Phase I study of zoledronic acid combined with escalated doses of interleukine-2 for early in vivo generation of Vγ9Vδ2 T-cells after haploidentical stem cell transplant with posttransplant cyclophosphamide.

The presence of donor Vγ9Vδ2 T-cells after haploidentical hematopoietic stem cell transplant (h-HSCT) has been associated with improved disease-free survival. These cells kill tumor cells in a non-MHC restricted manner, do not induce graft-versus-host disease (GVHD), and can be generated by stimulation with zoledronic acid (ZA) in combination with interleukin-2 (IL-2). This monocentric phase I, open-label, dose-escalating study (ClinicalTrials.gov: NCT03862833) aimed at evaluating the safety and possibility to generate Vγ9Vδ2 T-cells early after h-HSCT. It applied a standard 3 + 3 protocol to determine the maximum tolerated dose (MTD) of increasing low-doses of IL-2 (5 days [d] per week, 4 weeks) in combination with a single dose of ZA, starting both the first Monday after d + 15 posttransplant. Vγ9Vδ2 T-cell monitoring was performed by multiparameter flow cytometry on blood samples and compared with a control cohort of h-HSCT recipients. Twenty-six patients were included between April 2019 and September 2022, 16 of whom being ultimately treated and seven being controls who received h-HSCT only. At the three dose levels tested, 1, 0, and 1 dose-limiting toxicities were observed. MTD was not reached. A significantly higher number of Vγ9Vδ2 T-cells was observed during IL-2 treatment compared with controls. In conclusion, early in vivo generation of Vγ9Vδ2 T-cells is feasible after h-HSCT by using a combination of ZA and repeated IL-2 infusions. This study paves the way to a future phase 2 study, with the hope to document lesser posttransplant relapse with this particular adaptive immunotherapy.

Quad-class exposed/refractory myeloma is associated with short survival.

Very scarce data exist about outcomes of relapsed multiple myeloma patients who have failed proteasome inhibitor, immunomodulatory drug, anti-CD38 monoclonal antibody and therapies targeting B-cell maturation antigen (BCMA) (Quad-class exposed [QCE]). In this retrospective single-centre study, we determined progression-free survival (PFS) and overall survival (OS) from anti-BCMA failure in 45 QCE patients. Seven (16%) patients received antibody-drug conjugate, 20 (44%) bispecific antibodies and 18 (40%) CAR-T cell. Thirty patients (67%) received ≥1 subsequent line of treatment. PFS was 4.4 months (95% CI = 2.4-12.5) and OS 6.3 months (95% CI = 3.9-14.4). Having an adverse prognosis, QCE myeloma patients remain an unmet medical need.

Hematopoietic stem cell transplantation for acute lymphoblastic leukemia: why do adolescents and young adults outcomes differ from those of children? A retrospective study on behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC).

PURPOSE: In the acute lymphoblastic leukemia (ALL) landscape, adolescents and young adults (AYA) often present high-risk diseases and increased chemotherapy-related toxicity. Studies analyzing the outcomes of AYA after hematopoietic stem cell transplantation (HSCT) are scarce. Our study aimed to compare the outcomes of children and AYA with ALL after HSCT and to determine the factors influencing potential differences. METHOD: 891 patients, from the SFGM-TC registry, aged between 1 and 25 years who received HSCT between 2005 and 2012 were included. The outcomes of AYA were compared to the ones of their younger counterparts. RESULTS: Five-year OS and GRFS were lower in AYA: 53.1% versus 64% and 36% versus 47% (p = 0.0012 and p = 0.007, respectively). WhileCIR was similar in both groups, 5 year-treatment related mortality was higher in AYA: 19% versus 13% (p = 0.04). The lower GRFS in AYA was mainly explained by a higher chronic graft versus host disease (cGvHD) incidence: 32% versus 19% (p < 0.001). Use of peripheral blood stem cells and use of anti-thymoglobulin appeared to be the main factors impacting cGvHD occurrence in AYA. CONCLUSION: AYA have worse outcomes than children after HSCT for ALL because of a greater risk of TRM due to cGvHD. HSCT practices should be questioned in this population.

B Cell Aplasia Is the Most Powerful Predictive Marker for Poor Humoral Response after BNT162b2 mRNA SARS-CoV-2 Vaccination in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation.

