Raúl Córdoba

Chronic Lymphocytic Leukemia: A Paradigm of Innate Immune Cross-Tolerance

Infections are a significant cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). The pathogenesis of infections is multifactorial and includes hypogammaglobulinemia, conventional therapy with alkylating drugs, and recently, purine analogs and mAb-associated T cells. Patients without these risk factors also suffer from infections, although the mechanism remains unknown. In a cohort of 70 patients with CLL, we demonstrated that their monocytes were locked into a refractory state and were unable to mount a classic inflammatory response to pathogens. In addition, they exhibited the primary features of endotoxin tolerance, including low cytokine production, high phagocytic activity, and impaired Ag presentation. The involvement of miR-146a in this phenomenon was suspected. We found miR-146a target genes, such as IRAK1 and TRAF6, were manifestly downregulated. Our study provides a new explanation for infections in patients with CLL and describes a cross-tolerance between endotoxins and tumors.

Validation of the NCCN-IPI for diffuse large B-cell lymphoma (DLBCL): the addition of β2 -microglobulin yields a more accurate GELTAMO-IPI.

The study included 1848 diffuse large B‐cell lymphoma (DLBCL)patients treated with chemotherapy/rituximab. The aims were to validate the National Comprehensive Cancer Network International Prognostic Index (NCCN‐IPI) and explore the effect of adding high Beta‐2 microglobulin (β2M), primary extranodal presentation and intense treatment to the NCCN‐IPI variables in order to develop an improved index. Comparing survival curves, NCCN‐IPI discriminated better than IPI, separating four risk groups with 5‐year overall survival rates of 93%, 83%, 67% and 49%, but failing to identify a true high‐risk population. For the second aim the series was split into training and validation cohorts: in the former the multivariate model identified age, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, Stage III‐IV, and β2M as independently significant, whereas the NCCN‐IPI‐selected extranodal sites, primary extranodal presentation and intense treatments were not. These results were confirmed in the validation cohort. The Grupo Español de Linfomas/Trasplante de Médula ósea (GELTAMO)‐IPI developed here, with 7 points, significantly separated four risk groups (0, 1–3, 4 or ≥5 points) with 11%, 58%, 17% and 14% of patients, and 5‐year overall survival rates of 93%, 79%, 66% and 39%, respectively. In the comparison GELTAMO IPI discriminated better than the NCCN‐IPI. In conclusion, GELTAMO‐IPI is more accurate than the NCCN‐IPI and has statistical and practical advantages in that the better discrimination identifies an authentic high‐risk group and is not influenced by primary extranodal presentation or treatments of different intensity.

Two distinct molecular subtypes of chronic lymphocytic leukemia give new insights on the pathogenesis of the disease and identify novel therapeutic targets

Biopsy samples of lymph nodes from 38 patients with CLL were analyzed. We found differential expression in 1092 genes in two different subgroups: 418 overexpressed in one subgroup and 674 in another. Molecular pathways identified in one subgroup appear to be characterized by greater dependence of signaling by cytokines and activation of the NFkB pathway, while in the other seem to depend on cell cycle. Despite having found a differential expression between both subgroups, none of these genes reached FDR < 0.25. We have not found significant association with survival or any prognostic factors. Analysis of the differences between normal lymph node and CLL in 253 genes with difference in the intensity of expression revealed upregulated genes different to BCR: CD40, TCL1, IL-7, and PAX5. Using large-scale molecular analysis, we may obtain information about molecular mechanisms of CLL pathogenesis and may contribute to the identification of new therapeutic targets.

