Sequence analyses of relapsed or refractory diffuse large B-cell lymphomas unravel three genetic subgroups of patients and the GNA13 mutant as poor prognostic biomarker, results of LNH-EP1 study.

Advances in molecular profiling of newly diagnosed diffuse large B-cell lymphoma (DLBCL) have recently refine genetic subgroups. Genetic subgroups remain undetermined at the time of relapse or refractory (RR) disease. This study aims to decipher genetic subgroups and search for prognostic molecular biomarkers in patients with RR-DLBCL. From 2015 to 2021, targeted next-generation sequencing analyses of germline-matched tumor samples and fresh tissue from RR-DLBCL patients were performed. Unsupervised clustering of somatic mutations was performed and correlations with patient outcome were sought. A number of 120 patients with RR-DLBCL were included in LNH-EP1 study and a molecular tumor landscape was successfully analyzed in 87% of patients (104/120 tumor samples). The median age was 67.5 years (range 27.4-87.4), median number of previous treatments was 2 (range 1-9). The most frequently mutated genes were TP53 (n = 53 mutations; 42% of samples), CREBBP (n = 39; 32%), BCL2 (n = 86; 31%), KMT2D (n = 39; 28%) and PIM1 (n = 54; 22%). Unsupervised clustering separated three genetic subgroups entitled BST (enriched in BCL2, SOCS1, and TNFRSF14 mutations); TKS (enriched in TP53, KMT2D, and STAT6 mutations); and PCM (enriched in PIM1, CD79B, and MYD88 mutations). Median overall survival (OS) was 11.0 (95% confidence interval [CI]: 8.1-12.6) months. OS was not significantly different between the three genetic subgroups. GNA13 mutant was significantly associated with an increased risk of death (hazard ratio: 6.6 [95% CI: 2.1-20.6]; p = .0011) and shorter OS (p = .0340). At the time of relapse or refractory disease, three genetic subgroups of DLBCL patients were delineated, which could help advance precision molecular medicine programs.

Reduced frequency of cytotoxic CD56dim CD16+ NK cells leads to impaired antibody-dependent degranulation in EBV-positive classical Hodgkin lymphoma.

Around 30-50% of classical Hodgkin lymphoma (cHL) cases in immunocompetent individuals from industrialized countries are associated with the B-lymphotropic Epstein-Barr virus (EBV). Although natural killer (NK) cells exhibit anti-viral and anti-tumoral functions, virtually nothing is known about quantitative and qualitative differences in NK cells in patients with EBV+ cHL vs. EBV- cHL. Here, we prospectively investigated 36 cHL patients without known immune suppression or overt immunodeficiency at diagnosis. All 10 EBV+ cHL patients and 25 out 26 EBV- cHL were seropositive for EBV antibodies, and EBV+ cHL patients presented with higher plasma EBV DNA levels compared to EBV- cHL patients. We show that the CD56dim CD16+ NK cell subset was decreased in frequency in EBV+ cHL patients compared to EBV- cHL patients. This quantitative deficiency translates into an impaired CD56dim NK cell mediated degranulation toward rituximab-coated HLA class 1 negative lymphoblastoid cells in EBV+ compared to EBV- cHL patients. We finally observed a trend to a decrease in the rituximab-associated degranulation and ADCC of in vitro expanded NK cells of EBV+ cHL compared to healthy controls. Our findings may impact on the design of adjunctive treatment targeting antibody-dependent cellular cytotoxicity in EBV+ cHL.

Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19.

Anti-CD20 monoclonal antibodies are widely used for the treatment of hematological malignancies or autoimmune disease but may be responsible for a secondary humoral deficiency. In the context of COVID-19 infection, this may prevent the elicitation of a specific SARS-CoV-2 antibody response. We report a series of 17 consecutive patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms, negative immunoglobulin G (IgG)-IgM SARS-CoV-2 serology, and positive RNAemia measured by digital polymerase chain reaction who were treated with 4 units of COVID-19 convalescent plasma. Within 48 hours of transfusion, all but 1 patient experienced an improvement of clinical symptoms. The inflammatory syndrome abated within a week. Only 1 patient who needed mechanical ventilation for severe COVID-19 disease died of bacterial pneumonia. SARS-CoV-2 RNAemia decreased to below the sensitivity threshold in all 9 evaluated patients. In 3 patients, virus-specific T-cell responses were analyzed using T-cell enzyme-linked immunospot assay before convalescent plasma transfusion. All showed a maintained SARS-CoV-2 T-cell response and poor cross-response to other coronaviruses. No adverse event was reported. Convalescent plasma with anti-SARS-CoV-2 antibodies appears to be a very promising approach in the context of protracted COVID-19 symptoms in patients unable to mount a specific humoral response to SARS-CoV-2.