Little is known about the immune response to SARS-CoV-2 vaccination in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, several studies have reported that adequate protection could be provided to this population. The purpose of this study was to evaluate which factors can predict the efficacy of SARS-CoV-2 vaccination in these specifically immunosuppressed patients. Specific anti-Spike (S) antibody responses were assessed in a cohort of 117 allo-HSCT recipients after 2 injections of BNT162b2 mRNA SARS-CoV-2 vaccine (V1 and V2). Factors considered liable to influence the antibody response and analyzed in this series were the interval between allo-HSCT and V1, donor source, recipient and donor age, current immunosuppressive/chemotherapy (I/C) treatment, and levels of CD4+and CD8+ T cells, B cells, and natural killer cells at the time of V1. Overall, the S-antibody response rate, evaluated at a median of 35 days after V2, was 82.9% for the entire cohort, with 71 patients (61%) reaching the highest titer. In univariate analysis, a lower pre-V1 median total lymphocyte count, lower CD4+ T cell and B cell counts, ongoing I/C treatment, and a haploidentical donor were characteristic of nonhumoral responders. However, multiparameter analysis showed that B cell aplasia was the sole factor predicting the absence of a specific immune response (odds ratio, 0.01; 95% confidence interval, 0.00 to 0.10; P < 10-3). Indeed, the rate of humoral response was 9.1% in patients with B cell aplasia versus 95.9% in patients with a B cell count >0 (P < 10-9). These results advocate for the administration of anti-SARS-CoV-2 vaccination in allo-HSCT recipients as early as peripheral B cell levels can be detected, and also suggest the need for close monitoring of B-cell reconstitution after Allo-HSCT.

The temporal origin of dentate granule neurons dictates their role in spatial memory.

The dentate gyrus is one of the only brain regions that continues its development after birth in rodents. Adolescence is a very sensitive period during which cognitive competences are programmed. We investigated the role of dentate granule neurons (DGNs) born during adolescence in spatial memory and compared them with those generated earlier in life (in embryos or neonates) or during adulthood by combining functional imaging, retroviral and optogenetic tools to tag and silence DGNs. By imaging DGNs expressing Zif268, a proxy for neuronal activity, we found that neurons generated in adolescent rats (and not embryos or neonates) are transiently involved in spatial memory processing. In contrast, adult-generated DGNs are recruited at a later time point when animals are older. A causal relationship between the temporal origin of DGNs and spatial memory was confirmed by silencing DGNs in behaving animals. Our results demonstrate that the emergence of spatial memory depends on neurons born during adolescence, a function later assumed by neurons generated during adulthood.

Safety and immunogenicity of a first dose of SARS-CoV-2 mRNA vaccine in allogeneic hematopoietic stem-cells recipients.

This was a monocentric prospective study testing the efficacy and safety of a first injection of BNT162b2 (Pfizer-BioNTech) in 112 Allo-HSCT patients. Antibody response to SARS-CoV-2 spike protein receptor-binding domain was tested at the time of the second injection (Roche Elecsys). The study also included a non-randomized control arm of 26 healthy controls. This study shows that a first dose of SARS-CoV-2 messenger RNA vaccine is safe and provides a 55% rate of seroconversion in allotransplanted patients compared to 100% for the controls (p < 0.001). Factors influencing the absence of response in patients were recent transplantation (<2 years), lymphopenia (<1 × 109/L) and immunosuppressive treatment or chemotherapy at the time of vaccination.

[Transition to adulthood: An essential period in the follow up of young patients]. / La transition vers l'âge adulte: une période charnière dans la prise en charge continue des jeunes patients.

In recent decades, follow-up of cancer survivors has taken on its full meaning with the gradual improvement in the survival of children and adolescents with cancer. This follow-up is associated specially for adolescents with a multitude of transitions: the transition from therapeutic management to the monitoring for possible relapse, the transition into long-term follow-up after childhood cancer, the transition from a pediatric system to an adult care system. If this transition can be perceived as difficult by patients, it gives young people the opportunity to access more autonomous follow-up and support in becoming an adult. Supporting the transition should make caregivers attentive to this time of consolidation of adolescence, favorable to the emergence of a sense of stable, mature identity that guarantees a certain autonomy. This is a key to a successful transition limiting breakdown of care and promoting "the work of the disease". The double contribution of adult and pediatric oncology provides support tailored to these psychic and societal issues. AYA teams can actively participate in this process by facilitating the acculturation of pediatric and adult care teams to the specificity of this group, thus allowing a continuum of care.

A new cytokine-based dynamic stratification during induction is highly predictive of survivals in acute myeloid leukemia.

