CD8+ NKs as a potential biomarker of complete response and survival with lenalidomide plus R-GDP in the R2-GDP-GOTEL trial in recurrent/refractory diffuse large B cell lymphoma.

Background: Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma worldwide. DLBCL is an aggressive disease that can be cured with upfront standard chemoimmunotherapy schedules. However, in approximately 35-40% of the patients DLBCL relapses, and therefore, especially in this setting, the search for new prognostic and predictive biomarkers is an urgent need. Natural killer (NK) are effector cells characterized by playing an important role in antitumor immunity due to their cytotoxic capacity and a subset of circulating NK that express CD8 have a higher cytotoxic function. In this substudy of the R2-GDP-GOTEL trial, we have evaluated blood CD8+ NK cells as a predictor of treatment response and survival in relapsed/refractory (R/R) DLBCL patients. Methods: 78 patients received the R2-GDP schedule in the phase II trial. Blood samples were analyzed by flow cytometry. Statistical analyses were carried out in order to identify the prognostic potential of CD8+ NKs at baseline in R/R DLBCL patients. Results: Our results showed that the number of circulating CD8+ NKs in R/R DLBCL patients were lower than in healthy donors, and it did not change during and after treatment. Nevertheless, the level of blood CD8+ NKs at baseline was associated with complete responses in patients with R/R DLBCL. In addition, we also demonstrated that CD8+ NKs levels have potential prognostic value in terms of overall survival in R/R DLBCL patients. Conclusion: CD8+ NKs represent a new biomarker with prediction and prognosis potential to be considered in the clinical management of patients with R/R DLBCL. Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001620-29 EudraCT, ID:2014-001620-29.

Lenalidomide plus R-GDP (R2-GDP) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Final Results of the R2-GDP-GOTEL Trial and Immune Biomarker Subanalysis.

PURPOSE: New therapeutic options are needed in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Lenalidomide-based schedules can reverse rituximab refractoriness in lymphoma. PATIENTS AND METHODS: In the phase II R2-GDP trial, 78 patients unsuitable for autologous stem cell transplant received treatment with the following schedule: lenalidomide 10 mg Days (D)1-14, rituximab 375 mg/m2 D1, cisplatin 60 mg/m2 D1, gemcitabine 750 mg/m2 D1 and D8, and dexamethasone 20 mg D1-3, up to 6 cycles (induction phase), followed by lenalidomide 10 mg (or last lenalidomide dose received) D1-21 every 28 days (maintenance phase). Primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and monitorization of key circulating immune biomarkers (EU Clinical Trials Register number: EudraCT 2014-001620-29). RESULTS: After a median follow-up of 37 months, ORR was 60.2% [37.1% complete responses (CR) and 23.1% partial responses (PR)]. Median OS was 12 months (47 vs. 6 months in CR vs. no CR); median PFS was 9 months (34 vs. 5 months in CR vs. no CR). In the primary refractory population, ORR was 45.5% (21.2% CR and 24.3% PR). Most common grade 3-4 adverse events were thrombocytopenia (60.2%), neutropenia (60.2%), anemia (26.9%), infections (15.3%), and febrile neutropenia (14.1%). Complete responses were associated with a sharp decrease in circulating myeloid-derived suppressor cells and regulatory T cells. CONCLUSIONS: R2-GDP schedule is feasible and highly active in R/R DLBCL, including the primary refractory population. Immune biomarkers showed differences in responders versus progressors.

Real-World Characteristics and Outcome of Patients Treated With Single-Agent Ibrutinib for Chronic Lymphocytic Leukemia in Spain (IBRORS-LLC Study).

