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Background: Optimal consolidation for young R/R FL in the rituximab age remains uncertain and the benefit of ASCT is not clearly established. Aims: The FIL FLAZ12 trial (NCT01827605) is a prospective, multicenter, randomized, phase 3 trial, comparing RIT versus ASCT, as consolidation after chemoimmunotherapy, both followed by R maintenance in R/R FL. Methods: Pts aged 18-65 yrs, with R/R FL after 1 or 2 lines of chemoimmunotherapy, without significant comorbidities were enrolled. Patients received 3 courses of therapy chosen by the investigator among RCHOP, R-DHAP, R-FM, R-ICE, R-IEV or R-B. Pts achieving at least PR (according to Cheson et al. 2007) were randomized 1:1 to either RIT or ASCT before CD34+ collection. Conditioning for ASCT was BEAM or TEAM. RIT was given as previously described (Morschhauser et al., 2008). After consolidation, pts received R maintenance every 3 months for eight courses. Primary endpoint was PFS. Considering ASCT toxicity, it was hypothesized to be a superior choice, if capable of increasing 3-years PFS from 40% to 60% (two-side log-rank test with alpha of 5% and a power of 85%). Clinical secondary endpoints were ORR, CRR, OS, EFS and TTF. Results: Between Aug 2012, and Sep 2019, 164 pts were screened and 159 enrolled by 38 FIL Centers (enrolled population). Unfortunately, the study was prematurely closed due to low accrual. The data were analyzed on an ITT basis on May 2, 2021 with a median follow-up (mFU) from enrollment of 43 months and 75 PFS events. The two arms were clinically well balanced, with median age of 57 yrs (IQR 49-62), 55% male, 57% stage IV, 20% bulky disease. Tumor re-biopsy was performed in 79% pts. POD-24, retrospectively assessed was observed in 32% of pts. Two pts (1%) did not start treatment (non-confirmed histology and withdrawal). Sixteen (10%) pts discontinued before randomization (7 SD, 3 PD, 3 AE, 1 withdrawal, 2 poor compliance) and 141 (89%) were randomized to either RIT (71) or ASCT (70) (randomized population). Of these 19 (13%) (RIT 8, ASCT 11) did not receive the planned consolidation due to 7 PD, 4 AE, 1 medical decision, 2 poor mobilization, 2 withdrawals, 1 poor compliance, 2 protocol breaches, while 63 (89%) received RIT and 59 (84%) ASCT. After RIT, 61% of pts achieved CR and 23% PR, while after ASCT these were 70% and 9%. Estimated PFS at 3 yrs was 60% (95% CI: 46%-71%) in the RIT arm vs. 59% (95% CI:45%-70%) in the ASCT arm, p = 0.8613 (HR 0.96, 95%CI: 0.57,1.59). (Figure 1) 3yrs-OS was again superimposable in the two arms: 83% (95%CI: 69%-91%) in the RIT vs 85% (95% CI: 72%-91%) in the ASCT, p = 0.8310 (HR 1.10, 95%CI: 0.45,2.72). Grade ≥ 3 hematological toxicity was 46% in the RIT vs 94% in the ASCT arm (p < 0.001). For ASCT vs RIT grade ≥3 neutropenia occurred in 94% vs 41% of pts (p < 0.001). During follow-up, 4 pts died in remission: 1 AML (RIT), 2 SARS-COV2 infections (RIT) and 1 pneumonia (ASCT). Second cancers occurred in 3 pts after RIT and 7 after ASCT (p = 0.480). Multivariable analysis for PFS indicated POD-24, male sex, LDH and refractory disease as adverse parameters. Subgroup analysis for PFS including gender, age, LDH, POD-24 and extranodal disease show no subgroup favoring RIT nor ASCT. Image: Summary/Conclusion: Even if prematurely interrupted, our study demonstrated no meaningful difference in efficacy between ASCT and RIT, but ASCT was more toxic and more demanding for pts and health service. Both strategies induced a similar and favorable long-term outcome suggesting that consolidation programs milder than ASCT require further investigation in R/R FL.
