A multi-center real-life prospective study of axicabtagene ciloleucel versus tisagenlecleucel toxicity and outcomes in Large B-Cell Lymphomas.

This real-world prospective observational study across 21 Italian centers (CART-SIE) compares axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) outcomes in 485 relapsed-refractory large B-cell lymphoma patients with baseline characteristics matched by Stabilized Inverse Propensity-Score Weighting. Axi-cel versus tisa-cel had higher all-grade cytokine release syndrome (78.6% vs 89.3%, p=0.0017) and neurotoxicity (9.9% vs 32.2%, p<0.0001), but also superior progression-free survival (PFS) at one year (46.5% vs 34.1%, p=0.0009). Even among patients who failed bridging therapy, axi-cel PFS was superior to tisa-cel (37.5% vs 22.7%, p=0.0059). Differences in overall survival (OS) and high-grade immune toxicities were not significant. The CAR-HEMATOTOX score not only predicted hematologic toxicity but also 1-year survival outcomes (51.5% in CAR-HEMATOTOX high vs. 77.2% in CAR-HEMATOTOX low, p<0.0001). Twenty patients developed second primary malignancies, including two cases of T-cell neoplasms. These findings enable more informed selection of anti-CD19 CAR T-cell therapy balancing bridging, safety and efficacy considerations for individual patients.

Secondary primary malignancies after CD-19 directed CAR-T-cell therapy in lymphomas: A report from the Italian CART-SIE study.

Secondary primary malignancies (SPM) have been reported after anti-BCMA or anti-CD19 chimeric antigen receptor (CAR)-T-cell therapies. While the cytotoxic effect of antecedent therapies, including chemotherapy and radiotherapy, has been well established, few data are available on risk related to CAR-T immunotherapies. The study aimed to analyse the incidence of SPM in 651 patients enrolled in the Italian prospective observational CART-SIE study. SPMs were documented in 4.3% (28/651), and the most frequent SPMs were haematological malignancies. In conclusion, the frequency of SPMs in our cohort of heavily pretreated patients receiving CAR-T was relatively low and consistent with previous studies.

Carfilzomib, lenalidomide, dexamethasone (KRD) in BTKi relapsed or refractory mantle cell lymphoma: A phase II study from Fondazione Italiana Linfomi.

Mantle cell lymphoma (MCL) is a rare lymphoproliferative neoplasm considered incurable, with a median survival of 3-5 years. In recent years, Bruton's tyrosine kinase inhibitors (BTKi) have been introduced, demonstrating high therapeutic activity. However, the prognosis for MCL patients failing ibrutinib therapy is particularly poor, with a survival expectation of a few months. In this phase II trial, we assessed the efficacy and safety of the carfilzomib-lenalidomide-dexamethasone (KRD) combination in MCL patients who were relapsed/refractory (R/R) or intolerant to BTKi and in need of treatment. The primary objective of the study was to evaluate the antitumor efficacy of the KRD combination in terms of 12-month overall survival (12-month OS). From September 2019 to December 2020, 16 patients were enrolled from 11 Italian centers. After a median follow-up of 2.37 months (95% CI 0.92-6.47), the 12-month OS was 13%. The rate of grade 3-4 adverse events (AEs) was 35%, and the overall response rate (ORR) was 19%. These results led to the premature termination of enrollment, as defined in the protocol stopping rules. The efficacy of the KRD combination in advanced-stage MCL patients who are R/R to BTKi is unsatisfactory and too toxic.

Early reappearance of intraclonal proliferative subpopulations in ibrutinib-resistant chronic lymphocytic leukemia.

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib represents an effective strategy for treatment of chronic lymphocytic leukemia (CLL), nevertheless about 30% of patients eventually undergo disease progression. Here we investigated by flow cytometry the long-term modulation of the CLL CXCR4dim/CD5bright proliferative fraction (PF), its correlation with therapeutic outcome and emergence of ibrutinib resistance. By longitudinal tracking, the PF, initially suppressed by ibrutinib, reappeared upon early disease progression, without association with lymphocyte count or serum beta-2-microglobulin. Somatic mutations of BTK/PLCG2, detected in 57% of progressing cases, were significantly enriched in PF with a 3-fold greater allele frequency than the non-PF fraction, suggesting a BTK/PLCG2-mutated reservoir resident within the proliferative compartments. PF increase was also present in BTK/PLCG2-unmutated cases at progression, indicating that PF evaluation could represent a marker of CLL progression under ibrutinib. Furthermore, we evidence different transcriptomic profiles of PF at progression in cases with or without BTK/PLCG2 mutations, suggestive of a reactivation of B-cell receptor signaling or the emergence of bypass signaling through MYC and/or Toll-Like-Receptor-9. Clinically, longitudinal monitoring of the CXCR4dim/CD5bright PF by flow cytometry may provide a simple tool helping to intercept CLL progression under ibrutinib therapy.

XPO1 mutations identify early-stage CLL characterized by shorter time to first treatment and enhanced BCR signalling.

