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The risk of T cell malignancies after chimeric antigen receptor (CAR) T cell therapy is a concern, although the true incidence remains unclear. Here we analyzed the DESCAR-T registry database, encompassing all pediatric and adult patients with hematologic malignancies who received CAR T cell therapy in France since 1 July 2018. Of the 3,066 patients included (2,536 B cell lymphoma, 162 B cell acute lymphoblastic leukemia (ALL) and 368 multiple myeloma), 1,680 (54.8%) received axicabtagene ciloleucel, 205 (6.7%) brexucabtagene autoleucel, 44 (1.4%) lisocabtagene maraleucel and 769 (25.1%) tisagenlecleucel. All multiple myeloma patients received idecabtagene vicleucel, with none receiving ciltacabtagene autoleucel. After a median follow-up of 12.7 months for B cell lymphoma, 17.7 months for B cell ALL and 6.3 months for multiple myeloma, only one (0.03%) patient developed a T cell malignancy after CAR T infusion. Specifically, the patient was diagnosed with a primary cutaneous CD30 + T cell lymphoproliferative disorder (anaplastic lymphoma kinase-negative) 3 years after receiving tisagenlecleucel therapy for diffuse large B cell lymphoma. This was associated with the integration of a CAR clone into the tumor suppressor gene PLAAT4 (phospholipase A and acyltransferase 4). Thus, the development of this secondary T cell malignancy might be linked to the use of CAR T cell therapy. In conclusion, our findings indicate a very low risk of T cell malignancy after CAR T cell therapy. This analysis of the registry database DESCAR-T of more than 3,000 pediatric and adult patients with hematological malignancies who received CAR T cell therapy in France between 2018 and 2024 shows that only one person developed a secondary T cell malignancy following CAR T cell therapy.

Bispecific antibodies (BsAbs) are a new group of targeted therapies that are revolutionizing the treatment landscape of B-cell non-Hodgkin’s lymphoma (B-NHL). In the relapsed/refractory setting, salvage chemotherapy and autologous stem cell transplantation are capable of curing 50% of patients, whereas the other half will have a dismal outcome with a median overall survival of less than 12 months. This unmet need reinforced the importance of innovative therapies like the BsAbs and CAR-T cell therapies. In this review, we delve into BsAbs in B-NHL from the preclinical development to clinical data in both refractory and frontline settings, and then discuss future perspectives.

Although post-transplant cyclophosphamide (PT-Cy) is effective for graft-versus-host disease (GVHD) prophylaxis, it is associated with toxicities, which might be dose-dependent. We compared the outcomes with PT-Cy at 80 mg/kg to those with PT-Cy at 100 mg/kg in elderly patients undergoing haploidentical hematopoietic cell transplantation (HCT). Inclusion criteria included peripheral blood stem cells, hematological malignancy, and age>65 years (or age>60 years if cardiac event history). Thirty-eight patients received PT-Cy at 80 mg/kg and 55 100 mg/kg, divided in two doses. The cumulative incidences (CI) of acute grade II–IV, acute grade III–IV, and moderate/severe chronic GVHD were 32%, 16%, and 13% with PT-Cy at 80 mg/kg compared to 33%, 13%, and 16% with 100 mg/kg, respectively. In multivariable analysis, reducing PT-Cy dose had no significant impact on GVHD. Neutrophil and platelet engraftments were significantly improved, and CI of BK virus-associated hemorrhagic cystitis was reduced with 80 mg/kg of PT-Cy compared to 100 mg/kg. At 2 years, non-relapse mortality was 16% and 31%, progression-free survival 65% and 49%, overall survival 70% and 56%, and GVHD-free, relapse-free survival 52% and 36% with 80 mg/kg and 100 mg/kg, respectively. Reducing PT-Cy dose to 80 mg/kg is safe and associated with improved hematological recovery and lower CI of hemorrhagic cystitis in elderly patients undergoing haploidentical HCT.

Post-transplant cyclophosphamide (PT-Cy) is effective for graft-versus-host disease (GVHD) prophylaxis, but it may cause dose-dependent toxicities, particularly in frail patients. Therefore, we compared the outcomes with a reduced PT-Cy total dose (70 mg/kg) to those with the standard PT-Cy dose (100 mg/kg) in haploidentical hematopoietic cell transplantation (HCT) patients aged ≥ 65 years and those with cardiac comorbidities. All consecutive patients with a hematological malignancy receiving peripheral blood stem cells (PBSCs) after a thiotepa-based conditioning with low-dose antithymocyte globulin were included. Thirty-three patients received PT-Cy at 70 mg/kg and 25 at 100 mg/kg. PT-Cy dose reduction did not increase the risk of GVHD and was associated with faster neutrophil and platelet recovery, and lower cumulative incidences of bacteremia (38% versus 72%, p = 0.004) and cardiac complications (12% versus 44%, p = 0.028). At 2 years, GVHD-free, relapse-free survival (GRFS) was higher with the reduced dose compared to the standard dose (60% versus 33%, p = 0.04). In conclusion, reducing PT-Cy total dose to 70 mg/kg is a safe and valid approach for elderly patients and those with cardiac comorbidities underdoing haploidentical HCT with PBSCs and low-dose antithymocyte globulin. The reduced PT-Cy dose was associated with improved hematological count recovery, lower incidence of toxicities, and higher GRFS.

