disease was refractory to various immunosuppressive treatments, tocilizumab added to ongoing therapy with prednisone and methotrexate allowed prednisone withdrawal and induced resolution of symptoms, acute‐phase reactant normalization, and reduction in 18 F‐fluorodeoxyglucose ( 18 F‐FDG) uptake on positron emission tomography. The patient experienced a relapse 7 months later and was successfully retreated with tocilizumab. In the second patient, who was unable to tolerate glucocorticoids because of psychiatric side effects, tocilizumab monotherapy induced sustained clinical and laboratory remission, 18 F‐FDG uptake disappearance, and CP shrinkage. Serum IL‐6 levels were significantly higher in patients with active CP than in controls ( P 〈 0.0001), and IL‐6 was abundantly expressed in biopsy specimens from CP patients, particularly by T cells, B cells, histiocytes, fibroblasts, and vascular smooth muscle cells. Conclusion Tocilizumab may be a therapeutic option for CP. The systemic and tissue up‐regulation of IL‐6 in CP, together with the clinical benefit of IL‐6R blockade observed in our 2 patients, suggest that IL‐6 may contribute to CP pathogenesis.

Type of Medium: Online Resource

ISSN: 0004-3591 , 1529-0131

URL: Issue

URL: Article

DOI: 10.1002/art.v65.9

DOI: 10.1002/art.38032

Language: English

Publisher: Wiley

Publication Date: 2013

detail.hit.zdb_id: 2014367-9

detail.hit.zdb_id: 2754614-7