ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
Introduction: Mature T and NK-cell lymphomas represent a heterogeneous group of lymphoid disorders (29 subtypes according to the 2016 WHO classification) arising from mature T cells of post-thymic origin with different morphological characteristics, phenotypes, and clinical presentation. Following the success of the T Cell Project (TCP), which allowed the analysis of more than 1,500 cases of peripheral T-Cell lymphomas (PTCLs) collected prospectively in 18 Countries, in 2018 the TCP 2.0 was launched. Here we report the global distribution of PTCLs, from the cases registered so far based on the locally established histological diagnosis. Methods: The TCP2.0 (ClinicalTrials.gov Identifier: NCT03964480) is a prospective, international, observational study which adapts to changes made in the new WHO classification. Results: Since the beginning of the study (October 2018), 648 patients with newly diagnosed PTCL were registered by 75 active centers across 14 countries. Of these data, 594 patients have been validated by the centralized trial office. Overall, PTCL-NOS, Anaplastic large cell lymphoma (ALCL) ALK-negative, and Angioimmunoblastic T-cell lymphoma (AITL), represent the most frequent subtypes, representing 31.3%, 18,9% and 13,5% of cases, respectively. As reported in Table 1, PTCL-NOS represents the most frequent subtype worldwide, whereas Adult T-cell leukemia/lymphoma was more frequent in Brazil, AITL and ALCL ALK-negative in Australia/ India, and ALCL ALK-positive in North America and Europe. Extranodal NK/T-cell lymphoma, nasal type was relatively frequent in Brazil and quite rare in the other Latin America Countries. Finally, many sub-types represent less than 5% of cases in all geographic areas. Conclusions: The TCP2.0 continues to recruit very well, despite the difficulties linked to the COVID-19 pandemic, and may represent a useful resource for the prospective study of this group of rare lymphomas.