Baseline PET radiomics outperforms the IPI risk score for prediction of outcome in diffuse large B-cell lymphoma.

The objective of this study is to externally validate the clinical positron emission tomography (PET) model developed in the HOVON-84 trial and to compare the model performance of our clinical PET model using the international prognostic index (IPI). In total, 1195 patients with diffuse large B-cell lymphoma (DLBCL) were included in the study. Data of 887 patients from 6 studies were used as external validation data sets. The primary outcomes were 2-year progression-free survival (PFS) and 2-year time to progression (TTP). The metabolic tumor volume (MTV), maximum distance between the largest lesion and another lesion (Dmaxbulk), and peak standardized uptake value (SUVpeak) were extracted. The predictive values of the IPI and clinical PET model (MTV, Dmaxbulk, SUVpeak, performance status, and age) were tested. Model performance was assessed using the area under the curve (AUC), and diagnostic performance, using the positive predictive value (PPV). The IPI yielded an AUC of 0.62. The clinical PET model yielded a significantly higher AUC of 0.71 (P < .001). Patients with high-risk IPI had a 2-year PFS of 61.4% vs 51.9% for those with high-risk clinical PET, with an increase in PPV from 35.5% to 49.1%, respectively. A total of 66.4% of patients with high-risk IPI were free from progression or relapse vs 55.5% of patients with high-risk clinical PET scores, with an increased PPV from 33.7% to 44.6%, respectively. The clinical PET model remained predictive of outcome in 6 independent first-line DLBCL studies, and had higher model performance than the currently used IPI in all studies.

A systematic review of contemporary phase I trials in patients with lymphoma.

We performed a systematic review of phase I trials specifically designed for lymphoma patients. PubMed and Cochrane Library databases were searched using (lymphoma*) AND (phase 1) and publication date 2015-2020 to identify phase I dose-finding trials including a majority of lymphoma patients. Eighty-two trials (n = 3289 lymphoma patients) were included: 46 (55%) enrolled only lymphoma patients, 34 (41%) included also other hematologic malignancies, 2 (2%) solid tumors. Forty-six trials (56%) evaluated a combination (in 25 addition of experimental drug to standard therapy). Seven trials (9%) enrolled untreated patients. Among trials reporting activity in lymphoma patients, 74% (n = 57) reported an overall response rate ≥ 30%. All trials reported grade ≥ 3 adverse events; however, rates were not comparable across trials. Thirty-one treatment-related deaths in lymphoma patients were reported (overall treatment-related grade 5 adverse events rate 0.94%). Phase I trials designed for lymphoma patients were generally safe and the majority reported overall response rate ≥ 30%.

Cost-Effectiveness of Shortening Treatment Duration Based on Interim PET Outcome in Patients With Diffuse Large B-cell Lymphoma.

BACKGROUND: Guideline recommendations for diffuse large-B-cell lymphoma (DLBCL) treatment are shifting from long to short treatment duration, although it is still unclear whether shortening treatment duration does not cause any harm. As interim PET (I-PET) has high negative predictive value for progression, we evaluated the cost-effectiveness of shortening treatment duration dependent on I-PET result. MATERIALS AND METHODS: We developed a Markov cohort model using the PET Re-Analysis (PETRA) database to evaluate a long treatment duration (LTD) strategy, ie 8x R-CHOP or 6x R-CHOP plus 2 R, and a short treatment duration (STD) strategy, ie 6x R-CHOP. Strategies were evaluated separately in I-PET2 positive and I-PET2 negative patients. Outcomes included total costs and quality-adjusted life-years (QALYs) per patient (pp) from a societal perspective. Net monetary benefit (NMB) per strategy was calculated using a willingness-to-pay threshold of €50,000/QALY. Robustness of model predictions was assessed in sensitivity analyses. RESULTS: In I-PET2 positive patients, shortening treatment duration led to 50.4 additional deaths per 1000 patients. The STD strategy was less effective (-0.161 [95%CI: -0.343;0.028] QALYs pp) and less costly (-€2768 [95%CI: -€8420;€1105] pp). Shortening treatment duration was not cost-effective (incremental NMB -€5281). In I-PET2 negative patients, shortening treatment duration led to 5.0 additional deaths per 1000 patients and a minor difference in effectiveness (-0.007 [95%CI: -0.136;0.140] QALY pp). The STD strategy was less costly (-€5807 [95%CI: -€10,724;-€2685] pp) and led to an incremental NMB of €5449, indicating that it is cost-effective to shorten treatment duration. Robustness of these findings was underpinned by deterministic and probabilistic sensitivity analyses. CONCLUSION: Treatment duration should not be shortened in I-PET2 positive patients whereas it is cost-effective to shorten treatment duration in I-PET2 negative patients.