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Background: Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is an effective option for the treatment of relapsed/refractory diffuse large B-cell lymphoma. In order to control lymphoma progression during the manufacturing period, a bridge therapy regimen is required for most patients. Radiotherapy (RT) may be used for patients with localized chemorefractory disease as a bridge therapy. Patients: Here we report a case series of 6 patients (1 primary mediastinal, PMBCL, and 5 diffuse large B-cell lymphoma, DLBCL) treated with radiotherapy as bridge to CAR-T. (Figure 1 summarizes the treatment history). Four patients received tisagenlecleucel (tisa-cel), and one axicabtagene- ciloleucel (axi-cel);one patient died before reinfusion of CAR-T. Results: The dose of RT was 30 Gy in 15 fractions, the site was mediastinum for pt 001, abdominal adenopathy for pt 002, 003 and 005, inguinal adenopathy for pt 004, laterocervical adenopathy for pt 006). Median volume of irradiation was 210 ml (avg. 270 ml, min 79,6 ml, max 635 ml). Response to bridging RT was achieved in 3/ patients (2 PR, 1 CR), one patient had stable disease, and one patient ha disease progression at the time of CAR-T infusion. One patient died for severe Covid19 pneumonia before receiving the planned CART infusion. The outcome is favorable at the time of writing for all infused patient but one, who died for progression 3 months after infusion (the one with progressive disease at the time of infusion). Toxicity was manageable, with no grade 3-4 CRS;maximum CRS grade was 2 in 3 cases. Only one patient receiving axi-cel needed admission at ICU for grade 4 ICANS, with complete resolution after treatment with high dose steroids. Conclusions: We showed in this report that RT is feasible and effective as bridging therapy for patients with localized disease before CAR-T therapy.
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Background: Given the multifactorial immune defect characterizing chronic lymphocytic leukemia (CLL), it appears conceivable that these patients have risk factors that increase their likelihood of complications and death from COVID-19. Aims: To evaluate incidence and severity of COVID-19 cases in a well-defined cohort of patients with CLL receiving venetoclax-based combinations. Methods: We administered a survey to a cohort of CLL treating hematologists from hematological centers in southern Italy. Participants were asked: a) to indicate whether they had offered a test for detection of COVID-19 infection (mainly nasopharyngeal swabs) only to CLL patients who reported symptoms or universally;b) to provide information on the incidence of COVID-19 infection and its severity;c) to specify reasons of possible treatment modifications. The survey was restricted to relapsed-refractory (R/R) CLL patients treated from Feb 1st to Dec 31th 2020 with time-limited venetoclax/rituximab (VR) combination as recommended by MURANO protocol (venetoclax for up to 2 years plus rituximab for the first 6 months), within their clinical practice. Results: A specific questionnaire was sent to 30 CLL hematologists, but only 26 responded to all questions. We considered suitable for the present analysis the 24 questionnaires compiled by hematologists who declared to have treated at least one patient with VR combination in the observation period. Of those, 20.8% worked in academic hospitals. Overall, the survey allowed to collect data on 124 patients who were treated with VR combination. The median number of patients treated in each center was 5 (range,1-15).COVID-19 surveillance tests consisted of viral RNA reverse transcriptase PCR (RT-PCR) on nasopharyngeal swabs. Generally, a policy of universal SARS-CoV-2 testing to be performed on patients at different time-points of therapy was used. Most patients (83/124, 66.9%) were tested before beginning the ramp-up with venetoclax;moreover 66/124 (53.2%) were regularly tested before each rituximab infusion (Fig 1).Reasons for potential change of the schedule of treatment were also investigated. The survey revealed that adherence to treatment was relatively high (70.8%). Only 29.1% physicians modified the therapeutic program mainly because of grade 3 neutropenia. Changes consisted of transient interruption of venetoclax, reduction of doses, and delay of rituximab infusion.Only 2/124 patients (1.6%) had a symptomatic RT-PCR proven diagnosis of COVID-19 infection and required hospitalization. Both patients needed oxygen therapy and admission into an intensive care unit. Of those, 1 patient who was receiving VR combination at the time of COVID infection, eventually died. The second patient developed COVID-19 infection while receiving venetoclax monotherapy (after the VR combination period). He recovered from COVID-19 infection and after 21 days of treatment interruption, he was able to restart venetoclax. Summary/Conclusion: Results of the present survey provide information, thus far lacking, on the use in real-world clinical practice of VR combination during the COVID19 pandemic in 2020. Current literature on the prevalence of COVID-19 infection in CLL, has some limitations (i.e., small size sample, heterogeneity of treatment, restriction to only the first pandemic wave);this survey, performed on a large number of CLL patients treated with VR combination only seems to provide additional information on safe management of CLL treatment during the COVID19 pandemic.