BACKGROUND: Ibrutinib demonstrated remarkable efficacy and favorable tolerability in patients with untreated or relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including those with high-risk genetic alterations. The IBRORS-CLL study assessed the characteristics, clinical management and outcome of CLL patients receiving ibrutinib in routine clinical practice in Spain. PATIENTS: Observational, retrospective, multicenter study in CLL patients who started single-agent ibrutinib as first-line treatment or at first or second relapse between January 2016 and January 2019. RESULTS: A total of 269 patients were included (median age: 70.9 years; cardiovascular comorbidity: 55.4%, including hypertension [47.6%] and atrial fibrillation [AF] [7.1%]). Overall, 96.7% and 69% of patients underwent molecular testing for del(17p)/TP53 mutation and IGHV mutation status. High-risk genetic features included unmutated IGHV (79%) and del(17p)/TP53 mutation (first-line: 66.3%; second-line: 23.1%). Overall, 84 (31.2%) patients received ibrutinib as first-line treatment, and it was used as second- and third-line therapy in 121 (45.0%) and 64 (23.8%) patients. The median progression-free survival and overall survival were not reached irrespective of del(17p)/TP53, or unmutated IGHV. Common grade ≥3 adverse events were infections (12.2%) and bleeding (3%). Grade ≥3 AF occurred in 1.5% of patients. CONCLUSION: This real-world study shows that single-agent ibrutinib is an effective therapy for CLL, regardless of age and high-risk molecular features, consistent with clinical trials. Additionally, single-agent ibrutinib was well tolerated, with a low rate of cardiovascular events. This study also emphasized a high molecular testing rate of del(17p)/TP53 mutation and IGHV mutation status in clinical practice according to guideline recommendations.

Circulating myeloid-derived suppressor cells and regulatory T cells as immunological biomarkers in refractory/relapsed diffuse large B-cell lymphoma: translational results from the R2-GDP-GOTEL trial.

BACKGROUND: The search for immunological markers with ability of predicting clinical outcome is a priority in lymphomas, and in cancer in general. It is well known that some immunomodulatory cells, such as myeloid derived suppressor cells (MDSCs) or regulatory T cells (Tregs), are recruited by tumors, jeopardizing antitumor immunosurveillance. In this work, we have studied blood levels of these immunosuppressive cells in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), prior to and along the course of the experimental rituximab, gemcitabine, dexamethasone, and cisplatin (R2-GDP) schedule, as a translational substudy of the R2-GDP-GOTEL trial (EudraCT Number: 2014-001620-29), which included lenalidomide as an immunomodulator. METHODS: Blood samples were taken before treatment, at cycle 3 and end of induction. Samples were analyzed by flow cytometry. Non-parametric tests were used. Mann-Whitney U test was used to compare basal cells distributions, and Wilcoxon test was considered to compare cells distribution at different times. Spearman test was performed to measure the degree of association between cell populations. RESULTS: In this study, MDSC and Treg circulating concentration was found increased in all patients compared with a healthy control group and decreased after treatment only in patients with longest overall survival (>24 months), reaching the levels of the healthy group. Likewise, the number of inhibited T lymphocytes expressing Programmed Death-1 (PD-1) were increased in peripheral blood from patients and decreased on the treatment, whereas activated T lymphocytes increased after therapy in those with better overall survival. CONCLUSIONS: In conclusion, blood concentration of MDSCs and Treg cells may be good prognostic markers for overall survival after 2 years in R/R DLBCL. These results point to a possible role of these elements in the immunosuppression of these patients, as assessed by the circulating activated and inhibited T lymphocytes, and therefore, they may be considered as therapeutic targets in DLBCL.

R-COMP versus R-CHOP as first-line therapy for diffuse large B-cell lymphoma in patients ≥60 years: Results of a randomized phase 2 study from the Spanish GELTAMO group.

The use of non-pegylated liposomal doxorubicin (Myocet® ) in diffuse large B-cell lymphoma (DLBCL) has been investigated in retrospective and single-arm prospective studies. This was a prospective phase 2 trial of DLBCL patients ≥60 years old with left ventricular ejection fraction (LVEF) ≥55% randomized to standard R-CHOP or investigational R-COMP (with Myocet® instead of conventional doxorubicin). The primary end point was to evaluate the differences in subclinical cardiotoxicity, defined as decrease in LVEF to <55% at the end of treatment. Secondary objectives were efficacy, safety, and variations of troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and LVEF along follow-up. Ninety patients were included, 45 in each group. No differences were observed in the percentage of patients with LVEF <55% at end of treatment (11% in R-CHOP arm vs. 7% in R-COMP arm, p = 0.697) or at 4 months (10% vs. 6%, respectively, p = 0.667) and 12 months (8% vs. 7%, respectively, p = 1). However, a higher percentage of R-CHOP compared with R-COMP patients showed increased troponin levels in cycle 6 (100% vs. 63%, p = 0.001) and at 1 month after treatment (88% vs. 56%, respectively, p = 0.015). Cardiovascular adverse events were seen in five R-CHOP patients (nine episodes, four grade ≥3) and in four R-COMP patients (five episodes, all grade 1-2). No significant differences in efficacy were observed. In conclusion, R-COMP is a feasible immunochemotherapy schedule for DLBCL patients ≥60 years, with similar efficacy to R-CHOP. However, the use of non-pegylated doxorubicin instead of conventional doxorubicin was not associated with less early cardiotoxicity, although some reduced cardiac safety signals were observed. Trial registration: ClinicalTrials.gov Identifier: NCT02012088.