Optimal timing and criteria of interim PET in DLBCL: a comparative study of 1692 patients.

Interim 18F-fluorodeoxyglucose positron emission tomography (Interim-18F-FDG-PET, hereafter I-PET) has the potential to guide treatment of patients with diffuse large B-cell lymphoma (DLBCL) if the prognostic value is known. The aim of this study was to determine the optimal timing and response criteria for evaluating prognosis with I-PET in DLBCL. Individual patient data from 1692 patients with de novo DLBCL were combined and scans were harmonized. I-PET was performed at various time points during treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Scans were interpreted using the Deauville score (DS) and change in maximum standardized uptake value (ΔSUVmax). Multilevel Cox proportional hazards models corrected for International Prognostic Index (IPI) score were used to study the effects of timing and response criteria on 2-year progression-free survival (PFS). I-PET after 2 cycles (I-PET2) and I-PET4 significantly discriminated good responders from poor responders, with the highest hazard ratios (HRs) for I-PET4. Multivariable HRs for a PET-positive result at I-PET2 and I-PET4 were 1.71 and 2.95 using DS4-5, 4.91 and 6.20 using DS5, and 2.93 and 4.65 using ΔSUVmax, respectively. ΔSUVmax identified a larger proportion of poor responders than DS5 did. For all criteria, the negative predictive value was >80%, and positive predictive values ranged from 30% to 70% at I-PET2 and I-PET4. Unlike I-PET1, I-PET3 discriminated good responders from poor responders using DS4-5 and DS5 thresholds (HRs, 2.94 and 4.67, respectively). I-PET2 and I-PET4 predict good response equally during R-CHOP therapy in DLBCL. Optimal timing and response criteria depend on the clinical context. Good response at I-PET2 is suggested for de-escalation trials, and poor response using ΔSUVmax at I-PET4 is suggested for randomized trials that are evaluating new therapies.

Clinical characteristics and outcome of patients over 60 years with Hodgkin lymphoma treated in Switzerland.

Hodgkin lymphoma (HL) in older patients appears to be a different disease compared with younger patients with historically lower survival rates. This is related to a variety of factors, including increased treatment-related toxicity, the presence of comorbidities, and biologic differences. In order to better assess the clinical characteristics, treatment strategies, and outcome of this particular population, we conducted a population-based, retrospective analysis including 269 patients with HL older than 60 years (median age 71 years, range 60-94), treated between 2000 and 2017 in 15 referral centers across Switzerland. Primary endpoints were overall survival (OS), progression-free survival (PFS), and cause-specific survival (CSS). The vast majority of patients were treated with curative intent, either with a combined modality approach (chemotherapy followed by radiation therapy) or with systemic therapy. At a median follow-up of 6.6 years (95% confidence interval [CI], 6.0-7.6), 5-year PFS was 52.2% (95% CI, 46.0-59.2), 5-year OS was 62.5% (95% CI, 56.4-69.2), and 5-year CSS was 85.1.8% (95% CI, 80.3-90.1) for the entire cohort. A significant difference in terms of CSS was observed for patients older than 71 years in comparison to patients aged 60-70 years (hazard ratio 2.6, 1.3-5.0, p = 0.005). Bleomycin-induced lung toxicity (BLT) was documented in 26 patients (17.7%) out of the 147 patients exposed to this compound and was more frequent in patients older than 71 years (15/60, 25%). Outcome of HL pts older than 71 years appeared to decrease substantially in comparison to the younger counterpart. Treatment-related toxicities appeared to be relevant, in particular, BLT. New, potentially less toxic strategies need to be investigated in prospective clinical trials in this particular frail population.

Methodology of clinical trials evaluating the incorporation of new drugs in the first-line treatment of patients with diffuse large B-cell lymphoma (DLBCL): a critical review.

Background: The first-line treatment of diffuse large B-cell lymphoma (DLBCL) is the combination of rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, curing approximately 60% of patients. Many clinical trials have been carried out over the last 10 years trying to improve the results of this treatment, but the appropriateness of their planning strategies could be rediscussed. Patients and methods: Reports of phase III trials evaluating the addition of molecularly targeted agents or new monoclonal antibodies to the classic R-CHOP backbone in first-line induction or maintenance treatment were reviewed. The trial design, primary end point, number of patients enrolled, patient selection criteria, treatment schedule and results were registered for each one. In addition, the phases I and II trials which preceded these phase III trials were also reviewed. Results: Among six phase III trials with results, only one trial evaluating lenalidomide maintenance after response to R-CHOP induction was positive and reached its primary end point. The other five trials did not show an improved outcome with the addition of the new agent. The preceding phases I and II trials were very heterogeneous in their end points and design. Even though most of these trials were considered positive, thus encouraging further investigation, so far they failed to predict the results of the subsequent phase III trials. Conclusion: The standard of care for DLBCL is still R-CHOP. Phase I/II trials failed to predict the results of subsequent phase III trials evaluating non-chemotherapeutic agents added to R-CHOP. The methodology of phase II trials evaluating new agents in DLBCL needs to be better defined in the future.

