PURPOSE: We compared 2 years of rituximab maintenance (RM) with a response-adapted postinduction approach in patients with follicular lymphoma who responded to induction immunochemotherapy. METHODS: We randomly assigned treatment-naïve, advanced-stage, high-tumor burden follicular lymphoma patients to receive standard RM or a response-adapted postinduction approach on the basis of metabolic response and molecular assessment of minimal residual disease (MRD). The experimental arm used three types of postinduction therapies: for complete metabolic response (CMR) and MRD-negative patients, observation; for CMR and MRD-positive (end of induction or follow-up) patients, four doses of rituximab (one per week, maximum three courses) until MRD-negative; and for non-CMR patients, one dose of ibritumomab tiuxetan followed by standard RM. The study was designed as noninferiority trial with progression-free survival (PFS) as the primary end point. RESULTS: Overall, 807 patients were randomly assigned. After a median follow-up of 53 months (range, 1-92 months), patients in the standard arm had a significantly better PFS than those in the experimental arm (3-year PFS 86% v 72%; P < .001). The better PFS of the standard versus experimental arm was confirmed in all the study subgroups except non-CMR patients (n = 65; P = .274). The 3-year overall survival was 98% (95% CI, 96 to 99) and 97% (95% CI, 95 to 99) in the reference and experimental arms, respectively ( P = .238). CONCLUSION: A metabolic and molecular response-adapted therapy as assessed in the FOLL12 study was associated with significantly inferior PFS compared with 2-year RM. The better efficacy of standard RM was confirmed in the subgroup analysis and particularly for patients achieving both CMR and MRD-negative.

Central nervous system (CNS) relapse of mantle cell lymphoma (MCL) is a rare phenomenon with dismal prognosis, where no standard therapy exists. Since the covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in relapsed/refractory MCL and penetrates the blood–brain barrier (BBB), on behalf of Fondazione Italiana Linfomi and European Mantle Cell Lymphoma Network we performed a multicenter retrospective international study to investigate the outcomes of patients treated with ibrutinib or chemoimmunotherapy. In this observational study, we recruited patients with MCL with CNS involvement at relapse who received CNS-directed therapy between 2000 and 2019. The primary objective was to compare the overall survival (OS) of patients treated with ibrutinib or BBB crossing chemotherapy. A propensity score based on a multivariable binary regression model was applied to balance treatment cohorts. Eighty-eight patients were included. The median age at study entry was 65 years (range, 39-87), 76% were males, and the median time from lymphoma diagnosis to CNS relapse was 16 months (range, 1-122). Patients were treated with ibrutinib (n = 29, ibrutinib cohort), BBB crossing chemotherapy (ie, high-dose methotrexate ± cytarabine; n = 29, BBB cohort), or miscellaneous treatments (n = 30, other therapy cohort). Both median OS (16.8 vs 4.4 months; P = .007) and median progression-free survival (PFS) (13.1 vs 3.0 months; P = .009) were superior in the ibrutinib cohort compared with the BBB cohort. Multivariable Cox regression model revealed that ibrutinib therapeutic choice was the strongest independent favorable predictive factor for both OS (hazard ratio [HR], 6.8; 95% confidence interval [CI], 2.2-21.3; P < .001) and PFS (HR, 4.6; 95% CI, 1.7-12.5; P = .002), followed by CNS progression of disease (POD) >24 months from first MCL diagnosis (HR for death, 2.4; 95% CI, 1.1-5.3; P = .026; HR for death or progression, 2.3; 95% CI, 1.1-4.6; P = .023). The addition of intrathecal (IT) chemotherapy to systemic CNS-directed therapy was not associated with superior OS (P = .502) as the morphological variant (classical vs others, P = .118). Ibrutinib was associated with superior survival compared with BBB-penetrating chemotherapy in patients with CNS relapse of MCL and should be considered as a therapeutic option.

Treatment of diffuse large B-cell lymphoma (DLBCL) in older patients is challenging, especially for those who are not eligible for anthracycline-containing regimens. Fondazione Italiana Linfomi (FIL) started the FIL_ReRi study, a 2-stage single-arm trial to investigate the activity and safety of the chemo-free combination of rituximab and lenalidomide (R2) in ≥70-year-old untreated frail patients with DLBCL. Frailty was prospectively defined using a simplified geriatric assessment tool. Patients were administered a maximum of 6 28-day cycles of 20 mg oral lenalidomide from days 2 to 22 and IV rituximab 375 mg/m2 on day 1, with response assessment after cycles 4 and 6. Patients with partial response or complete response (CR) at cycle 6 were administered lenalidomide 10 mg/d from days 1 to 21 for every 28 cycles for a total of 12 cycles or until progression or unacceptable toxicity. The primary end point was the overall response rate (ORR) after cycle 6; the coprimary end point was the rate of grade 3 or 4 extrahematological toxicity. The ORR was 50.8%, with 27.7% CR. After a median follow-up of 24 months, the median progression-free survival was 14 months, and the 2-year duration of response was 64%. Thirty-four patients experienced extrahematological toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events grade ≥3. The activity of the R2 combination was observed in a significant proportion of subjects, warranting further exploration of a chemo-free approach in frail older patients with DLBCL. This trial was registered at EudraCT as #2015-003371-29 and clinicaltrials.gov as #NCT02955823.

Background: The ASPIRE (NCT01080391) phase 3 trial showed the efficacy of carfilzomib, lenalidomide and dexamethasone (KRd) triplet for relapse and refractory multiple myeloma (RRMM). However, little is known about safety and efficacy of KRd outside a clinical trial context. Methods: Herein we report real life results of KRd given to 130 RRMM patients from 12 Sicilian Centers. Results: Median age was 62 years; patients had received a median of two previous lines of treatment (range 1–10) and 52% were refractory to previous treatment. Median number of KRd cycles was 12 (2–29), with a mean duration of treatment of 12 months; 21 patients had received at least 18 cycles. Overall response rate was 61%, including 18% complete response. Median PFS was 22.9 months, median OS was not reached. Creatinine clearance >30 mL/min, quality of the best achieved response and standard Fluorescence In Situ Hybridization (FISH) risk were independent predictors of favorable outcome. Patients who received the full-dosage of carfilzomib in the first two cycles had a better outcome. Conclusions: KRd was effective and well tolerated and in a considerable proportion of patients, therapy continued beyond the 18th cycle. The finding of a better outcome in patients with the higher cumulative dose of carfilzomib in the first two cycle encourages to maintain the maximum tolerated dose.

A reduction in BCR-ABL1/ABL1^IS transcript levels to <10% after 3 months or 10% at 3 months but <1% at 6 months fared significantly better than individuals with BCR-ABL1/ABL1^IS 1% at 6 months (event-free survival 68.2% vs. 32.7%; p < 0.001). Likewise, subjects with BCR-ABL1/ABL1^IS at 3 months >10% but <1% at 6 months showed a higher cumulative incidence of MR⁴ compared to patients with BCR-ABL1/ABL1^IS 1% at 6 months (75% vs. 18.2%; p < 0.001). Finally, lower BCR-ABL1/GUS^IS transcripts at diagnosis were associated with BCR-ABL1/ABL1^IS values <1% at 6 months (p < 0.001). Our data suggest that when assessing early molecular responses to therapy, the 6-month BCR-ABL1/ABL1^IS level displays a superior prognostic value compared to the 3-month measurement in patients with discordant oncogenic transcripts at these two pivotal time points.