Survival outcomes of patients with extranodal natural-killer T-cell lymphoma: a prospective cohort study from the international T-cell Project.

BACKGROUND: Extranodal natural killer (NK) T-cell lymphoma (ENKTL) is a unique clinicopathological entity, typically associated with poor survival outcomes. Most published data have come from east Asian study groups, with little information available from international cohorts. The effects of treatment advances on routine clinical practice across continental territories has not been clear. We aimed to improve understanding of the clinical characteristics and outcomes of patients with ENKTL. METHODS: We did a substudy of patients with ENKTL from the T-cell Project, a global prospective cohort study. The T-cell Project registered consecutively diagnosed adults (>18 years) with newly diagnosed, untreated mature T-cell or NK lymphomas (WHO 2001 or 2008 classifications) from 74 centres in 13 countries (in Asia, Europe, North America, and South America). In total, 1695 patients with mature T-cell or NK lymphomas were enrolled between Oct 12, 2006 and Feb 28, 2018 in the T-cell Project. The first patient with ENKTL was enrolled on Feb 15, 2007, and the last on May 26, 2017. Data on baseline characteristics, first-line treatment, treatment response, and survival outcomes were recorded in a central database (locked March 30, 2019). The primary outcome was 5-year overall survival. The T-cell Project is registered on ClinicalTrials.gov, NCT01142674. FINDINGS: 166 patients were diagnosed with ENKTL, comprising 11% of 1553 eligible registered cases and distributed across 40 participating centres in four continents. At a median follow-up of 44 months (IQR 20-61), overall survival at 5 years was 54% (95% CI 44-63) in patients with nasal disease (n=98) and 34% (27-46) in patients with extranasal disease (n=68). INTERPRETATION: To our knowledge, this study presents the largest international cohort of patients with ENKTL. We describe a clinically significant improvement in the survival of patients with ENKTL treated in routine clinical practice over the past decade, likely to be attributable to the increasing use of treatment protocols specific for ENKTL. FUNDING: The Fondazione Cassa di Risparmio di Modena, the Associazione Angela Serra per la Ricerca sul Cancro, the Fondazione Italiana Linfomi, Allos Therapeutics, Spectrum Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro, and the National Cancer Institute at the National Institutes of Health.

Refractoriness to immunochemotherapy in follicular lymphoma: Predictive factors and outcome.

Follicular lymphoma is characterized by a good response to immunochemotherapy (ICT). However, a small percentage of patients responds poorly to treatment and seems to have a worse outcome. This study attempted to identify the predictive factors and outcome of refractoriness to first-line ICT. All patients diagnosed with stage II to IV follicular lymphoma between 2002 and 2014 and treated with first-line ICT in 4 Spanish institutions were analyzed. Those with no response or progression or relapse within 6 months of first-line response assessment were considered ICT refractory. Three hundred forty-three patients were included (median age 58 years, 48% male), of whom 53 (15%) were ICT refractory. On multivariate analysis, high-risk follicular lymphoma international prognostic index (FLIPI) score, B symptoms, and elevated ß2-microglobulin were correlated with refractoriness, and refractoriness, high-risk FLIPI score, and ß2-microglobulin were correlated with overall survival (OS). Compared with ICT-sensitive, ICT-refractory patients had a higher incidence of histological transformation (5-year cumulative incidence 25% [14%-39%] vs. 6% [3%-10%], P < .001), a higher rate of refractoriness to second-line therapy (16/33 [48%] vs. 13/57 [23%], P = .01), and a lower OS (5-year OS probability 38% [95% CI 23%-53%] vs. 87% [82%-92%%], P < .001). In conclusion, refractoriness to ICT was seen in 15% of patients and was predicted by high-FLIPI scores, B symptoms, and elevated serum ß2-micrglobulin. Immunochemotherapy-refractory patients had a worse prognosis than ICT-sensitive patients, and current treatment options for this subgroup are not satisfactory.

[Plasmablastic lymphoma]. / Linfoma plasmablástico.

