Characteristics and incidence of infections in patients with multiple myeloma treated by bispecific antibodies: a national retrospective study on the behalf of G2I and Intergroupe Francophone du Myélome.

OBJECTIVES: Bispecific antibodies (BsAbs) are an effective treatment used in relapsed or refractory multiple myeloma. Despite a well-tolerated safety profile, infectious events appear to be frequent in clinical trials. Real-world data on epidemiology, characteristics, risk factors, and outcomes of infections in patients treated with BsAb are still needed. METHODS: A retrospective, multicentre study in BsAb-treated patients with multiple myeloma was performed in 14 French centres from December 2020 to February 2023. The primary objective was to describe the incidence of infections that required hospitalization, specific treatment, or adaptation in BsAb administration. RESULTS: Among 229 patients with multiple myeloma treated with BsAb, 153 (67%) received teclistamab, 47 (20%) received elranatamab, and 29 (13%) talquetamab. We reported a total of 234 infections, including 123 (53%) of grade of ≥3. Predominant infections affected the respiratory tract (n = 116, 50%) followed by bacteraemias (n = 36, 15%). The hospitalization rate was 56% (n = 131), and 20 (9%) infections resulted in death. Global cumulative incidence of the first infection was 70% in all patients, 73% in patients treated with B-cell maturation antigen-targeting, and 51% with GPRC5D-targeting BsAb. In univariate analyses, corticosteroids for cytokine release syndrome (CRS)/immune effector cell-associated neurotoxicity syndrome (ICANS) were associated with a higher risk of first infection (HR = 2.13; 95% CI, 1.38-3.28), whereas GPRC5D-targeting BsAb and anti-bacterial prophylaxis were associated with a lower risk (HR = 0.53; 95% CI, 0.3-0.94 and HR = 0.65; 95% CI, 0.46-0.9). Fine and Gray multivariate model found that only corticosteroids for CRS/ICANS were correlated with a higher risk of first infection (HR = 2.01; 95% CI, 1.27-3.19). DISCUSSIONS: The implementation of preventive measures that aim to mitigate the risk of infection under BsAb is pivotal, notably in patients who received corticosteroids for CRS/ICANS.

Vowel production: a potential speech biomarker for early detection of dysarthria in Parkinson's disease.

Objectives: Our aim is to detect early, subclinical speech biomarkers of dysarthria in Parkinson's disease (PD), i.e., systematic atypicalities in speech that remain subtle, are not easily detectible by the clinician, so that the patient is labeled "non-dysarthric." Based on promising exploratory work, we examine here whether vowel articulation, as assessed by three acoustic metrics, can be used as early indicator of speech difficulties associated with Parkinson's disease. Study design: This is a prospective case-control study. Methods: Sixty-three individuals with PD and 35 without PD (healthy controls-HC) participated in this study. Out of 63 PD patients, 43 had been diagnosed with dysarthria (DPD) and 20 had not (NDPD). Sustained vowels were recorded for each speaker and formant frequencies were measured. The analyses focus on three acoustic metrics: individual vowel triangle areas (tVSA), vowel articulation index (VAI) and the Phi index. Results: tVSA were found to be significantly smaller for DPD speakers than for HC. The VAI showed significant differences between these two groups, indicating greater centralization and lower vowel contrasts in the DPD speakers with dysarhtria. In addition, DPD and NDPD speakers had lower Phi values, indicating a lower organization of their vowel system compared to the HC. Results also showed that the VAI index was the most efficient to distinguish between DPD and NDPD whereas the Phi index was the best acoustic metric to discriminate NDPD and HC. Conclusion: This acoustic study identified potential subclinical vowel-related speech biomarkers of dysarthria in speakers with Parkinson's disease who have not been diagnosed with dysarthria.

Physical Activity Program for the Survival of Elderly Patients With Lymphoma: Study Protocol for Randomized Phase 3 Trial.