Ibrutinib as a treatment of hematologic autoimmune disorders in patients with indolent B-cell lymphoma.

BACKGROUND: Autoimmune conditions in B-cell lymphomas are frequent. Steroids are standard of care, but many patients require other immunosuppressive agents. Ibrutinib is a Bruton Tyrosine Kinase inhibitor that is approved for B-cell indolent lymphoma treatment. We evaluated the use of ibrutinib in previously treated hematologic immune manifestations associated with B-cell lymphomas. RESULTS: We conducted a retrospective multicentric observational study. Patients presenting with active, relapsed/refractory B-cell lymphoma associated hematological immune manifestation (autoimmune cytopenia, acquired immune-mediated bleeding disorders) were included. Twenty-five patients were identified. Median age at ibrutinib introduction was 69 years (range 44-84) and median number of previous treatment lines before ibrutinib was 2 (1-7). Twenty-two patients (88%) were on concomitant stable treatment at inclusion. Within a median exposure of 8 months (2-35), overall response rate to ibrutinib on immune manifestations was 76% (95% CI, 54.9-90.6); complete response rate 44%. Fourteen patients (63%) were able to be weaned from concomitant treatments. Fourteen patients (56%) presented treatment-related adverse events, mostly Grade 1 or 2. CONCLUSIONS: Ibrutinib in this setting provides good efficacy and safety profile. Clinical trials are needed to define subgroups of patients who will benefit from this strategy and establish its place in the therapeutic arsenal.

Impact of age, functional status, and comorbidities on quality of life and outcomes in elderly patients with AML: review.

The incidence of acute myeloid leukemia increases with age, and more than half of AML patients are over 60 years old. Treating elderly AML patients presents several challenges and uncertainties, linked partly to disease characteristics and partly to the difficulty of establishing which patients could benefit from the best treatment. Although some elderly fit patients can receive intensive therapy, many of them are not treated and not enrolled in clinical trials. Yet supportive care is associated with significantly lower survival rates compared to intensive therapy or lower intensive therapy. A poorer prognosis in elderly patients is related to age, functional status, and comorbidities, combined with leukemia characteristics. Chronological age is not the best surrogate factor for selecting patients eligible for intensive chemotherapy. Scoring systems-including patient characteristics (ECOG, comorbidities) and disease characteristics (cytogenetics and molecular parameters)-designed to evaluate probabilities of response to treatment, morbidity, and survival may be used to balance the risk-benefit ratio for intensive therapy. A geriatric assessment (GA) to evaluate physical function, comorbidities, nutritional status, cognitive function, and social support could help identify the most vulnerable patients so that they can receive intensive therapy. A GA would also help take the necessary steps to improve tolerance to treatment. Evaluating markers of fitness and quality of life as part of clinical trials should be favored.

Attenuated cytarabine, etoposide, dexamethasone plus rituximab (R-Mini-CYVE) regimen for patients with relapsed or refractory B-cell non-Hodgkin's lymphoma not eligible for intensive chemotherapy.

OBJECTIVES: To evaluate the efficacy and tolerability of an attenuated immunochemotherapy regimen based on cytarabine, etoposide and dexamethasone plus rituximab (R-mini-CYVE) in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). METHODS: We included pretreated adult patients with B-cell NHL who were ineligible for high-dose immunochemotherapy (HDT). Cytarabine and etoposide were given at four different dose levels, depending on the patient's frailty. Up to 8 cycles were administered. RESULTS: Between 2013 and 2019, 56 patients with diffuse large B-cell lymphoma (n = 45, 80%) and indolent B-cell lymphoma (n = 11, 20%) were included. Median age was 75 (range: 36-88). Nineteen patients (35%) had a performance status ≥2. Patients received a median of 4 cycles of R-mini-CYVE. The objective response and the complete response rates were 50% and 33%, respectively. Median progression-free survival and overall survival times were 5.7 (95% CI: 0.5-10.9) and 14.7 (95% CI: 3.5-25.9) months, respectively. Grade ≥3 anaemia, thrombocytopenia and neutropenia occurred in 44%, 55% and 60% of the patients, respectively. The most frequent non-haematological grade ≥3 adverse events were sepsis (21%), fatigue (13%) and cytarabine-related neurotoxicity (5%). CONCLUSION: R-mini-CYVE demonstrated a meaningful antitumour efficacy and an acceptable safety profile in patients with relapsed/refractory B-cell NHL who were ineligible for HDT.

Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib.