Here we evaluated the epigenomic and transcriptomic profile of XPO1 mutant chronic lymphocytic leukaemia (CLL) and their clinical phenotype. By ATAC-seq, chromatin regions that were more accessible in XPO1 mutated CLL were enriched of binding sites for transcription factors regulated by pathways emanating from the B-cell receptor (BCR), including NF-κB signalling, p38-JNK and RAS-RAF-MEK-ERK. XPO1 mutant CLL, consistent with the chromatin accessibility changes, were enriched with transcriptomic features associated with BCR and cytokine signalling. By combining epigenomic and transcriptomic data, MIR155HG, the host gene of miR-155, and MYB, the transcription factor that positively regulates MIR155HG, were upregulated by RNA-seq and their promoters were more accessible by ATAC-seq. To evaluate the clinical impact of XPO1 mutations, we investigated a total of 957 early-stage CLL subdivided into 3 independent cohorts (N = 276, N = 286 and N = 395). Next-generation sequencing analysis identified XPO1 mutations as a novel predictor of shorter time to first treatment (TTFT) in all cohorts. Notably, XPO1 mutations maintained their prognostic value independent of the immunoglobulin heavy chain variable status and early-stage prognostic models. These data suggest that XPO1 mutations, conceivably through increased miR-155 levels, may enhance BCR signalling leading to higher proliferation and shorter TTFT in early-stage CLL.

Comparison of first-line treatment with bendamustine plus rituximab versus R-CHOP for patients with follicular lymphoma grade 3A: Results of a retrospective study from the Fondazione Italiana Linfomi.

In the setting of follicular lymphoma (FL), frontline therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) has represented for many years the standard of care for patients with symptomatic advanced disease. More recently, the combination of bendamustine plus rituximab (R-B) has emerged as an alternative therapeutic option. We present a retrospective, multicenter, observational study aimed at comparing outcomes and toxicities observed in 145 patients diagnosed with grade 3A FL treated with a first line therapy in 15 Italian Fondazione Italiana Linfomi centers between the 1st of January 2014 and the 30th of May 2018. Seventy patients were treated with R-B and 75 with R-CHOP. In the R-B group, the median age at the time of diagnosis was 67 years compared with 59 years in the R-CHOP group. Patients in R-B group achieved a similar overall response rate (96% vs. 99%) and a better complete remission rate (87% vs. 80%, p=0.035) compared with patients in R-CHOP group. Progression free survival (PFS) was similar between individual treated with R-CHOP and R-B (48- month PFS 77.7% vs. 76.6% respectively, p=0.745). The overall survival was significantly longer with R-CHOP treatment (HR=0.16; 95% IC, 0.04-0.74; p=0.007); however, no statistical significant difference was observed after adjustment for age. With the limitations of the study design, our results suggest that both R-B and R-CHOP seem to be valid first-line treatment options in FL3A.

Response-Adapted Postinduction Strategy in Patients With Advanced-Stage Follicular Lymphoma: The FOLL12 Study.

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.

Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.

BACKGROUND: Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed. METHODS: In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score. RESULTS: After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%). CONCLUSIONS: This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.

TP53 Mutations with Low Variant Allele Frequency Predict Short Survival in Chronic Lymphocytic Leukemia.

PURPOSE: In chronic lymphocytic leukemia (CLL), TP53 mutations are associated with reduced survival and resistance to standard chemoimmunotherapy (CIT). Nevertheless, the clinical impact of subclonal TP53 mutations below 10% to 15% variant allele frequency (VAF) remains unclear. EXPERIMENTAL DESIGN: Using a training/validation approach, we retrospectively analyzed the clinical and biological features of TP53 mutations above (high-VAF) or below (low-VAF) the previously reported 10.0% VAF threshold, as determined by deep next-generation sequencing. Clinical impact of low-VAF TP53 mutations was also confirmed in a cohort (n = 251) of CLL treated with fludarabine-cyclophosphamide-rituximab (FCR) or FCR-like regimens from two UK trials. RESULTS: In the training cohort, 97 of 684 patients bore 152 TP53 mutations, while in the validation cohort, 71 of 536 patients had 109 TP53 mutations. In both cohorts, patients with the TP53 mutation experienced significantly shorter overall survival (OS) than TP53 wild-type patients, regardless of the TP53 mutation VAF. By combining TP53 mutation and 17p13.1 deletion (del17p) data in the total cohort (n = 1,220), 113 cases were TP53 mutated only (73/113 with low-VAF mutations), 55 del17p/TP53 mutated (3/55 with low-VAF mutations), 20 del17p only, and 1,032 (84.6%) TP53 wild-type. A model including low-VAF cases outperformed the canonical model, which considered only high-VAF cases (c-indices 0.643 vs. 0.603, P < 0.0001), and improved the prognostic risk stratification of CLL International Prognostic Index. Clinical results were confirmed in CIT-treated cases (n = 552) from the retrospective cohort, and the UK trials cohort. CONCLUSIONS: TP53 mutations affected OS regardless of VAF. This finding can be used to update the definition of TP53 mutated CLL for clinical purposes.

Health-related quality of life in patients with acute promyelocytic leukemia: a systematic literature review.

Introduction: Remarkable advances have been made in acute promyelocytic leukemia (APL) research over the past decades and many patients can now also be cured without traditional chemotherapy. Therefore, the assessment of health-related quality of life (HRQoL) and other types of patient-reported outcomes (PROs) is highly relevant in the current APL treatment landscape.Areas covered: A systematic literature review was performed to identify APL studies assessing HRQoL that were published over the last 15 years. Eligible studies were evaluated on a predetermined data extraction form including information on the study design, PRO measure used, as well patient characteristics and summary of HRQoL findings. For descriptive purposes, selected studies were grouped and discussed based on the type of treatment: standard chemotherapy only versus those also including more recent targeted arsenic trioxide (ATO)-based strategies.Expert opinion: Inclusion of HRQoL in APL research was important to better understand the benefit-risk profile of intravenous ATO compared to traditional chemotherapy. While some information on HRQoL and symptoms in APL survivors treated with standard chemotherapy is available, the long-term effects of ATO therapy on patients' HRQoL are largely unknown. Additionally, future studies are needed to evaluate the potential advantages of oral ATO over intravenous administration.