BACKGROUND: The practice of regular physical activity can reduce the incidence of certain cancers (colon, breast, and prostate) and improve overall survival after treatment by reducing fatigue and the risk of relapse. This impact on survival has only been demonstrated in active patients with lymphoma before and after treatment. As poor general health status reduces the chances of survival and these patients are most likely to also have sarcopenia, it is important to be able to improve their physical function through adapted physical activity (APA) as part of supportive care management. Unfortunately, APA is often saved for patients with advanced blood cancer. As a result, there is a lack of data regarding the impact of standardized regular practice of APA and concomitant chemotherapy as first-line treatment on lymphoma survival. OBJECTIVE: This study aimed to assess the impact of a new and open rehabilitation program suitable for a frail population of patients treated for diffuse large B-cell lymphoma (DLBCL). METHODS: PHARAOM (Physical Activity Program for the Survival of Elderly Patients with Lymphoma) is a phase 3 randomized (1:1) study focusing on a frail population of patients treated for DLBCL. The study will include 186 older adult patients with DLBCL (aged >65 years) receiving rituximab and chemotherapy. Overall, 50% (93/186) of patients (investigational group) will receive APA along with chemotherapy, and they will be supervised by a dedicated qualified kinesiologist. The APA program will include endurance and resistance training at moderate intensity 3 times a week during the 6 months of chemotherapy. The primary end point of this study will be event-free survival of the patients. The secondary end points will include the overall survival, progression-free survival, prevalence of sarcopenia and undernutrition, and patients' quality of life. This study will be conducted in accordance with the principles of the Declaration of Helsinki. RESULTS: Recruitment, enrollment, and data collection began in February 2021, and 4 participants have been enrolled in the study as of July 2022. Data analysis will begin after the completion of data collection. Future outcomes will be published in peer-reviewed health-related research journals and presented at national congress, and state professional meetings. This publication is based on protocol version 1.1, August 3, 2020. CONCLUSIONS: The PHARAOM study focuses on highlighting the benefits of APA intervention on survival during the period of first-line treatment of patients with DLBCL. This study could also contribute to our understanding of how an APA program can reduce complications such as sarcopenia in patients with lymphoma and improve their quality of life. By documenting the prevalence and relationship between sarcopenia and exercise load, we might be able to help physicians plan better interventions in the care of patients with DLBCL. TRIAL REGISTRATION: ClinicalTrials.gov NCT04670029; https://clinicaltrials.gov/ct2/show/NCT04670029. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/40969.

Reduced-dose WBRT as consolidation treatment for patients with primary CNS lymphoma: an LOC network study.

The optimal consolidation strategy for primary central nervous system lymphoma (PCNSL) remains controversial. Preventing radio-induced neurotoxicity of consolidation treatment through reduced-dose whole-brain radiotherapy (rdWBRT) at a dose of 23.4 Gy is an interesting alternative to conventional WBRT in patients aged <60 years. From the LOC Network (Network for Oculo-cerebral Lymphomas) database, we retrospectively selected patients with PCNSL aged <60 years who showed complete (CR) or unconfirmed CR after high-dose methotrexate-based chemotherapy and had received consolidation rdWBRT as the first-line treatment. If available, prospective neuropsychological follow-ups were reported. Twenty-nine patients diagnosed between 2013 and 2018 met the study selection criteria. Nine (31%) patients experienced relapse during the follow-up, with a median time from radiotherapy to recurrence of 8.7 months (interquartile range, 4-11.5). Five of those patients received salvage treatment and consolidation with intensive chemotherapy and autologous stem cell transplantation. Progression-free survival rates were 89% (95% confidence interval [CI] 79%-100%), 72% (95% CI, 56%-88%), and 69% (95% CI, 52%-85%) at 1, 2, and 5 years, respectively. Overall survival rates were 100%, 89% (95% CI, 79%-100%), and 86% (95% CI, 74%-99%) at 1, 2, and 5 years, respectively, and were consistent with those observed for standard-dose WBRT (sdWBRT). No prognostic factor was identified. The results of the 36-month neuropsychological follow-up for a subset of patients appeared reassuring, with most patients exhibiting maintenance of or improvements in their baseline conditions. Our results, combined with phase 2 study results, support the use of rdWBRT instead of sdWBRT as a consolidation treatment in <60-year-old patients showing CR after induction treatment.

Clinical presentation, outcome, and prognostic markers in patients with intravascular large B-cell lymphoma, a lymphoma study association (LYSA) retrospective study.

BACKGROUND: Intravascular large B-cell lymphoma (lVLBCL) is a very rare type of large B-cell lymphoma. METHODS: We conducted a retrospective study on IVLBCL patients treated from 2000 to 2016 in LYSA cooperative group centers. RESULTS: Sixty-five patients were identified in 23 centers. Median age at diagnosis was 69 years (range 23-92). Thirty-four patients (64%) had an IPI score >3 and 40 patients (67%) had a performance status ≥2. The most frequent extra-nodal locations were bone marrow (n = 34; 52%), central nervous system (n = 25; 39%), and skin (n = 21; 33%). Nodal involvement and endocrine system were observed in 34% (n = 22) and 18% (n = 12) of all cases, respectively. Twenty-six patients (41%) had macrophage activation syndrome. Tumor cells were frequently CD5 positive (52%) with a non-germinal center origin (86%). BCL2 was expressed in 87% of all samples analyzed (n = 20) and 43% of patients had a MYC/BCL2 double expression. Fifty-six patients were treated with a regimen of chemotherapy containing rituximab, among whom 73% reached complete remission. The median progression-free survival (PFS) and median overall survival (OS) were 29.4 months and 63.8 months, respectively. History of autoimmune disorder (Hazard ratio [HR] 3.3 [1.4-7.8]; p < 0.01), nodal involvement (HR 2.6 [1.4-5.1]; p < 0.01), lack of anthracycline (HR 0.1 [0-0.4] for use; p < 0.001), or no intensification at first-line regimen (p = 0.02) were associated with worse PFS. High-dose methotrexate use was not associated with better PFS or OS. CONCLUSIONS: Our study highlights the aggressive clinical picture of IVLBCL, in particular the frequency of macrophage activation syndrome, and the need for new therapies despite a response to R-CHOP-like regimen similar to non-intravascular diffuse large B-cell lymphomas.