Ibrutinib has revolutionized the management of chronic lymphocytic leukemia and is now being increasingly used. Although considered to be less immunosuppressive than conventional immunochemotherapy, the observation of a few cases of invasive fungal infections in patients treated with ibrutinib prompted us to conduct a retrospective survey. We identified 33 cases of invasive fungal infections in patients receiving ibrutinib alone or in combination. Invasive aspergillosis (IA) was overrepresented (27/33) and was associated with cerebral localizations in 40% of the cases. Remarkably, most cases of invasive fungal infections occurred with a median of 3 months after starting ibrutinib. In 18/33 cases, other conditions that could have contributed to decreased antifungal responses, such as corticosteroids, neutropenia, or combined immunochemotherapy, were present. These observations indicate that ibrutinib may be associated with early-onset invasive fungal infections, in particular IA with frequent cerebral involvement, and that patients on ibrutinib should be closely monitored in particular when other risk factors of fungal infections are present.

Ibrutinib induces multiple functional defects in the neutrophil response against Aspergillus fumigatus.

The Bruton tyrosine kinase inhibitor ibrutinib has become a leading therapy against chronic lymphoid leukemia. Recently, ibrutinib has been associated with the occurrence of invasive fungal infections, in particular invasive aspergillosis. The mechanisms underlying the increased susceptibility to fungal infections associated with exposure to ibrutinib are currently unknown. Innate immunity, in particular polymer-phonuclear neutrophils, represents the cornerstone of anti-Aspergillus immunity; however, the potential impact of ibrutinib on neutrophils has been little studied. Our study investigated the response to Aspergillus fumigatus and neutrophil function in patients with chronic lymphoid leukemia or lymphoma, who were undergoing ibrutinib therapy. We studied the consequences of ibrutinib exposure on the functions and anti-Aspergillus responses of neutrophils obtained from healthy donors and 63 blood samples collected at different time points from 32 patients receiving ibrutinib for lymphoid malignancies. We used both flow cytometry and video-microscopy approaches to analyze neutrophils' cell surface molecule expression, cytokine production, oxidative burst, chemotaxis and killing activity against Aspergillus Ibrutinib is associated, both in vitro and in patients under treatment, with multiple functional defects in neutrophils, including decreased production of reactive oxygen species, impairment of their capacity to engulf Aspergillus and inability to efficiently kill germinating conidia. Our results demonstrate that ibrutinib-exposed neutrophils develop significant functional defects that impair their response against Aspergillus fumigatus, providing a plausible explanation for the emergence of invasive aspergillosis in ibrutinib-treated patients.

High-dose cyclophosphamide for hard-to-treat patients with relapsed or refractory B-cell non-Hodgkin's lymphoma, a phase II result.

BACKGROUND: High-dose cyclophosphamide to treat solid refractory tumors demonstrated meaningful activity, while data to treat lymphoma remain scarce. This study aims to assess high-dose cyclophosphamide to treat relapsed or refractory lymphoma. METHODS: A phase II study included adult patients with relapsed or refractory B-cell non-Hodgkin's lymphoma, previously treated by ≥2 prior lines with no other available option of therapy. High-dose cyclophosphamide was given intravenously 3 g/m2 over two consecutive days and repeated once at 28 days in responding patients. Rituximab 375 mg/m2 intravenously was added in patients not refractory to anti-CD20 antibody. RESULTS: Forty-two patients with median age 65 [56-70] years were included. Patients had previously received a median of four lines of therapies. Tumor types were diffuse large B-cell lymphoma (n = 26; 62%), indolent B-cell non-Hodgkin lymphoma (n = 10; 24%), or mantle lymphoma (n = 6; 14%). Hematologic and non-hematologic grade 3-5 toxicities occurred in 42 (100%) and 18 (43%) of patients, respectively. The overall response rate was 45%. CONCLUSION: One to two cycles of high-dose cyclophosphamide in hard-to-treat patients with relapsed or refractory B-cell non-Hodgkin lymphoma demonstrated a favorable safety and efficacy profile. This regimen could serve as a bridge to modern cellular therapy with CAR-T cell.

Outcomes and prognostic factors for relapsed or refractory lymphoma patients in phase I clinical trials.