The aim of this study was to assess the potential impact of the kinetics of serum levels of seven cytokines during induction in acute myeloid leukemia (AML) patients. Indeed, the role of cytokines, in the pathophysiology and response to therapy of AML patients, remains under investigation. Here, we report on the impact of peripheral levels of two cytokines, the Fms-like tyrosine kinase 3 ligand (FL) and interleukin-6 (IL-6), evaluated during first-line intensive induction. A new risk stratification can be proposed, which supersedes the ELN 2017 classification to predict survivals in AML patients by examining the kinetic profile of these cytokines during the induction phase. It segregates three groups of, respectively, high-risk, characterized by a stagnation of low FL levels, intermediate risk, with dynamic increasing FL levels and high IL-6 at day 22, and favorable risk with increasing FL levels but low IL-6 at day 22.

Grade 2 acute GVHD is a factor of good prognosis in patients receiving peripheral blood stem cells haplo-transplant with post-transplant cyclophosphamide.

BACKGROUND: The impact of acute graft versus host disease (GVHD) on survivals for patients receiving a haploidentical allogeneic stem-cell transplant (Allo-SCT) with peripheral blood stem-cells (PBSC) complemented by post-transplant cyclophosphamide (PTCY) is ill-known. MATERIAL AND METHODS: This retrospective study included 131 patients who received a PBSC haplograft in order to precise the impact of acute GVHD on outcomes. There were 78 males and 53 females and the median age for the whole cohort was 59 years (range: 20-71). Thirty-five patients were allografted for a lymphoid disease and 96 for a myeloid malignancy, including 67 patients with acute myeloid leukemia (AML). RESULTS: The cumulative incidence (CI) of day 100 grade 2-4 and 3-4 acute GVHD was 43.4 + 4.6% and 16.7 + 3.4%, respectively. The 2-year CI of moderate/severe chronic GVHD was 10.1 + 2.8%. The only factor affecting the occurrence of GVHD was GVHD prophylaxis. Indeed, CI of day 100 grade 2-4 (but not grade 3-4) acute GVHD was significantly reduced when adding anti-thymoglobulin (ATG) to PTCY. However, in multivariate analysis, grade 2 acute GVHD was significantly associated with better disease-free (HR: 0.36; 95%CI: 0.19-0.69, p = .002) and overall (HR: 0.35; 95%CI: 0.1-0.70, p = .003) survivals. The same results were observed when considering only AML patients. CONCLUSION: Acute grade 2 GVHD is a factor of good prognosis after PBSC haplotransplant with PTCY. Further and larger studies are needed to clarify the complex question of GVHD prophylaxis in the setting of haplo-transplant, especially that of combining ATG and PTCY.

Autologous stem-cell collection following VTD or VRD induction therapy in multiple myeloma: a single-center experience.

Triplet-drug regimen bortezomib-thalidomide-dexamethasone (VTD) and bortezomib-lenalidomide-dexamethasone (VRD) are considered as standard of care induction prior autologous stem-cell transplantation (ASCT) in myeloma. In addition to improve response rate, induction therapy should preserve an adequate stem-cell collection. In the present retrospective study, we analyzed stem-cell collection in 325 newly diagnosed myeloma patients who received either VTD or VRD induction before ASCT. Stem-cell mobilization consisted of intravenous cyclophosphamide plus G-CSF. Plerixafor was administered preemptively to rescue mobilization. In comparison with VTD, VRD induction was associated with a more frequent use of plerixafor (19.3% versus 5.4%, p = 0.004) and with an increased number of apheresis to reach adequate collection (>2 apheresis required in 42.3% versus 30.2%, p = 0.05). Moreover, more patients experienced collection failure in the VRD group (6% versus 1.8%, p = 0.004). The median number of CD34-positive cells (×106/kg) was lower in the VRD group: 8.5 versus 9.3 (p = 0.05) in the VTD group. The vast majority of patients underwent ASCT (93% versus 98%, in VRD and VTD group, respectively). These data highlight the need of optimal stem-cell collection strategy, especially in the context of tandem transplantation and incorporation of anti-CD38 monoclonal antibody into induction.

Antithymocyte globulin administration in patients with profound lymphopenia receiving a PBSC purine analog/busulfan-based conditioning regimen allograft.