Intensive chemotherapy followed by autologous stem cell transplantation in primary central nervous system lymphomas (PCNSLs). Therapeutic outcomes in real life-experience of the French Network.

We analysed the therapeutic outcomes of all consecutive patients with primary central nervous system lymphoma (PCNSL) registered in the prospective French database for PCNSL and treated with intensive chemotherapy (IC) followed by autologous stem cell transplantation (IC-ASCT) between 2011 and November 2019 (271 patients recruited, 266 analysed). In addition, treatment-related complications of thiotepa-based IC-ASCT were analysed from the source files of 85 patients from 3 centers. Patients had received IC-ASCT either in first-line treatment (n = 147) or at relapse (n = 119). The median age at IC-ASCT was 57 years (range: 22-74). IC consisted of thiotepa-BCNU (n = 64), thiotepa-busulfan (n = 24), BCNU-etoposide-cytarabine-melphalan (BEAM, n = 36) and thiotepa-busulfan-cyclophosphamide (n = 142). In multivariate analysis, BEAM and ASCT beyond the first relapse were adverse prognostic factors for relapse risk. The risk of treatment-related mortality was higher for ASCT performed beyond the first relapse and seemed higher for thiotepa-busulfan-cyclophosphamide. Thiotepa-BCNU tends to result in a higher relapse rate than thiotepa-busulfan-cyclophosphamide and thiotepa-busulfan. This study confirms the role of IC-ASCT in first-line treatment and at first-relapse PCNSL (5-year overall survival rates of 80 and 50%, respectively). The benefit/risk ratio of thiotepa-busulfan/thiotepa-busulfan-cyclophosphamide-ASCT could be improved by considering ASCT earlier in the course of the disease and dose adjustment of the IC.

Nodular lymphocyte predominant Hodgkin lymphoma: a Lymphoma Study Association retrospective study.

Nodular lymphocyte predominant Hodgkin lymphoma represents a distinct entity from classical Hodgkin lymphoma. We conducted a retrospective study to investigate the management of patients with nodular lymphocyte predominant Hodgkin lymphoma. Clinical characteristics, treatment and outcome of adult patients with nodular lymphocyte predominant Hodgkin lymphoma were collected in Lymphoma Study Association centers. Progression-free survival (PFS) and overall survival (OS) were analyzed, and the competing risks formulation of a Cox regression model was used to control the effect of risk factors on relapse or death as competing events. Among 314 evaluable patients, 82.5% had early stage nodular lymphocyte predominant Hodgkin lymphoma. Initial management consisted in watchful waiting (36.3%), radiotherapy (20.1%), rituximab (8.9%), chemotherapy or immuno-chemotherapy (21.7%), combined modality treatment (12.7%), or radiotherapy plus rituximab (0.3%). With a median follow-up of 55.8 months, the 10-year PFS and OS estimates were 44.2% and 94.9%, respectively. The 4-year PFS estimates were 79.6% after radiotherapy, 77.0% after rituximab alone, 78.8% after chemotherapy or immuno-chemotherapy, and 93.9% after combined modality treatment. For the whole population, early treatment with chemotherapy or radiotherapy, but not rituximab alone (Hazard ratio 0.695 [0.320-1.512], P=0.3593) significantly reduced the risk of progression compared to watchful waiting (HR 0.388 [0.234-0.643], P=0.0002). Early treatment appears more beneficial compared to watchful waiting in terms of progression-free survival, but has no impact on overall survival. Radiotherapy in selected early stage nodular lymphocyte predominant Hodgkin lymphoma, and combined modality treatment, chemotherapy or immuno-chemotherapy for other patients, are the main options to treat adult patients with a curative intent.

Prognostic impact of immune status and hematopoietic recovery before and after fludarabine, IV busulfan, and antithymocyte globulins (FB2 regimen) reduced-intensity conditioning regimen (RIC) allogeneic stem cell transplantation (allo-SCT).

