Efficacy comparison of tisagenlecleucel vs usual care in patients with relapsed or refractory follicular lymphoma.

The ELARA trial indicates tisagenlecleucel (tisa-cel) is an effective anti-CD19 chimeric antigen receptor T-cell therapy for relapsed or refractory follicular lymphoma (r/r FL). As ELARA is a single-arm trial, this study compares tisa-cel outcomes from the ELARA trial with usual care from a real-world cohort. ELARA enrolled 98 patients as of 29 March 2021 (median follow-up: 15 months from enrollment). Usual care data were obtained from ReCORD-FL, a global retrospective study of patients with r/r FL, who met similar eligibility criteria to ELARA. With a data cutoff date of 31 December 2020, 187 patients with ≥2 preceding treatment lines were included in the ReCORD-FL (median follow-up: 57 months from third-line) study. An indirect treatment comparison was performed for 97 patients from the ELARA trial and 143 patients from the ReCORD-FL study with no missing data on baseline factors. The line of therapy for which outcomes were assessed was selected or matched between cohorts using propensity score modeling. After baseline factor adjustment via weighting by odds, complete response rate (CRR; 95% confidence interval) was 69.1% (59.8%-78.3%) for tisa-cel vs. 37.3% (26.4%-48.3%) for usual care; overall response rate was 85.6% (78.7%-92.5%) vs. 63.6% (52.5%-74.7%). Kaplan-Meier probability of being progression/event-free at 12 months was 70.5% (61.4%-79.7%) for tisa-cel vs. 51.9% (40.6%-63.3%) for usual care, with hazard ratio (HR)=0.60 (0.34-0.86); 12-month overall survival was 96.6% (92.9%-100%) vs. 71.7% (61.2%-82.2%), with HR=0.2 (0.02-0.38). In conclusion, tisa-cel was associated with a 1.9-fold higher complete response rate and a 1.4-fold higher rate of being progression or event free at 12 months vs usual care, as well as a death risk reduction of 80%. The findings provide additional evidence on the benefit of tisa-cel in patients with r/r FL after ≥2 treatment lines. This trial was registered at www.clinicaltrials.gov as NCT03568461.

Persistence of minimal residual disease in bone marrow predicts outcome in follicular lymphomas treated with a rituximab-intensive program.

We assessed the prognostic value of minimal residual disease (MRD) within the ML17638 phase 3 trial from the Fondazione Italiana Linfomi, investigating the role of rituximab maintenance in elderly follicular lymphoma (FL) patients after a brief first-line chemoimmunotherapy. MRD for the bcl-2/IgH translocation was determined on bone marrow cells in a centralized laboratory belonging to the Euro-MRD consortium, using qualitative and quantitative polymerase chain reactions (PCRs). Of 234 enrolled patients, 227 (97%) were screened at diagnosis. A molecular marker (MM) was found in 51%. Patients with an MM were monitored at 8 subsequent times. Of the 675 expected follow-up samples, 83% were analyzed. Conversion to PCR negativity predicted better progression-free survival (PFS) at all post-treatment times (eg, end of therapy: 3-year PFS, 72% vs 39%; P < .007). MRD was predictive in both maintenance (83% vs 60%; P < .007) and observation (71% vs 50%; P < .001) groups. PCR positivity at the end of induction was an independent adverse predictor (hazard ratio, 3.1; 95% confidence interval, 1.36-7.07). MRD is a powerful independent outcome predictor in FL patients who receive rituximab-intensive programs, suggesting a need to investigate its value for decision-making. This trial was registered at www.clinicaltrial.gov as #NCT01144364.

Rituximab maintenance compared with observation after brief first-line R-FND chemoimmunotherapy with rituximab consolidation in patients age older than 60 years with advanced follicular lymphoma: a phase III randomized study by the Fondazione Italiana Linfomi.