We performed a single-centre retrospective study to evaluate the effectiveness of Toxoplasma gondii prevention strategies after allogeneic stem-cell transplantation. The charts of 138 allogeneic stem-cell recipients over a 4-year period were reviewed. Forty-nine percent of patients were not receiving optimal trimethoprim–sulfamethoxazole (TMP–SMZ) prophylaxis at day +30, mainly due to persistent cytopenia. Six months after transplantation, the rate of toxoplasmosis reactivation was 11.6%, including nine cases of Toxoplasma infection and seven cases of Toxoplasma disease. Fifty-six percent of cases of reactivation occurred before day +30. Thirty-eight percent occurred in patients receiving atovaquone prophylaxis. In 57% of patients presenting with Toxoplasma disease, signs of disease were present at first evidence of Toxoplasma DNA in peripheral blood samples. This study illustrates the limitations inherent to currently used toxoplasmosis prevention strategies and argues for the use of a combined prophylactic and preemptive approach. After performing the initial study, we limited the use of atovaquone in favour of TMP–SMZ when possible, and implemented an early prevention strategy consisting of the introduction of prophylaxis starting on day of engraftment. Over the following 16 months, 88.9% of eligible Toxoplasma-seropositive patients were receiving TMP–SMZ at day +30, and the rate of early Toxoplasma reactivation was 1.5%.

The goal of this review is to firstly address the concept of chimeric antigen receptor T-cell (CAR T-cell) therapy and where it fits in the evolving landscape of the management of patients with refractory/relapsed diffuse large B-cell lymphoma. The recognition of the indications for CAR T-cell therapy for patients with aggressive B-cell lymphoma will be discussed, including a review of the algorithms and selection criteria for CAR T-cell therapy and finally, the role of bridging therapy and the timing of CAR T-cell therapy in augmenting chances of a successful outcome.

Background C ytokine i nduced m emory- l ike natural killer (CIML NK) cells combined with an IL-15 super-agonist (N-803) are a novel modality to treat relapsed/refractory head and neck cancer. Methods We report data from a phase I trial of haploidentical CIML NK cells combined with N-803 with or without ipilimumab (IPI) in relapsed/refractory head and neck cancer patients after a median of 6 prior lines of therapy. The trial adhered to a 3 + 3 dose de-escalation design, with primary endpoint being safety. High-resolution immunophenotypic and transcriptional profiling characterized the NK cells and their interacting partners in vivo. Results The primary safety endpoint was established, with dose-limiting toxicity in 1/10 patients. A transient disease control rate correlated with donor NK cell expansion, the latter occurring irrespective of IPI. The combination of CIML NK cells with N-803 and IPI was associated with increased early NK cell proliferation, contraction of Treg: Tcon, rapid recovery of recipient CD8 + T cells, and subsequent accelerated rejection of donor NK cells. Conclusions CIML NK cells combined with N-803 and ipilimumab to treat head and neck cancer is safe, and associated with a more proliferative NK cell phenotype. However, the combination leads to reduced HLA mismatched NK cell persistence, resulting in an important limitation affecting NK cell combination therapies in clinical trials. These results inform evaluation of CIML NK therapy for advanced malignancies, with considerations for combination with IPI. Trial Registration NCT04290546.

Autologous hematopoietic stem cell transplantation (AHSCT) has emerged as a promising treatment option in severely affected and refractory patients with autoimmune diseases. This is a retrospective survey of patients reported to the EBMT registry between 1998 and 2019, who received AHSCT for TAK. Data from six patients treated with AHSCT for refractory TAK have been identified, five were female (83%), median age 25 (9–39) years. All patients were pretreated with a median of 6 (4–8) lines of therapy, including steroids (six patients), methotrexate (five patients), cyclophosphamide, mycophenolate mofetil or infliximab (four patients), tocilizumab or etanercept (two patients). Conditioning included cyclophosphamide and rabbit anti-thymocyte globulin in all patients. At 6 months post transplantation, remission was obtained in all cases, which persisted at 12 months in five cases. Four patients reactivated TAK at a median time of 27 (7–52) months after AHSCT, and three resumed disease-modifying therapy. At last follow-up, all patients were alive, two patients were in remission (off-therapy), two patients improved compared with baseline, and two patients were in complete and partial remission, respectively, under immunosuppressive treatment. This retrospective case-series demonstrates that AHSCT has the potential to provide significant clinical responses in TAK patients, but large prospective trials are necessary to confirm these preliminary data.

This study evaluated the safety and immunogenicity of BNT162b2 vaccine in patients with hematological malignancies. Antibodies blocking spike binding to immobilized ACE-2 (NAb) correlated with anti-Spike (S) IgG d42 titers (Spearman r = 0.865, p < 0.0001), and an anti-S IgG d42 level ≥3100 UA/mL was predictive of NAb ≥ 30%, the positivity cutoff for NAb (p < 0.0001). Only 47% of the patients achieved an anti-S IgG d42 level ≥3100 UA/mL after the two BNT162b2 inocula, compared to 87% of healthy controls. In multivariable analysis, male patients, use of B-cell targeting treatment within the last 12 months prior to vaccination, and CD19+ B-cell level <120/uL, were associated with a significantly decreased probability of achieving a protective anti-S IgG level after the second BNT162b2 inoculum. Finally, using the IFN-γ ELISPOT assay, we found a significant increase in T-cell response against the S protein, with 53% of patients having an anti-S IgG-positive ELISPOT after the second BNT162b2 inoculum. There was a correlation between the anti-S ELISPOT response and IgG d42 level (Spearman r = 0.3026, p = 0.012). These findings suggest that vaccination with two BNT162b2 inocula translates into a significant increase in humoral and cellular response in patients with hematological malignancies, but only around half of the patients can likely achieve effective immune protection against COVID-19.