Background: Elderly patients with relapsed/refractory (R/R) FL have limited treatment options. Lenalidomide has direct tumoricidal and antiangiogenetic actions on tumor cells and is able to modulate ...tumor-cell microenvironment. Lenalidomide combined with Rituximab (R 2) in induction has shown a good clinical activity with low toxicity in both untreated and R/R FL patients. R 2 as maintenance treatment is less studied. Methods: RENOIR (NCT02390869) is an Italian FIL multicenter phase III open-label study for elderly subjects with grades 1-3a R/R FL in advanced stage who received 1 or 2 prior anti-lymphoma therapy and required treatment. Induction treatment consisted in 4 cycles of standard Rituximab-chemotherapy (Bendamustine or CHOP or CVP) according to physician choice or to previous lines. Two additional courses of R-chemotherapy were given for patients with partial remission (PR) or stable disease (SD). Those with stable disease (SD) or better after induction were randomized 1:1 to standard arm (ARM A) with Rituximab maintenance (Rituximab IV 375 mg/m 2 every 12 weeks for 8 doses) or to experimental arm (ARM B) with R 2 maintenance (Rituximab IV 375 mg/m 2 every 12 weeks for 8 doses and Lenalidomide 10 mg/day, days 1-21 per 28-day cycle for 24 cycles). The primary endpoint was 2-yr progression-free survival (PFS) comparing R 2 vs standard Rituximab maintenance using a two-sided test with alpha=0.05. An improvement of PFS from 60% to 78% in favor of R 2 arm was considered relevant. Secondary endpoints included safety, overall survival (OS), response rates (ORR), complete remission (CR), minimal residual disease (MRD) and quality of life (QOL). Results: From May 2014 to October 2022, 152 subjects were enrolled. Median age was 71 years (range, 67-77), 55% male, 82% had stage III/IV disease, 41% and 39% were at FLIPI intermediate-high or high risk, 25% had LDH above normal value, 78% relapsed and 22% were refractory to last treatment. One or 2 prior lines were given to 71% and 29%, R-Bendamustine was the preferred induction treatment (83%). All patients received prior Rituximab. At the end of induction ORR was 84% (n = 128) with CR 57% (n = 87). One hundred and twenty-eight (84%) completed the induction phase and 24 (16%) discontinued treatment because of: 9 progressive disease, 6 withdrawals of consent, 6 adverse events (AEs), 1 death, 2 other. One hundred and twenty-eight patients were randomized (ARM A 64 and ARM B 64) with well-balanced clinical characteristics. During maintenance 34 patients in ARM A and 38 in ARM B discontinued the treatment or are ongoing. At a median follow up of 58 months, 2-yr PFS rate was higher in R 2 arm, though not statistically significant: ARM B vs ARM A 2-yr PFS 72% vs 60% (HR 0.69, 95%CI 0.42-1.14, p=0.149 Fig 1). Subgroup analysis suggests a greater benefit in terms of PFS of R 2 in patients <70y (R 2 vs. R HR=0.34 vs HR=1.00 p-interaction=0.066 for patients < 70 and >=70 respectively). Two-yr OS rates for ARM B vs ARM A were: 80% vs 89% (HR 0.91, 95%CI 0.48-1.73, p=0.777). At three years from the randomization, patients who required further treatment were: 14% in ARM B vs 28% in ARM A (HR 0.64, 95%CI 0.31-1.32, p=0.225). The overall 2-yr PFS and OS rates from enrollment were: 66% (95%CI 57-73) and 83% (95%CI 75-89). The most common grade 3/4 AEs during maintenance in ARM A vs ARM B were: neutropenia (15% vs 41%, p=0.002), gastrointestinal disorders (2% vs 9%, p=0.116), infections (3% vs 11%, p=0.166). Deaths were 49: 10 patients not randomized (5 progressive disease, 1 COVID, 2 infections, 1 secondary neoplasia, 1 cachexia); 20 in ARM A (4 secondary neoplasia, 4 COVID, 4 other infections, 4 unknown, 2 progressive disease, 1 car accident, 1 cachexia) and 19 in arm B (3 secondary neoplasia, 5 COVID, 2 infections, 2 heart attack, 2 unknown, 3 progressive disease, 2 cachexia). Conclusions: the addition of Lenalidomide to Rituximab as maintenance treatment had a clinical benefit but with a limited impact on the overall outcome in this cohort of elderly R/R FL. R 2 maintenance reduced the risk of progression mostly in patients < 70 years, but without a statistically significant difference and with a higher number of adverse events that led to R 2 interruption more frequently. Indeed, the overall outcome of this elderly R/R cohort of FL patients was excellent with a short chemoimmunotherapy followed by two years of Rituximab ± Lenalidomide. Different treatment strategies or a different R 2 schedule might improve the outcome.