CC-122 immunomodulatory effects in refractory patients with diffuse large B-cell lymphoma

ABSTRACT In the three patients included in a phase I clinical trial (NCT01421524), we report the immunomodulatory effects and efficacy of CC-122, a novel pleiotropic pathway modifier compound originally developed for broad diffuse large B-cell lymphoma (DLBCL). The chemical structure of CC-122 includes the glutarimide moiety that is known to modulate the immune response. The immunomodulatory agents including lenalidomide represent a promising therapeutic strategy targeting tumors in B-cell lymphoid malignancies. We observed that CC-122 might regulate the NK phenotype and its activity due to the reduced accumulation of myeloid-derived suppressor cell and eventually decrease the Tregs subsets. Finally, the activation of T cells through co-stimulatory molecule (CD28) was detected as a delayed CC-122 effect. In this context, CC-122 arises as an alternative option for DLBCL patients refractory to the traditional chemotherapeutic agents.

Ibrutinib as an antitumor immunomodulator in patients with refractory chronic lymphocytic leukemia.

ABSTRACT Ibrutinib has emerged as a promising therapy for patients with chronic lymphocytic leukemia (CLL) who are nonresponsive to standard therapies. The refractory state of monocytes and T-cell exhaustion in patients with CLL could explain the morbidity and mortality reported in these patients. We studied the effect of ibrutinib on the immune response of four relapsed patients with CLL during the first treatment cycle. We observed the ability to recover the standard response against bacterial stimulus in CD14+ cells, improving levels of phospho-Erk1/2 and antigen presentation. Meanwhile, ibrutinib drove Th1-selective pressure in T lymphocytes, thus, reducing the PD-1 and PDL-1 expression. Our data suggest the impact of BTK inhibition along with immunomodulation on the innate immune response and a switch to the specific adaptive immune response, which might help to decrease infectious complications. The potential effect of ibrutinib on CLL patient outcomes is worthy of further study, because infections could be reduced with the use of ibrutinib.

Unilateral uveitis masquerade syndrome caused by diffuse large B‐cell lymphoma diagnosed using multiparametric flow cytometry of the aqueous humor

The uveitis masquerade syndromes (UMS) are a group of ocular diseases that may mimic chronic intraocular inflammation. Many malignant entities such as non‐Hodgkins lymphomas may masquerade as uveitis. We report a case of an HIV‐positive patient with masquerade syndrome presenting unilateral uveitis.

The utility of multiparametric seven‐color flow cytometry in the detection of double hit lymphoma in ascitic fluid samples

Double‐hit lymphoma (DHL) is a rare type of lymphoma with concurrent chromosomal translocations of C‐MYC with BCL2 or BCL6, associated with unfavorable prognosis. We describe a case of DHL in a 79‐year‐old female patient previously diagnosed with diffuse large B‐cell lymphoma (DLBCL) with an early relapse in the ascitic fluid. A seven‐color multiparametric flow cytometry immunophenotyping study of the ascitic fluid was carried out, and revealed 99.78% of large in size and high cellular complexity B‐cells positive for CD19, CD10 (64.27%), CD45 dim, CD22 dim, CD25 (60%), CD43 bright, CD38 bright, and IgM (18.53%); and negative for CD20, CD5, CD23, CD79b, CD103, CD200, CD11c, and FMC7, and 78.99% without light chain expression and 21% with Lambda chain restriction. Due to the expression of CD19 and CD10 with overexpression of BCL‐2 protein and due to CD43 and CD38 positivity detected, those cells showed features between DLBCL and Burkitt lymphoma. Fluorescence in situ hybridization (FISH) confirmed both c‐MYC/IGH and BCL2/IGH rearrangement. Our findings may help to identify cases requiring additional cytogenetic analysis.

A drug–drug interaction study of ibrutinib with moderate/strong CYP3A inhibitors in patients with B-cell malignancies

Abstract This was an open-label, multicenter, phase-1 study to evaluate the drug interaction between steady-state ibrutinib and moderate (erythromycin) and strong (voriconazole) CYP3A inhibitors in patients with B-cell malignancies and to confirm dosing recommendations. During cycle 1, patients received oral ibrutinib 560 mg qd alone (Days 1–4 and 14–18), and ibrutinib 140 mg (Days 5–13; 19–27) plus erythromycin 500 mg tid (Days 5–11) and voriconazole 200 mg bid (Days 19–25). Twenty-six patients (median [range] age: 64.5 [50–88] years) were enrolled. Geometric mean ratio (90% confidence intervals) after co-administration of ibrutinib 140 mg with erythromycin and voriconazole was 74.7 (53.97–103.51) and 143.3 (107.77–190.42), respectively, versus ibrutinib 560 mg alone. The most common (≥20%) adverse events were diarrhea (27%) and neutropenia (23%). The results demonstrate that ibrutinib 140 mg with voriconazole or erythromycin provides exposure within the clinical range for patients with B-cell malignancies.