Graft-versus host disease (GVHD) remains one of the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (ASCT). Prophylactic T cell depletion via antithymocyte globulin (ATG) during ASCT conditioning is one of the standards of care for GVHD prophylaxis, although the optimal dosing strategy is still unclear. Recent studies have reported that absolute lymphocyte count at the time of ATG administration could predict survivals in ASCT from unrelated donors. Here this issue was examined in 116 patients receiving peripheral blood stem cells (PBSC) ASCT with purine analog/busulfan-based conditioning regimens between 2009 and 2019 in our department. The impact of lymphopenia at the time of ATG administration was evaluated in terms of overall survival, disease-free survival and GVHD-free/relapse-free survival. After a median follow-up of 4 years, no adverse effect of a profound lymphopenia was observed on patients' outcome. Notably, a reduced dose of ATG in patients with profound lymphopenia did not translate into better survivals. This study indicates that ATG can be administered whatever the recipient's lymphocyte counts in patients receiving a PBSC purine analog/busulfan-based conditioning regimen ASCT.

Responsiveness of dentate neurons generated throughout adult life is associated with resilience to cognitive aging.

During aging, some individuals are resilient to the decline of cognitive functions whereas others are vulnerable. These inter-individual differences in memory abilities have been associated with differences in the rate of hippocampal neurogenesis measured in elderlies. Whether the maintenance of the functionality of neurons generated throughout adult life is linked to resilience to cognitive aging remains completely unexplored. Using the immediate early gene Zif268, we analyzed the activation of dentate granule neurons born in adult (3-month-old), middle-aged (12-month-old), or senescent (18-month-old) rats (n = 96) in response to learning when animals reached 21 months of age. The activation of neurons born during the developmental period was also examined. We show that adult-born neurons can survive up to 19 months and that neurons generated 4, 10, or 19 months before learning, but not developmentally born neurons, are activated in senescent rats with good learning abilities. In contrast, aged rats with bad learning abilities do not exhibit activity-dependent regulation of newborn cells, whatever their birthdate. In conclusion, we propose that resilience to cognitive aging is associated with responsiveness of neurons born during adult life. These data add to our current knowledge by showing that the aging of memory abilities stems not only from the number but also from the responsiveness of adult-born neurons.

Randomized Trial Comparing Double Versus Triple Bortezomib-Based Regimen in Patients With Multiple Myeloma and Acute Kidney Injury Due to Cast Nephropathy.

PURPOSE: We report a multicenter controlled trial comparing renal recovery and tolerance profile of doublet versus triplet bortezomib-based regimens in patients with initial myeloma cast nephropathy (CN) and acute kidney injury (AKI) without need for dialysis. METHODS: After symptomatic measures and high-dose dexamethasone, patients were randomly assigned to receive bortezomib plus dexamethasone (BD), or BD plus cyclophosphamide (C-BD). In patients with < 50% reduction of serum free light chains (sFLCs) after 3 cycles, chemotherapy was reinforced with either cyclophosphamide (BD group) or thalidomide (C-BD group). RESULTS: Ninety-two patients were enrolled in each group. At random assignment, characteristics of the 2 groups were similar, including median age (68 years) and serum creatinine level (305.5 and 273.5 µmol/L in BD and C-BD group, respectively). At 3 months, renal response rate (primary end point) was not different (41 v 47 responders in the BD and C-BD groups, respectively; relative risk [RR], 0.87; P = .46). Very good partial response (free light chain reduction ≥ 90%) or more was achieved in 36 and 47 patients, respectively (RR, 0.76; P = .10). After 1 cycle of chemotherapy, 69 in the BD group and 67 patients in the C-BD group had achieved sFLC level ≤ 500 mg/L. Serious adverse events were recorded in 30 and 40 patients, respectively. At 12 months, 19 patients had died (9 in the BD group v 10 in the C-BD group), including 10 (6 in the BD group and 4 in the C-BD group) from myeloma progression and 3 (0 in the BD group and 3 in the C-BD group) from infection. Within median follow-up of 27 months, 43 and 42 patients switched to new therapy, respectively. Overall, 50 patients (24 in the BD group and 26 in the C-BD group) had died. CONCLUSION: This randomized study did not show any benefit of C-BD compared with BD on renal recovery of patients with initial CN not requiring dialysis. Adding cyclophosphamide did not sufficiently improve the efficacy-toxicity balance. Patients with myeloma with AKI are fragile, and indication for doublet or triplet regimen should be adapted to frailty.

Progression of disease within 2 years (POD24) is a clinically relevant endpoint to identify high-risk follicular lymphoma patients in real life.