PURPOSE: To evaluate the efficacy of rituximab maintenance in 60- to 75-year-old patients with advanced follicular lymphoma responding to brief first-line chemoimmunotherapy followed by rituximab consolidation. PATIENTS AND METHODS: A total of 234 treatment-naive 60- to 75-year-old patients began chemoimmunotherapy with four monthly courses of rituximab, fludarabine, mitoxantrone, and dexamethasone (R-FND) followed by four weekly cycles of rituximab consolidation. Of these, 210 patients completed the planned treatment, and 202 responders were randomly assigned to rituximab maintenance (arm A) for 8 months, once every 2 months for a total of four doses, or to observation (arm B). RESULTS: Median ages in arms A and B were 66 and 65 years, respectively. After induction and consolidation therapy, the overall response rate was 86%, with 69% complete remissions (CR). After a 42-month median follow-up from diagnosis, 3-year progression-free survival (PFS; the primary end point) and overall survival (OS) were 66% (95% CI, 59% to 72%) and 89% (95% CI, 85% to 93%), respectively. After randomization, 2-year PFS was 81% for rituximab maintenance versus 69% for observation, with a hazard ratio of 0.74 (95% CI, 0.45 to 1.21; P = .226), although this was not statistically significant. No differences between the two arms were detected for OS. Overall, the regimen was well-tolerated. The most frequent grade 3 to 4 toxicity was neutropenia (25% of treatment courses), with 13 infections. Two toxic deaths (0.8%) occurred during induction treatment. CONCLUSION: A brief R-FND induction plus rituximab consolidation achieved excellent results with high CR and PFS rates, supporting the feasibility of this regimen in patients older than 60 years. A short rituximab maintenance did not achieve a statistically significant PFS improvement over observation.

Clinical implications and prognostic role of minimal residual disease detection in follicular lymphoma.

The identification of patients at high risk of relapse is a critical goal of modern translational research in oncohematology. Minimal residual disease (MRD) detection by polymerase chain reaction-based methods is routinely employed in the management of patients with acute lymphoblastic leukemia. Current knowledge indicates that it is also a useful prognostic tool in several mature lymphoproliferative disorders and particularly in follicular lymphoma (FL). Based on this evidence clinical trials employing MRD-based risk stratification are currently ongoing in FL. In this review the 'state of the art' of MRD evaluation in FL is discussed. A short description of technical issues and recent methodological advances is provided. Then, the bulk of the review focuses on critical take-home messages for clinicians working in the field. Finally, we discuss future perspectives of MRD detection and more generally outcome prediction in FL.

Rituximab-based pre-emptive treatment of molecular relapse in follicular and mantle cell lymphoma.

Pre-emptive rituximab (pRTX) might represent an effective approach for patients with follicular (FL) and mantle cell lymphoma (MCL) experiencing molecular relapse (M-rel). However, available experience is still limited. We retrospectively collected FL and MCL cases that underwent pRTX with four weekly rituximab infusions (375 mg/m²) due to molecular persistence or M-rel. M-rel was assessed using nested polymerase chain reaction (PCR) and real-time quantitative PCR using the Bcl-1/IGH, Bcl-2/IGH or the immunoglobulin heavy chain rearrangement. Twenty-three occurrences of M-rel or persistence were treated in 18 patients (nine MCL and nine FL). The pRTX reinduced molecular remission (MR) in 17/23 cases (7/9 FL and 10/14 MCL). The median time to MR reinduction was 4.5 months (range 3-12), and the median duration of the first MR reinduction was 34 months (range 12-72). In five MCL cases, pRTX was used to treat subsequent M-rels, with success in four cases. No clinical relapses were seen within 2 years of successful reinduction of MR. Progression-free survival after pRTX was 64 % at a median follow-up of 6 years. pRTX was feasible and safe and effectively reinduced MR in FL and MCL patients (74 %). Prospective trials are needed to verify the clinical benefit of similar approaches.

The changing paradigm of chronic lymphocytic leukemia management.

B cell-chronic lymphocytic leukemia (CLL), the commonest adult leukemia in western world, is today most often diagnosed at early-stage, following the accidental detection of lymphocytosis during a routine blood analysis. Moreover, the expectations of CLL patients have dramatically changed in the past decade and for the first time a significant overall survival improvement has been demonstrated in the disease--at least in the younger and fit patients--with the use of the FCR regimen, which combines rituximab fludarabine and cyclophosphamide. New drugs and new regimens are currently being developed for the relapsed patients and for those too old or too frail to receive aggressive treatments. Some of these promising compounds will likely be part of the future front-line treatments. Additionally, the increasing knowledge on the molecular features that predict the clinical outcome may soon result in a molecular classification of the disease. These acquisitions are producing a migration from palliative care to a curative and individually-tailored approach. In this review we tried to summarize the advances achieved in the past decade and help the specialists in internal medicine and the general practitioners to understand the completely changed scenario in which the disease should nowadays be managed.

Risk factors of central nervous system relapse in mantle cell lymphoma.