Differential prognostic impact of GELTAMO-IPI in cell of origin subtypes of Diffuse Large B Cell Lymphoma as defined by the Hans algorithm

The Grupo Español de Linfomas y Trasplantes de Médula Ósea International Prognostic Index (GELTAMO‐IPI) stratifies four risk groups in diffuse large B cell lymphoma (DLBCL) patients treated with immunochaemotherapy: low (LR), low‐intermediate (LIR), high‐intermediate (HIR), and high (HR). The present study explores the effect of GELTAMO‐IPI in the DLBCL subtypes defined by the immunohistochaemistry‐based Hans algorithm, Germinal Centre B (GCB) and non‐GCB. A multivariate Cox regression model including GELTAMO‐IPI risk groups, cell of origin (COO) subtypes and their product was developed to evaluate interaction between the two variables. The COO subtype was available in 839 patients (380 GCB; 459 non‐GCB) and both the GELTAMO‐IPI and the COO subtype in 780 (353 GCB; 427 non‐GCB). There were no differences in 5‐year overall survival (OS) between the two subtypes. The Cox model revealed interaction between the GELTAMO‐IPI risk groups and the COO subtypes (P = 0·005), indicating that GELTAMO‐IPI has a different effect in the two subtypes. Three risk groups were stratified in both COO subtypes: in the GCB subtype, LR, LIR and the combined HIR+HR had 5‐year OS of 100%, 75% and 52%, respectively. In the non‐GCB subtype, LR, the combined LIR+HIR and HR had a 5‐year OS of, 97%, 82% and 35% respectively. GELTAMO‐IPI identifies a genuine poor outcome group of patients in the DLBCL non‐GCB subtype.

A new prognostic model identifies patients aged 80 years and older with diffuse large B-cell lymphoma who may benefit from curative treatment: A multicenter, retrospective analysis by the Spanish GELTAMO group

The means of optimally managing very elderly patients with diffuse large B‐cell lymphoma (DLBCL) has not been established. We retrospectively analyzed 252 patients aged 80‐100 years, diagnosed with DLBCL or grade 3B follicular lymphoma, treated in 19 hospitals from the GELTAMO group. Primary objective was to analyze the influence of the type of treatment and comorbidity scales on progression‐free survival (PFS) and overall survival (OS). One hundred sixty‐three patients (63%) were treated with chemotherapy that included anthracyclines and/or rituximab, whereas 15% received no chemotherapeutic treatment. With a median follow‐up of 44 months, median PFS and OS were 9.5 and 12.5 months, respectively. In an analysis restricted to the 205 patients treated with any kind of chemotherapy, comorbidity scales did not influence the choice of treatment type significantly. Independent factors associated with better PFS and OS were: age < 86 years, cumulative illness rating scale (CIRS) score < 6, intermediate risk (1‐2) R‐IPI, and treatment with R‐CHOP at full or reduced doses. We developed a prognostic model based on the multivariate analysis of the 108 patients treated with R‐CHOP‐like: median OS was 45 vs. 12 months (P = .001), respectively, for patients with 0‐1 vs. 2‐3 risk factors (age > 85 years, R‐IPI 3‐5 or CIRS > 5). In conclusion, treatment with R‐CHOP‐like is associated with good survival in a significant proportion of patients. We have developed a simple prognostic model that may aid the selection patients who could benefit from a curative treatment, although it needs to be validated in larger series.