This retrospective analysis aimed to assess hematopoietic and immune recovery in a cohort of 53 patients [males: n = 33; median age: 59 yr (range: 22-70)] who received a FB2 (fludarabine 120-150 mg/m² + IV busulfan 6.4 mg/kg + antithymocyte globulin thymoglobulin 5 mg/kg) reduced-intensity conditioning (RIC) allo-stem cells transplantations (SCT). With a median follow-up of 19 months (range: 2-53), the 2-yr overall survival, disease-free survival (DFS), relapse incidence, and non-relapse mortality were 63%, 59.5%, 35%, and 6%, respectively. In univariate analysis, the factors correlated with a significantly higher 2-yr OS and DFS were a higher total circulating lymphocytes count at transplant (>730/mm(3) ; OS: 81% vs. 43%, P = 0.02; DFS: 73% vs. 45.5%, P = 0.03) and a higher recovery of leukocytes (>5300/mm(3) ) (2-yr OS: 81% vs. 44%, P = 0.007; 2-yr DFS: 72% vs. 46%, P = 0.08), neutrophils (>3200/mm(3) ) (2-yr OS: 76% vs. 50%, P = 0.03; 2-yr DFS: 67% vs. 52.0%, P = 0.1), and monocytes (>590/mm(3) ; 2-yr OS: 80% vs. 45%, P = 0.004; 2-yr DFS: 76% vs. 42%, P = 0.01) at day +30 post-transplant. In multivariate analysis, the only independent factors associated with a significantly higher OS and DFS were a better immune status at transplant (lymphocytes count >730/mm(3) ) and a higher monocytes count (>590/mm(3) ) at day +30 post-transplant. These results suggest that immune status and hematopoietic recovery before and after FB2 RIC allo-SCT can be significant predictors of outcome. This paves the way for future studies aiming to closely monitor the kinetics of immune recovery after RIC allo-SCT and to evaluate the impact of growth factors and other immunostimulatory cytokines in the setting of RIC allo-SCT.

Is ASCT with TBI superior to ASCT without TBI in mantle cell lymphoma patients?

BACKGROUND: Impact of total-body irradiation (TBI) in conditioning regimen on outcome for patients with mantle cell lymphoma (MCL) remains unknown. METHODS: Patients with MCL who underwent autologous stem-cell transplantation (ASCT) in our institution were eligible for the present study (n=73). We analyzed the impact of various biologic and clinical parameters, with and without TBI, on patient outcome. RESULTS: All patients presented with chemosensitive disease at transplantation. Median follow-up from ASCT was 37.2 months. One- and three-year overall survival (OS) rates were 90.3% and 74.5%, progression-free survival (PFS) rates were 85% and 59%, respectively. Three-year OS and PFS rates in the non-TBI group versus TBI group were similar: 80% versus 72.5% and 60% versus 57%, respectively. In univariate analysis, the use of TBI did not modify OS or PFS (P=0.93 and P=0.48, respectively). This remains true for patients who underwent ASCT up front. According to multivariate analysis, OS tended to be shorter for patients presenting with high Mantle Cell Lymphoma International Prognostic Index or low hemoglobin level. CONCLUSIONS: Absence of TBI in conditioning regimen modifies neither PFS nor OS. The present retrospective and monocentric analysis shows that transplant patients with MCL remain highly exposed to relapse.

Efficacy of lenalidomide plus dexamethasone in patients older than 75 years with relapsed multiple myeloma.

Few data are available on the efficacy of the combination of lenalidomide plus dexamethasone (Len/Dex) in very elderly patients above 75 years of age with relapsed multiple myeloma (MM). We report here a single-center series of 45 consecutive patients aged 75 years or older with relapsed MM treated with this combination. The overall response rate was 62% and the median progression-free survival was 14 months, which compares favorably to that described in the two pivotal prospective studies that formed the basis for the approval of Len/Dex in the relapse setting. Our study confirms that Len/Dex is an effective combination in very elderly patients with relapsed MM.

Administration of mylotarg 4 days after beginning of a chemotherapy including intermediate-dose aracytin and mitoxantrone (MIDAM regimen) produces a high rate of complete hematologic remission in patients with CD33+ primary resistant or relapsed acute myeloid leukemia.

We have used the dose of 9 mg/m(2) of mylotarg 4 days after the beginning of a chemotherapy including intermediate-dose aracytin and mitoxantrone (MIDAM) in 17 patients with refractory (n=4) or relapsed (n=13) AML. Thirteen patients (76%) achieved CR (n=12) or partial CR (n=1). All four refractory patients and all four patients with poor risk cytogenetic achieved CR or CRp. Although the dose of mylotarg given in combination with chemotherapy was not reduced, the toxicity profile was acceptable (1VOD/17 patients). The MIDAM protocol appears to be highly effective especially in patients with poor risk cytogenetic and/or refractory disease.