Central nervous system (CNS) relapse has not been extensively studied in mantle cell lymphoma (MCL). We retrospectively analyzed the risk factors and pattern of CNS relapse in consecutive patients with MCL. We identified 142 cases of MCL treated from 1980 to 2011. Median age at diagnosis was 68 years; 82% of patients had advanced stage; extranodal disease was reported in 89% of cases and high serum lactate dehydrogenase (LDH) in 40%. Fourteen patients (10%) did not receive treatment at diagnosis. Chemotherapy was administered to 125 patients (88%), in 21 cases (15%) including drugs penetrating into the CNS or given intrathecally; 49 patients (35%) had rituximab. Ten patients had front-line autologous transplant. After a median follow-up of 7.9 years, CNS relapse occurred in 11 cases (7.8%) at a median of 13.8 months. Actuarial risk of CNS relapse was higher in patients with elevated LDH (p = 0.002), higher International Prognostic Index (IPI) score (p = 0.018) and blastoid histology (p < 0.0001). Blastoid histology retained significance at multivariate analysis. Median survival after CNS relapse was 6.3 months. No front-line treatment reduced the risk of CNS relapse. Our analysis confirms the poor outcome of MCL after CNS relapse and may allow the identification of patients needing prophylaxis of CNS relapse.

Telomere loss in Philadelphia-negative hematopoiesis after successful treatment of chronic myeloid leukemia: evidence for premature aging of the myeloid compartment.

Telomere shortening, a well-known marker of aging and cellular stress, occurs under several conditions in the hematopoietic compartment, including aplastic anemia and following iatrogenic noxae. We decided to verify whether pathological telomere erosion also arises in restored Philadelphia-negative (Ph-negative) hematopoiesis following successful treatment of chronic myeloid leukemia (CML). Eighty-one CML patients in complete cytogenetic remission were compared to 76 age-matched healthy subjects. Myeloid cells of CML patients had shorter telomeres than controls (6521 bp vs 7233 bp, p<0.001). This difference was specific for the myeloid compartment, since it was not observed in lymphoid cells (6774 bp vs 6909 bp, p=0.620). Acquired Ph-negative cytogenetic abnormalities (p=0.010), lack of complete molecular remission (p=0.016) and age (p=0.013) were independent predictors of telomere shortening. Telomere dynamics were assessed over a median follow-up period of 22 months. We documented accelerated non-physiological ongoing telomere shortening in 17/59 CML patients (28%). Patients experiencing grade 2-4 hematological toxicity, during CML remission possessed significantly shorter telomeres compared to those lacking toxicity (p=0.005 for any toxicity, p=0.007 for anemia). CML patients suffer from significant and often ongoing telomere stress resulting in premature and selective aging of the myeloid compartment which might have long-term consequences on function and integrity of Ph-negative hematopoiesis.

Incidence, risk factors and outcome of histological transformation in follicular lymphoma.

Histological transformation (HT) into diffuse large B-cell lymphoma (DLBCL) was documented in 37 of the 281 (13%; 95% CI, 9-18) follicular lymphoma (FL) patients treated at our institute from 1979 to 2007. HT occurred at a median of 2·75 years from initial FL diagnosis and HT rate was 15% at 10 years and 26% at 14 years, with a plateau from that point onward. Patients with bulky or extranodal disease, or those diagnosed before 1990 had a significantly higher risk of HT. When initial treatment strategies were taken into account, a reduced HT risk was seen in the patients initially managed with a 'watch and wait' policy, while the risk appeared significantly increased in the small subset of 18 patients initially managed with rituximab plus chemotherapy (P = 0·0005). HT was associated with a significantly shorter cause-specific survival (P = 0·0002). Predictors of survival after HT were the Follicular Lymphoma International Prognostic Index at diagnosis, as well as age and performance status at the time of HT. Our data confirm the adverse clinical outcome of FL after HT. In keeping with previous isolated reports, our findings suggest that there is a subgroup of patients in whom HT may not occur.

Hepatitis C virus and GBV-C virus prevalence among patients with B-cell lymphoma in different European regions: a case-control study of the International Extranodal Lymphoma Study Group.

Hepatitis C virus (HCV) infection is associated with some B-cell non-Hodgkin lymphoma (B cell-NHLs). Patients with HCV infection frequently show co-infections with GB virus C (GBV-C, formerly known as hepatitis G virus), and some studies have suggested a higher incidence of GBV-C infection in patients with B cell-NHLs. The aim of this study was to prospectively evaluate the association between HCV and/or GBV-C infection and B cell-NHLs in different geographic areas. One hundred thirty-seven lymphoma cases and 125 non-lymphoma matched controls were enrolled in an international case-control study conducted in Switzerland (Bellinzona), Spain (Barcelona) and England (Southampton) on samples collected from 2001 to 2002. In Bellinzona (41 cases and 81 controls), the overall prevalence of HCV was 3.3% (4.9% in NHLs), and the overall prevalence of GBV-C was 24% (22% in NHLs). In Barcelona (46 cases and 44 controls), the prevalence of HCV was 10% (8.7% in NHLs) and the prevalence of GBV-C 20% (13% in NHLs). There was no statistically significant difference in the frequency of both infections between patients with NHL and controls. In Southampton, 50 NHL cases were analysed, none of them was found to be HCV-positive; therefore, no control group was analysed and GBV-C analysis was not performed, too. Both in Bellinzona and in Barcelona, the seropositivity rate was significantly lower for HCV than for GBV-C, suggesting that their transmission can be independent. The incidence of HCV was significantly higher in Barcelona than that in Bellinzona. This study confirmed the existence of marked geographic differences in the prevalence of HCV in NHL but cannot provide any significant evidence for an association between HCV and/or GBV-C and B-cell NHLs.