AbstractIn consideration of the high vulnerability of the built environment, the assessment of seismic behavior of existing masonry buildings is a key topic in view of their retrofitting and reuse. ...Because masonry’s behavior depends on complex nonhomogeneous, anisotropic, asymmetric, and nonlinear properties, the definition of suitable mechanical models is still a critical issue, especially for stone masonry. Structural analyses of existing masonry buildings in seismic-prone areas are thus significantly influenced by the adopted mechanical models and assumptions about their relevant masonry properties, which are characterized by large uncertainty. In this study, a procedure for the definition of masonry classes and probability density functions of relevant mechanical parameters, such as elastic modulus and shear modulus, is proposed. The general procedure is illustrated referring to a significant number of in situ double-flat-jack test results on stone masonry obtained by the authors during an ad hoc experimental campaign. Finally, combining information on masonry quality obtained by visual inspection with results of in situ tests, a Bayesian methodology is proposed for the updating of masonry mechanical parameters, thereby providing the basis for a more refined probabilistic assessment of the seismic risk index.
Ibrutinib represents the first approved treatment for patients with Waldenström macroglobulinemia (WM). There are very few published experiences outside of a clinical trial. In this study, we ...investigated treatment response, survival, and safety in a real life setting. We retrospectively analyzed 49 consecutive R/R WM patients, managed in 8 Tuscan onco-hematological centers, that received ibrutinib after its approval, at a maximum dose of 420 mg once per day, until disease progression or unacceptable toxicity. Median age was 65 years (range 32–86), and the median number of previous regimens was 2 (range 1–5). Overall and major response rate were 91.8% and 87.7%, respectively. At best response, median IgM level declined from 3,094 to 831 mg/dl, and Hb level increased from 10.4 to 12.7 g/dl. In an intention-to-treat analysis, 36/49 patients (73.5%) were still receiving treatment, while 13/49 (26.5%) had discontinued therapy. Six out of 49 cases (12.2%) relapsed after an initial response, and 13/49 (26.5%) had a dose reduction. Estimated 2-year PFS, DOR, and OS were 76.7%, 88.7%, and 84.1%, respectively. After a median follow-up of 18.3 months, 43/49 patients (87.8%) were alive. The most frequent AE included atrial fibrillation or flutter (6/49 cases, 12.2%), bleeding (6/49 cases, 12.2%), arthralgia/myalgia (5/49 cases, 10.2%). Ibrutinib is a suitable treatment option for R/R WM patients and also suggested by ESMO, NCCN, and other societies. PFS and OS were durable, and DOR was sustained for responsive patients. Treatment toxicity is not negligible, but manageable in most cases without treatment discontinuation.
Introduction: The R-BAC regimen is considered among standard first-line treatments for elderly fit patients with mantle cell lymphoma (MCL). We previously reported (RBAC500 trial) a significantly ...inferior progression-free survival (PFS) for patients with high risk (HR) features, namely blastoid morphology and/or elevated Ki67 proliferative index, as compared to other patients, that were defined as low risk (LR). Indeed, when treated with R-BAC, LR patients had excellent outcome, albeit no maintenance therapy was delivered. Methods: We designed a phase 2 prospective multicenter study, which enrolled patients aged ≥65 years and fit according to the geriatric CGA assessment, or age ≤64 years if not eligible to high-dose chemotherapy plus transplantation. Asymptomatic patients with non-nodal disease were excluded. At presentation patients were allocated by central review as LR or HR, depending on tumor morphology (blastoid versus others), Ki67 expression (≥30% versus others), or presence of TP53 mutation and/or deletion. Patients with any of the three risk factors were classified as HR. Patients with LR disease were treated with 6 cycles of R-BAC (rituximab 375 mg/m2 d 1; bendamustine 70 mg/m2 d 1,2; cytarabine 500 mg/m2 d 1,2,3), while HR patients received abbreviated induction with 4 R-BAC followed by consolidation (4 months, 800 mg/d), and maintenance (20 months, 400 mg/d) with venetoclax. The primary endpoint was 2-years PFS for the HR patients. The sample size was calculated with the one arm non parametric survival analysis (alpha-error 0.05, power 90%), assuming that the addition of venetoclax would improve 2-years PFS from 40% (null hypothesis) to 60%. Tumor response was assessed with Lugano criteria. All patients were analyzed by real-time quantitative PCR at baseline on peripheral blood and bone marrow samples for minimal residual disease (MRD) evaluation, and HR patients were followed up at different time points. Results of this specific analysis will be subject of future reports. This trial was registered at ClinicalTrials.gov Identifier: NCT03567876. Results: Overall, 140 patients from 35 centers of the Fondazione Italiana Linfomi (FIL) were prospectively enrolled between 2018 and 2021. Of them, 54 were HR (39%). Median age was 72 (range 57-79), and 44% had elevated MIPI. LR and HR patients had similar clinical characteristics, but differed for LDH, and MIPI, both being significantly higher in the HR group. Overall, 28 (20%) patients had TP53 mutations, 19 (14%) had TP53 