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Fixed-duration treatment with venetoclax (Ven), a highly selective Bcl-2 inhibitor combined with an anti-CD20 monoclonal antibody, showed high efficacy inducing high rates of deep responses with undetectable minimal residual disease (uMRD) in patients with previously treated and untreated chronic lymphocytic leukemia (CLL). The efficacy and safety of the Ven and rituximab (VenR) combination have been investigated in a multicenter, prospective study of the GIMEMA group that included young patients with previously untreated CLL (LLC 1518, VERITAS, NCT03455517). The primary endpoint of this study was the CR rate assessed according to the iwCLL criteria. Inclusion criteria were: treatment requirement per iwCLL criteria, age ≤65 years, cumulative Illness rating scale score ≤6, creatinine clearance ≥30 mL/min, and an unfavorable biologic profile with IGHV unmutated and or TP53 disruption. Treatment consisted of the Ven dose ramp-up (from 20 to 400 mg daily, during 5-weeks) followed by Ven 400 mg daily, combined with R for six 28-day courses (375 mg/m2, course 1;500 mg/m2, courses 2-6). Patients continued with Ven single agent, 400 mg daily, until month 13. Tumor lysis syndrome (TLS) prophylaxis measures included hydration, allopurinol, or rasburicase. All patients received Pneumocystis Jirovecii prophylaxis. G-CSF was given in patients with recurrent and severe granulocytopenia. Adverse events (AEs) were graded according to the CTCAE criteria v.5, TLS events were classified according to Howard's criteria. Response was assessed at months 7 and 15 and included clinical examination, PB evaluation, BM aspirate, BM biopsy, and CT scan. MRD was checked centrally in the PB and BM by a 6/4-color flow-cytometry assay with a sensitivity of at least 10-4 according to the internationally standardized European Research Initiative on CLL. Quantitative MRD results assessed by flow-cytometry were categorized as uMRD (uMRD4;<10-4), intermediate MRD, or high MRD (≥10-2). MRD was further evaluated by allele-specific oligonucleotide PCR with a sensitivity up to 10-5 in the PB and BM of patients who showed uMRD4 by flow-cytometry. During the follow-up, MRD was monitored every 6 months. Between October 2018 and May 2020, 77 patients with CLL were included in this study. Two patients were off study before the start of treatment (withdrawal of consent, 1;Covid-19 infection, 1) and were not included in the analysis. The median age was 53.5 years (range 38-65). Binet stage B/C was present in 84% of patients, increased beta-2 microglobulin in 41%. Seventy-one (96%) of patients were IGHV unmutated, while 3 (4%) were IGHV mutated and showed TP53 mutation (Table 1). At the data cutoff of June 30, 2020, 65 (87%) patients completed the ramp-up phase. The planned 400 mg dose of Ven was reached within 5 weeks in 78.5% of patients. Response was assessed in 34 patients at the end of the VenR combination therapy. A response was achieved by 32 (94%) patients. Responses included 20 (59%) CRs, 1 CRi (3%) and 11 (32%) PRs due to residual enlarged nodes (median maximum size, 1.9 cm). Treatment failure due to toxicity was recorded in 2 (6%) patients. Overall, a response with uMRD4 by flow-cytometry in the PB was observed in 26 (76.5%) cases, and in the PB and BM, in 17 (50.0%). The rates of patients with CR and uMRD4 by flow-cytometry in the PB, and both in the PB and BM, were 44%, and 35%, respectively (Table 2). No detectable disease by PCR, both in the PB and BM, was observed in 4 (12%) patients. With a median follow-up of 4.5 months from the start of therapy, no patient has progressed or died. Fifty-three percent of patients were hospitalized during the first seven days of the Ven ramp-up phase. A transient laboratory TLS was observed in 3 patients. Treatment was discontinued after the first dose of Ven in 1 patient with evidence of laboratory TLS associated with severe neurologic toxicity due to the concomitant administration of fentanyl. Selected grade ≥3 AEs included neutropenia in 10 patients (ramp-up phase, 5) and neutropenic fever in 4. Gra e ≥3 infection was recorded in 3 patients and was the reason for treatment discontinuation in 1 who developed COVID-19 pneumonia. In conclusion, the preliminary results of this study demonstrate the high efficacy of the front-line VenR combination, which resulted in a high proportion of CRs and responses with uMRD4 in young patients with CLL and an unfavorable biologic profile. [Formula presented] Disclosures: Mauro: Astrazeneca: Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Jannsen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Octopharma: Consultancy. Reda: Gilead: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees. Trentin: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Shire: Honoraria;Takeda: Membership on an entity's Board of Directors or advisory committees;Octapharma: Membership on an entity's Board of Directors or advisory committees. Coscia: Shire: 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;Karyopharm Therapeutics: Research Funding;Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Sportoletti: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Laurenti: Roche: Membership on an entity's Board of Directors or advisory committees;AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gaidano: Astrazeneca: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Sunesys: Membership on an entity's