The host genetic background of DNA repair mechanisms is an independent predictor of survival in diffuse large B-cell lymphoma.

Several drugs used for diffuse large B-cell lymphoma (DLBCL) treatment rely on DNA damage for tumor cell killing. We verified the prognostic impact of the host DNA repair genotype in 2 independent cohorts of DLBCL treated with R-CHOP21 (training cohort, 163 cases; validation cohort, 145 cases). Among 35 single nucleotide polymorphisms analyzed in the training series, MLH1 rs1799977 was the sole predicting overall survival. DLBCL carrying the MLH1 AG/GG genotype displayed an increased death risk (hazard ratio [HR] = 3.23; P < .001; q =0 .009) compared with patients carrying the AA genotype. Multivariate analysis adjusted for International Prognostic Index identified MLH1 AG/GG as an independent OS predictor (P < .001). The poor prognosis of MLH1 AG/GG was the result of an increased risk of failing both R-CHOP21 (HR = 2.02; P = .007) and platinum-based second-line (HR = 2.26; P = .044) treatment. Survival analysis in the validation series confirmed all outcomes predicted by MLH1 rs1799977. The effect on OS of MLH1, a component of the DNA mismatch repair system, is consistent with its role in regulating the genotoxic effects of doxorubicin and platinum compounds, which are a mainstay of DLBCL first- and second-line treatment.

Telomeres and telomerase in normal and malignant B-cells.

The telomeric checkpoint is emerging as a critical sensor of cellular damage, playing a major role in human aging and cancer development. In the meantime, telomere biology is rapidly evolving from a basic discipline to a translational branch, capable of providing major hints for biomarker development, risk assessment and targeted treatment of cancer. These advances have a number of implications in the biology of lymphoid tumours. Moreover, there is considerable interest in the potential role of telomeric dysfunction in the wide array of immunological abnormalities, grouped under the definition of 'immunosenescence'. This review will summarize the impact of recent advances in telomere biology on the physiology and pathology of the B lymphocyte, with special interest in immunosenescence and lymphomagenesis.

Long-term lymphoma survivors following high-dose chemotherapy and autograft: evidence of permanent telomere shortening in myeloid cells, associated with marked reduction of bone marrow hematopoietic stem cell reservoir.

OBJECTIVE: To investigate telomere length (TL) and hematopoietic progenitors in long-term survivors after high-dose chemotherapy and peripheral blood stem cell (PBSC) autograft. METHODS: Peripheral blood (PB) and bone marrow (BM) samples were obtained from 31 subjects in continuous complete remission from a high-risk lymphoma, at a median of 5.8 years (range: 1-11 years) since autograft. Most of them were grafted with large PBSC quantities (median CD34(+ve) cells/kg: 7 x 10(6)). TL was determined by Southern blot analysis, BM progenitors by in vitro long-term culture-initiating cells (LTC-IC) and colony assays. RESULTS: TL of PB granulocytes was significantly shortened in autografted subjects compared with age-matched healthy subjects; a similar finding was observed in BM. The median TL reduction in granulocytes from autografted subjects compared with age-matched controls (Delta(TelShortening)) was then assessed according to time interval since autograft. Three subject subgroups were identified-at 1 to <3 years, 3 to <6 years, and 6 to 11 years since autograft-and their telomere loss was the same, with Delta(TelShortening) of 1132, 1379, and 1214 bp in the three subgroups, respectively. The longitudinal assessment of TL in five representative patients followed for up to 40 months since autograft confirmed that telomere shortening occurring during exposure to chemotherapy as well as postautograft is persistent at long term. BM LTC-IC and multipotent and committed progenitors were assessed in subjects at >3 years after autograft and found to be markedly reduced compared with normal controls. CONCLUSION: High-dose chemotherapy and PBSC autograft may result in myelopoietic cell abnormalities that appear to be irreversible.