deletions, Ki67 was ≥30% in 34 (24%), and blastoid variant was diagnosed in 13 patients (9%, Figure 1A). Toxicity during R-BAC was in line with previous reports, while most frequent grade >=3 adverse events during venetoclax treatment consisted of neutropenia (21%), followed by skin reactions (10%). Of note, there were 5 deaths due to COVID-19 infection in patients in CR (4 LR, 1 HR). Overall response at the end of R-BAC differed between HR and LR patients (85% vs 99%, p=0.001), as was for complete response (61% vs 91%, p=0.0001). Of the 54 HR patients, 43 (80%) started venetoclax consolidation, 37 (69%) started the maintenance phase, with 26 patients (48%) completing the whole treatment per protocol. Of 10 patients that started Venetoclax in partial remission (PR) or stable disease after R-BAC, 3 converted to CR, 1 maintained PR, while 6 patients progressed during maintenance. After a median follow-up of 34 months, the 2-years PFS for the whole population was 74.9% (95% CI 66-82), and OS was 80% (95% CI 72-85). Patients with HR MCL had 2-years PFS and OS of 58% (95% CI 43-70) and 66% (95% CI 50-77), respectively, which were significantly lower than LR patients (85% and 88%, respectively, p=0.0001 for both, see Figure 1B). Predictors of PFS using Cox regression models adjusted for MIPI were blastoid morphology (Hazard Ratio 3.51), and TP53 mutation (Hazard Ratio 4.17), with Ki67, and TP53 deletions that lost their power in multivariate analysis. Conclusions: The VR-BAC trial represents the first prospective study that stratified upfront patients with MCL to different treatments according to the risk profile. In this trial the null hypothesis (2-years PFS 40%) was rejected in HR patients, suggesting that the addition of venetoclax to R-BAC improves the performance of the induction strategy. These results point to the importance of identifying HR patients since initial diagnosis.
The activity of the combination of rituximab, bendamustine, and low dose cytarabine (R-BAC) was evaluated in a phase 2 multicentre trial from the Fondazione Italiana Linfomi (FIL RBAC500) in ...previously untreated patients with mantle cell lymphoma (MCL) who were not eligible to stem cell transplant. Maintenance treatment was not planned after induction therapy, and no patient in the study received rituximab maintenance. Fifty-seven patients (median age 71 years, range 61-79) were recruited and treated with 4 to 6 cycles between 2012 and 2014. Despite some concern in terms of hematological toxicity, the R-BAC regimen was associated with high complete remission (CR) rate (91%), 2-years overall survival (OS) of 86% (74-93), and 2-years progression free survival (PFS) of 81% (68-89). Here, we present long-term survival outcomes.
After 7 years of median follow-up (86 months, range 57-107), the median OS and PFS for all patients were not reached (Figure 1A and 1B). The 7-years PFS and OS rates were 56% (95%CI 41-67) and 63% (95%CI 46-72), respectively. Patients who achieved CR (n=53) had a 7 years PFS of 59% (95% CI 44-71), with the curve that appears to plateau after 6 years. Adverse predictive factors affecting PFS were blastoid morphology (p<0.05), elevated Ki67 > 30% (p<0.05), and failure to achieve CR after 2 cycles (p=0.03). Early-progression of disease (<24 months from start of R-BAC) was associated with impaired overall survival (p<0.05).
Eight patients (14%) developed a secondary neoplasia: 1 parotid heteroplasia, 1 parotid nodular hyperplasia, 1 prostate cancer, 1 bladder cancer, 1 larynx, 1 thyroid cancer, 1 lung cancer and 1 secondary acute myeloid leukemia.
Among the 25 relapsed patients, 8 did not receive any other treatment. Six had Ibrutinib monotherapy as second line, of whom 4 responded (3 are still in CR), 4 had CHOP or CHOP-like regimens with only partial responses.
As per protocol, 31 patients with molecular marker at diagnosis and available samples were followed-up for minimal residual disease (MRD) with ASO-droplet digital polymerase chain reaction (D-PCR). Patients with MRD persistence at the end of induction, either in peripheral blood or bone marrow, had significantly worse 7 years-PFS (p<0.05 for them both).
In conclusion, in elderly patients with newly diagnosed MCL, R-BAC showed sustained efficacy over time, which compared favorably with any other reported immuno-chemotherapy regimen (with or without maintenance) in similar populations. With a median OS exceeding 60% after 7-years this regimen has significantly impacted on the life-expectancy of elderly patients with MCL.
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Tisi: Incyte: Membership on an entity's Board of Directors or advisory committees; BWS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nassi: Takeda: Consultancy; Incyte: Consultancy; Kyowa Kirin: Consultancy; Roche: Consultancy. Ferrero: Gilead: Research Funding, Speakers Bureau; Morphosys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Clinigen: Membership on an entity's Board of Directors or advisory committees. Zilioli: Takeda: Other: travel expenses, accommodation; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Roche, Italfarmaco: Consultancy, Honoraria; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau. Merli: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; MSD: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; EUSA Pharma: Other: Travel, Accomodations, Expenses; Celgene: Other: Travel, Accomodations, Expenses.
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