Rituximab: a benchmark in the development of chemotherapy-free treatment strategies for follicular lymphomas.

Background: With the introduction of the anti-CD20 antibody rituximab, the outcome of patients with follicular lymphoma (FL) has greatly improved over the last two decades. First-line prolonged rituximab monotherapy is effective, achieving long-term remission and prolonged failure-free survival in some patients. Additionally, rituximab has been shown to synergize with chemotherapeutic and novel targeted agents alike with measurable gains in duration of response. As such, rituximab has made its mark in the treatment of FL and remains a valid agent despite the availability of newer monoclonal antibodies. This review summarizes the evolving role of rituximab as the first available anti-CD20 monoclonal antibody, emphasizing its clear activity as a single agent and in combination with chemotherapy or molecular targeted agents, and setting the standard for the development of new anti-CD20 monoclonal antibodies. Conclusion: We provide data that support the ongoing use of rituximab as a therapeutic partner for novel agents in future clinical trials exploring chemotherapy-free alternatives.

ESMO consensus conference on malignant lymphoma: general perspectives and recommendations for prognostic tools in mature B-cell lymphomas and chronic lymphocytic leukaemia.

The European Society for Medical Oncology (ESMO) consensus conference on mature B-cell lymphomas and chronic lymphocytic leukaemia (CLL) was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (i) the elderly patient, (ii) prognostic factors suitable for clinical use and (iii) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address four clinically relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the four questions assigned to their group. These recommendations were then presented to the entire panel and a consensus was reached. This manuscript presents recommendations dedicated to the second area of interest, i.e. prognostic factors suitable for clinical use. The four topics [i.e. interim positron emission tomography (PET), TP53 mutations, cell of origin (COO) and minimal residual disease (MRD)] were primarily chosen because of the bulk of available data together with the lack of clear guidance regarding their use in clinical practice and within clinical trials. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript. The panel acknowledged that detection of TP53 inactivation by deletion or mutation in CLL should be implemented in clinical practice (level of evidence I, strength of recommendation A). Due to their potentially high prognostic value, at least in some lymphoma entities, implementation of interim PET, COO and MRD was highly recommended in the context of clinical trials. All expert panel members approved this final article.

Combination of the MEK inhibitor pimasertib with BTK or PI3K-delta inhibitors is active in preclinical models of aggressive lymphomas.

BACKGROUND: Lymphomas are among the most common human cancers and represent the cause of death for still too many patients. The B-cell receptor with its downstream signaling pathways represents an important therapeutic target for B-cell lymphomas. Here, we evaluated the activity of the MEK1/2 inhibitor pimasertib as single agent and in combination with other targeted drugs in lymphoma preclinical models. MATERIALS AND METHODS: Cell lines derived mature B-cell lymphomas were exposed to increasing doses of pimasertib alone. Immunoblotting and gene expression profiling were performed. Combination of pimasertib with idelalisib or ibrutinib was assessed. RESULTS: Pimasertib as single agent exerted a dose-dependent antitumor activity across a panel of 23 lymphoma cell lines, although at concentrations higher than reported for solid tumors. Strong synergism was observed with pimasertib combined with the PI3K inhibitor idelalisib and the BTK inhibitor ibrutinib in cell lines derived from diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma. The data were confirmed in an in vivo experiment treating DLBCL xenografts with pimasertib and ibrutinib. CONCLUSION: The data presented here provide the basis for further investigation of regimens including pimasertib in relapsed and refractory lymphomas.

Rituximab and risk of second primary malignancies in patients with non-Hodgkin lymphoma: a systematic review and meta-analysis.