Plasmablastic lymphoma (PBL) is a rare and aggressive subtype of non-Hodgkin lymphoma that commonly occurs in human immunodeficiency virus (HIV)-positive individuals, and affects oral sites. Occasionally, it has been described in HIV-negative patients and involving non-oral sites. Pathologically, PBL is a high-grade B-cell lymphoma that displays the immunophenotype of a terminally differentiated B-lymphocyte with loss of B-cell markers (CD20) and expression of plasma-cell antigens. Epstein-Barr virus infection and MYC rearrangements are frequently observed. Treatment of PBL is challenging because of the lack of established treatment and poor outcomes, with median survival times shorter than one year. In this review, we discuss the clinical and epidemiologic spectrum of PBL as well as its distinct pathological features. Finally, we summarize the currently available approaches for the treatment of patients with PBL.

The long term follow-up of early stage follicular lymphoma treated with radiotherapy, chemotherapy or combined modality treatment.

Local (involved-field or recently involved-site) radiotherapy is the standard therapy in limited-stage follicular lymphoma (FL). We retrospectively analyzed the value of chemotherapy in 130 patients with limited-stage FL (46 treated with radiotherapy alone [RT group], 30 with radiotherapy plus chemotherapy [COMBINED group] and 43 with chemotherapy alone [CHEMO group], 11 were managed with observation). Ninety-six percent of patients responded (RT 98%, COMBINED 100%, CHEMO 91%, p=0.179), and 37% (40/107) of patients in complete response relapsed (RT 42%, COMBINED 27%, CHEMO 41%, p=0.371). Progression-free survival (PFS) and overall survival (OS) probabilities at 10 years were similar in RT, COMBINED and CHEMO patients (PFS 41%, 61% and 39% [p=0.167], and OS 77%, 81% and 72% [p=0.821], respectively), while the COMBINED group showed a trend to better time-to-progression (TTP 43%, 72% and 47% [p=0.055]). On multivariate analysis, only a FLIPI score ≥2 showed a trend to influence PFS (HR 2.1 [95% confidence interval 0.9-4.6], p=0.067), and OS (HR 2.4 [0.9-6.5], p=0.084), while patients treated with radiotherapy plus chemotherapy (COMBINED group) showed a significantly better TTP compared with those receiving only RT (HR 0.3 [0.1-0.8], p=0.024). In our study no benefit was observed in survival with the use of systemic therapy compared with local radiotherapy.

Serum ferritin as prognostic marker in classical Hodgkin lymphoma treated with ABVD-based therapy.

Ferritin levels might correlate with disease activity in classical Hodgkin lymphoma (cHL). We analyzed the prognostic significance of the ferritin value at diagnosis in 173 cHL patients treated with ABVD between 2003 and 2013. The 5-year overall survival (OS) and progression-free survival (PFS) probabilities were 80% and 64%, respectively. Patients with ferritin ≥ 350 µg/l [high ferritin group (HF), n = 62] were more likely to have advanced stage disease, B-symptoms and higher International Prognostic Score (IPS) compared with patients with ferritin < 350 µg/l [low ferritin group (LF), n = 111]. The complete remission (CR) rate and 5-year PFS and OS probabilities were lower in HF vs. LF patients (69% vs. 89%, p = 0.025; 40% vs. 78%, p < 0.001; 61% vs. 90%, p = 0.001; respectively). Multivariate analysis revealed that advanced stage (p = 0.001) and ferritin levels ≥ 350 µg/l (p = 0.002) were independent predictors for PFS. In conclusion, the ferritin level at diagnosis is a useful prognostic marker for cHL.

Lymphomatoid granulomatosis of central nervous system and lung driven by epstein barr virus proliferation: successful treatment with rituximab-containing chemotherapy.

Lymphomatoid granulomatosis (LYG) is a very rare Epstein-Barr virus (EBV) associated B-cell lymphoproliferative disorder. We report the case of a 41-year-old man who presented with fever and respiratory symptoms. Computed tomography showed multiple nodules in both lung fields. Polymerase chain reaction (PCR) analysis for EBV was positive in bronchoalveolar lavage and biopsy of lung node yielded a diagnosis of LYG, grade III. Shortly after initiation of treatment with agressive chemotherapy, neurological deterioration appeared. Neuroimaging findings revealed hydrocephalus and PCR analysis of the cerebrospinal fluid (CSF) was positive for EBV. Treatment with intravenous rituximab led to rapid reduction of EBV load in CSF, along with clinical and radiological improvement. After completion of treatment with immunochemotherapy, an autologous stem cell transplantation was performed. Patient stays in remission 18 months after diagnosis.