Background Although safety and prognostic factors for overall survival (OS) have been extensively studied in Phase I clinical trials on patients with solid tumours, data on lymphoma trials are scarce. Here, we investigated safety, outcomes and prognostic factors in relapsed or refractory lymphoma patients included in a series of Phase I trials. Method and patients All consecutive adult patients with recurrent/refractory lymphoma enrolled in 26 Phase I trials at a single cancer centre in France between January 2008 and June 2016 were retrospectively assessed. Results 133 patients (males: 65%) were included in the analysis. The median (range) age was 65 (23-86). Aggressive non-Hodgkin, indolent non-Hodgkin and Hodgkin types accounted for 64%, 25% and 11% of the patients, respectively. The patients had received a median (range) of 3 (1-13) lines of treatment prior to trial entry. The median [95% confidence interval] progression-free survival and OS times were 3.0 [1.8-3.6] and 17.8 [12.7-30.4] months, respectively. High-grade toxicity (grade 3 or higher, according to the National Cancer Institute's Common Terminology Criteria for Adverse Events classification) was experienced by 56 of the 133 patients (42%) and was related to the investigational drug in 44 of these cases (79%). No toxicity-related deaths occurred. Dose-limiting toxicity (DLT) was encountered in 11 (9%) of the 116 evaluable patients. High-grade toxicity occurred during the DLT period for 34 of the 56 patients (61%) and after the DLT period in the remaining 22 (39%). The main prognostic factors for poor OS were the histological type (i.e. tumour aggressiveness), an elevated serum LDH level, and a low serum albumin level. Early withdrawal from a trial was correlated with the performance status score, the histological type and the serum LDH level. The overall objective response and disease control rates were 24% and 57%, respectively. Conclusion Performance status, LDH, albumin and histological type (tumour aggressiveness) appear to be the most relevant prognostic factors for enrolling Phase I participants with relapsed or refractory lymphoma. 39% of the patients experienced a first high-grade toxic event after the dose-limiting toxicity period, suggesting that the conventional concept of dose-limiting toxicity (designed for chemotherapy) should be redefined in the era of modern cancer therapies.

Ibrutinib-Induced Neutrophilic Dermatosis.

We report the case of a 64-year-old woman treated with ibrutinib for a chronic lymphocytic leukemia with 17p deletion, who developed several erythematous, painful, and papulo-nodular skin lesions in the limbs, neck, and face. The skin biopsy was consistent with the diagnosis of neutrophilic dermatosis. Rechallenge with ibrutinib at full dose was followed by the recurrence of the same skin lesions, strongly suggesting a direct relationship.

Poor predictive value of positive interim FDG-PET/CT in primary mediastinal large B-cell lymphoma.

PURPOSE: Though commonly used to assess response to therapy, the prognostic value of interim FDG-PET/CT in Primary Mediastinal Large B-cell Lymphoma (PMBCL) is unclear. METHODS: We conducted a retrospective study on 36 consecutive patients treated at our institution for a PMBCL between 2006 and 2014. All patients with a positive interim FDG-PET/CT had undergone histological restaging consisting either in a surgical debulking of the residual lesion (15 patients) or a CT-guided core needle biopsy (two patients). All FDG-PET/CT were secondarily reviewed according to the more recent Deauville criteria. RESULTS: Interim FDG-PET/CT was considered positive in 17/36 patients using visual evaluation. Among these patients, 14 had a Deauville score of 4. Histological restaging was negative in all but one case, showing inflammation and/or fibrosis. After a median follow-up of 48.5 months, a total of five patients have relapsed, two patients in the positive FDG-PET/CT group, and three patients in the negative FDG-PET/CT group, respectively. CONCLUSIONS: These data indicate that a positive interim FDG-PET/CT does not reflect persistence of active disease in the vast majority of PMBCL cases. The relapse rate appears similar regardless of interim FDG-PET/CT results and interpretation criteria. This suggests that interim FDG-PET/CT has a poor positive predictive value, thus kt should be used with caution in PMBCL.

Single or tandem autologous stem-cell transplantation for first-relapsed or refractory Hodgkin lymphoma: 10-year follow-up of the prospective H96 trial by the LYSA/SFGM-TC study group.

We assessed the long-term results of autologous stem-cell transplantation for patients with first-relapsed or refractory Hodgkin lymphoma included in the prospective Lymphoma Study Association/Société Française de Greffe de Moelle H96 trial. This large multicenter phase II trial evaluated a risk-adapted strategy with single or tandem autologous stem-cell transplantation for 245 Hodgkin lymphoma patients. Poor-risk patients (n=150) had primary refractory Hodgkin lymphoma (n=77) or ≥2 risk factors at first relapse (n=73) and were eligible for tandem autologous stem-cell transplantation. Intermediate-risk patients (n=95) had one risk factor at first relapse and were eligible for single autologous stem-cell transplantation. With a median follow-up of 10.3 years, 10-year freedom from second failure and overall survival rates were, respectively: 64% (95% CI, 54% to 74%) and 70% (95% CI, 61% to 80%) for the intermediate-risk group, and 41% (95% CI, 33% to 49%) and 47% (95% CI, 39% to 55%) for the poor-risk group. Considering only patients who did not relapse after completing autologous stem-cell transplantation, the 15-year cumulative incidences of second primary malignancies were 24% for the 70 intermediate-risk patients and 2% for the 75 poor-risk ones. With long-term follow-up, the risk-adapted strategy remains appropriate. Tandem autologous stem-cell transplantation can still be considered an option for poor-risk patients, but integration of positron-emission tomography findings and new drugs may help to refine the need for a second autologous stem-cell transplant and possibly improve outcomes of patients with first-relapsed or refractory Hodgkin lymphoma.