BACKGROUND: Addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy improves response rates and survival in patients with B-cell non-Hodgkin lymphoma (NHL). However, rituximab induces a transient B-cell depletion and a dose-dependent T-cell inactivation that could impair T-cell immunosurveillance. The impact of rituximab on second primary malignancy (SPM) risk remains unclear so far. We thus carried out a systematic review to compare SPM risk among patients treated or not with rituximab. PATIENTS AND METHODS: We retrieved trials from MEDLINE and EMBASE and updated data presented at American Society of Hematology and American Society of Clinical Oncology meetings from 1998 to 2013. We selected randomized, controlled trials addressing newly or relapsed/progressive B-cell NHL in which randomization arms differed only from rituximab administration. Two authors extracted data and assessed the study quality. RESULTS: We analyzed nine trials involving 4621 patients. At a median follow-up of 73 months, a total of 169 SPMs were observed in patients randomized to rituximab compared with 165 SPMs in patients not randomized to rituximab (OR = 0.88; 95% CI 0.66-1.19). The proportion of females, histology subtypes, use of rituximab in first line or in maintenance did not influence SPM risk (P = 0.94, P = 0.80, P = 0.87, P = 0.87, respectively). Cumulative exposure through prolonged administration in trials with rituximab maintenance did not contribute to an increased risk of SPM (P = 0.86). CONCLUSION: Our meta-analysis suggests no SPM predisposition among NHL survivors exposed to rituximab at a median follow-up of 6 years.

Life expectancy of young adults with follicular lymphoma.

BACKGROUND: This study was aimed at investigating the clinical features and outcomes of follicular lymphoma (FL) patients younger than 40 years, which have not been extensively investigated yet. PATIENTS AND METHODS: One hundred and fifty-five patients younger than 40 years were retrospectively studied from a series of 1002 FL patients diagnosed in four different European Oncology Centres (Barcelona, Spain; Bellinzona, Switzerland; London, UK; Novara, Italy) from 1985 to 2010. RESULTS: Patients younger than 40 had a lower incidence of elevated LDH, high beta2-microglobulin, and a high-risk Follicular Lymphoma International Prognostic Index (FLIPI) score, whereas bone marrow involvement and bulky and disseminated lymphadenopathy were more frequent. At a median follow-up of 10 years, younger patients, in comparison with those older than 40, had significantly better overall (OS), cause-specific survival (CSS), and progression-free survival (PFS), with 10-year OS rate of 81% versus 51% (P < 0.0001), 10-year CSS rate of 82% versus 60% (P < 0.0001), and 10-year PFS of 39% versus 24% (P = 0.0098). However, there were no significant CSS and PFS differences in comparison with the patients aged 40-60. In multivariate analysis, having the lymphoma diagnosed in the last two decades and a favourable FLIPI score were associated with a significantly longer PFS and CSS in younger patients, whereas only FLIPI retained statistical significance for OS. CONCLUSIONS: In our series, FL patients younger than 40 have a median OS of 24 years and their outcome seems to be improving over time. However, they still have a significantly shorter life expectancy than that of an age-matched general healthy population.

Histologic transformation in marginal zone lymphomas†.

BACKGROUND: Histologic transformation (HT) is a poorly understood event in patients with marginal zone lymphoma (MZL). The aim of this study was to analyze incidence and risk factors for HT in a large series of MZL patients. PATIENTS AND METHODS: The studied cohort included 340 MZL patients diagnosed and treated between 1995 and 2012: 157 extranodal MZLs [mucosa-associated lymphoid tissue (MALT) lymphoma, 46%], 85 splenic MZLs (SMZLs, 25%) and 37 nodal MZLs (NMZLs, 11%). Sixty-one patients (18%) had bone marrow infiltration at presentation, with or without detectable involvement of peripheral blood, but without other involved sites; they were considered clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ). RESULTS: With a median follow-up of 4.8 years, the median overall survival and progression-free survival of the whole population were 14.5 and 5 years, respectively. HT was observed in 13 cases [3.8%, 95% confidence interval (95% CI) 2%-6.5%]. Elevated lactate dehydrogenase (LDH) at diagnosis was associated with the risk of HT (P = 0.019). HT occurred in 5% of SMZLs, 4% of MALT lymphomas, 3% of NMZLs and 3% of CBL-MZ (P = 0.974). The risk of HT was 5% (95% CI 3-9%) at 5 and 10 years after diagnosis and 10% (95% CI 5%-20%) at 12 years. At the time of HT, most patients had high LDH and B symptoms. At a median follow-up of 12 months after HT, 4 of 13 patients died, all for lymphoma-related causes, with a 2-year post-transformation survival rate of 57% (95% CI 13%-86%). CONCLUSIONS: In this large retrospective series, the risk of HT across all MZL types appeared lower than the one reported for follicular lymphoma.

Genetic lesions in diffuse large B-cell lymphomas.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults, accounting for 35%-40% of all cases. The combination of the anti-CD20 monoclonal antibody rituximab with anthracycline-based combination chemotherapy (R-CHOP, rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone) lead to complete remission in most and can cure more than half of patients with DLBCL. The diversity in clinical presentation, as well as the pathologic and biologic heterogeneity, suggests that DLBCL comprises several disease entities that might ultimately benefit from different therapeutic approaches. In this review, we summarize the current literature focusing on the genetic lesions identified in DLBCL.