Board of Directors or advisory committees. Marasca: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Shire: Honoraria;Roche: Membership on an entity's Board of Directors or advisory committees. Murru: Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rigolin: Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Janssen: 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. Scarfo: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AstraZeneca: Honoraria;Gilead: Membership on an entity's Board of Directors or advisory committees. Marchetti: Pfizer: Membership on an entity's Board of Directors or advisor committees;Takeda: Membership on an entity's Board of Directors or advisory committees;Amgen: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees;Gilead: Membership on an entity's Board of Directors or advisory committees. Levato: Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Galieni: Celgene: Honoraria;Takeda: Honoraria;AbbVie: Honoraria;Janssen: Honoraria. Liberati: Verastem: Research Funding;Onconova: Research Funding;Janssen: Honoraria, Research Funding;Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding;Abbvie: Honoraria, Research Funding;Pfizer: Research Funding;Karyopharm: Research Funding;Morphosys: Research Funding;Novartis: Research Funding;GSK: Research Funding;Incyte: Honoraria;Oncopeptides: Research Funding;Takeda: Research Funding. Molica: Roche: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Gilead: Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Visentin: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Gilead: Membership on an entity's Board of Directors or advisory committees, SpeakersBureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vitale: Janssen: Honoraria. Del Giudice: Janssen: Other: grant for meeting participation;Tolero: Membership on an entity's Board of Directors or advisory committees;Roche: Other: grant for meeting partecipation;AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Cuneo: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Astra Zeneca: Honoraria;Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Foà: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Incyte: Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Roche: Membership on an entity's Board of Directors or advisory committees;Novartis: Speakers Bureau;Roche: Membership on an entity's Board of Directors or advisory committees.
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Background: Early-stage follicular lymphoma (FL) is usually managed with involved field radiotherapy (IFRT), allowing a complete and long lasting eradication of the disease only in 40-50% of patients (pts). The aim of this multicenter phase II prospective study was to evaluate the role of MRD in identifying pts unlikely to be cured by IFRT, for whom an immunotherapy consolidation could improve outcome. Methods: 110 pts with stage I/II FL were enrolled and treated with 24 Gy IFRT. Peripheral blood (PB) and bone marrow (BM) samples were centralized to the FIL (Fondazione Italiani Linfomi) MRD Network of EuroMRD-certified laboratories. In BCL2/IGH+ pts at baseline by both nested PCR (NEST) and RQ-PCR (RQ) in BM a/o PB, MRD was analyzed after IFRT and every 6 months over a 3-year period. Pts with MRD+ by both NEST and RQ in BM a/o PB after IFRT or who became MRD+ during the follow-up were treated with 8 weekly doses of the anti-CD20 MoAb ofatumumab (OFA). The primary objective of the study was to define the efficacy of immunotherapy in obtaining a negative MRD. Results: Of the 106 evaluable pts, 50 were males. Median age was 55 y (29-83). The FLIPI score was 0 in 59% of pts, 1 in 35%, 2 in 6%. 68% of pts had inguinal site involvement. At baseline, 30% of pts had a BCL2/IGH rearrangement (30 MBR, 1 MBR and mcr, 1 mcr) in BM a/ o PB;the concordance between compartments was 90%. All but one pt achieved a clinical response after IFRT;one additional pt died soon after IFRT of unrelated causes. MRD evaluation after IFRT revealed the persistence of BCL2/IGH+ cells in PB a/o BM in 60% of pts. MRD + pts, either after IFRT (n = 18) or in case of conversion to MRD+ during the follow-up (n = 6), received OFA, obtaining a conversion to MRD-in 22/24 pts (91.7%-CI 73.0-99.0), significantly superior to the expected 50% (Fig). After a median F-U of 38 m, 17 pts who achieved a MRD-with OFA are still negative;5 converted to MRD+ (2 received OFA retreatment, achieving a second MRD-;2 pts were not re-treated due to Sars-Cov2 pandemic;1 relapsed). A clinical relapse or progression was observed in 23 pts: 18 (24.6%) among the 73 “no marker” pts and 5 (15.6%) among the 32 BCL2/IGH+ at baseline (p = 0.3), with no significant difference in PFS (p = 0.25). Two early relapses were observed among the 12 pts who became MRD-after IFRT and 3 among the 24 treated at least once with OFA (1 MRD+, 1 MRD-, 1 converted from MRD-to MRD+). Only 1 Pt relapsed while MRD-after OFA. Conclusions: MRD data indicate that RT alone is often insufficient to eradicate the disease, inducing a MRD-only in 40% of pts, notably long-lasting only in half of them. The primary objective of this study-MRD conversion after immunotherapy-was largely achieved. The strategy of an immunotherapy consolidation after IFRT in MRD+ pts allowed increasing molecular responses. However, this strategy is applicable only to 30% of enrolled pts. A clinical advantage of the MRD driven treatment strategy is suggested although not significan.