Follicular lymphoma (FL) is an indolent non-Hodgkin's lymphoma with heterogeneous outcomes. Progression or relapse of FL within 2 years (so-called POD24) after diagnosis is associated with a poor outcome for patients treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) in clinical trials. POD24 needs further validation before it can be used as a relevant endpoint to assess treatment efficacy. In the present retrospective monocentric study, we investigated the predictive value of POD24 in a cohort of grade 1, 2, or 3a FL patients treated in our institution (Nantes Medical University, France) and registered in our local database. We investigated the nature of treatment lines, patients' outcomes, and the prognostic value of POD24. Between 2007 and 2016, 317 patients were included. After first-line therapy, 60 patients relapsed within 2 years (POD24-pos cohort), and 254 patients did not relapse within 2 years (PO24-neg cohort). Thirty-three patients died, and 34 patients had an aggressive transformation. The median follow-up is 59.9 months (1.6-395.5). The median PFS is 59.9 months. Overall survival (OS) at 1 year, 3 years, and 5 years is 98.4% [97.0-99.8], 95.1% [92.6-97.6], and 92.5% [89.3-95.9], respectively. The 5-year OS was statistically lower for POD24-pos patients (82% [71.9-93.5]) than for POD24-neg patients (93.3% [88.98-97.8]) (p = 10-5). In multivariate analyses, transformation was predictive of OS, and PS (≥ 1) was predictive of POD24. POD24 is predictive of a worse OS and may be recommended as a relevant endpoint in clinical trials and in real life in particular for patients with advanced disease.

Absence of influence of peripheral blood CD34+ and CD3+ graft cell counts on outcomes after reduced-intensity conditioning transplantation using post-transplant cyclophosphamide.

The influence of peripheral blood stem cell (PBSC) graft cell contents after transplant with post-transplant cyclophosphamide (PTCY) remains unclear. Here, we retrospectively report on a cohort of 77 adults who received a Baltimore-based reduced-intensity conditioning regimen either with fludarabine (n = 40) or clofarabine (n = 37) and PTCY. With a median follow-up of 29.2 months, [2-]year overall (OS), disease-free (DFS), and GVHD/relapse-free survival (GRFS) rates were 62.8%, 51%, and 36.7%, respectively. The incidence of grades [2-]4 acute GVHD was significantly higher in patients transplanted with a haplodonor (n = 56), at 57.1% vs 19% (p = 0.006). PBSC graft cell contents (CD45+, CD34+, and CD3+ cells) had no impact on any outcome. Considering immune reconstitution until 1 year, only monocytes were above the normal range (as early as day + 30) during the first year post-transplant. In multivariate analysis, an older donor (> 45 years) and a high/very high disease risk index were independently associated with lower OS. A higher monocyte count (> median) at day + 90 was also associated with better OS, DFS, and GRFS. Donor/recipient CMV status matching was independently associated with GRFS. In conclusion, our data support the fact that there is no need to manipulate the graft before infusion in the particular context of PBSC/PTCY Baltimore-based allotransplant.

Coping Strategies and Factors Related to Problematic Substance Use and Behavioral Addictions Among Adolescents and Young Adults with Cancer.

Purpose: This study aimed to explore and identify the factors associated with problematic substance use (alcohol, tobacco, and cannabis) and behavioral addictions (internet and eating disorders) over time in adolescents and young adults (AYAs) treated for cancer. Methods: AYAs newly diagnosed with cancer, 15-25 years of age, completed a questionnaire during their hospitalization (T1), assessing their consumption of alcohol, tobacco, and cannabis (The Alcohol Use Disorders Identification Test; The Smoking Behavior Questionnaire; and The Cannabis Abuse Screening Test), their internet use (The Internet Addiction Test), their body preoccupations (The Eating Attitudes Test), as well as their coping strategies (Brief COPE) and emotional adjustment (The Hospital Anxiety and Depression Scale). Questionnaires were completed again 6 months later (T2). Results: Seventy-three AYAs were included at T1 and 21 AYAs at T2. Nearly one out of two (46.58%) AYAs had a problematic substance use or behavioral addiction after cancer diagnosis (T1). Problematic use of internet was frequently reported (23.29%), as well as harmful alcohol consumption or addiction (16.44%) and cannabis dependence (12.33%). The main factor related to problematic substance use was being older, while the main factor related to behavioral addiction was having a higher anxiety score. Substance use as a coping strategy was used more frequently by AYAs with problematic substance use and emotional support as a coping strategy was used more frequently by AYAs with a behavioral addiction. Conclusions: High rates of problematic substance use and behavioral addiction were reported in our sample. AYAs surveyed had high problematic use of cannabis and high internet use. Attention to substance use and addictive behaviors is recommended to ensure optimal care.