Late-onset relapsing neurotoxicity after Brexucabtagene autoleucel associated with high chimeric antigen receptor T cells in cerebrospinal fluid.

BACKGROUND AIMS: Mounting evidence suggests that persistent cell expansion is the main driver for both efficacy and toxicity of chimeric antigen receptor (CAR) T-cell therapy. Hereby, we describe a case of delayed recurrent neurotoxicity associated with late CAR T-cells re-expansion. CASE DESCRIPTION: A 44-year-old man suffering from mantle cell lymphoma received brexu-cel. After infusion, he developed grade 2 cytokine release syndrome. On day +11, grade 3 neurotoxicity was reported and high-dose methylprednisolone was started with a complete resolution of neurological manifestations. On day +30, he experienced a late-onset CAR T-cell toxicity associated with CAR T-cell re-expansion. The patient was treated with tocilizumab and dexamethasone, with resolution of symptoms. On day +58, he was readmitted for new onset of neurotoxicity. Notably, a new CAR T-cell expansion was observed, with an unexpectedly elevated cerebrospinal fluid/blood ratio. The patient was promptly treated with dexamethasone and then escalated to high-dose methylprednisolone and anakinra, with resolution of his neurologic condition noted. CONCLUSIONS: CAR T-cell-related neurotoxicity usually has an early monophasic course. To our knowledge, this is the first case of late-onset, recurrent neurotoxicity. Moreover, an elevated level of cerebrospinal fluid CAR T cells was observed, which may suggest that the delayed neurotoxicity was primarily caused by the brain infiltration of CAR T cells rather than driven by cytokine-mediated neuroinflammation.

Selected memory T cells infused post-haploidentical hematopoietic stem cell transplantation persist and hyperexpand.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplant cyclophosphamide is a curative treatment for many hematological malignancies, yet a majority of patients still suffers from recurrent infections. Post-transplant infusion of memory T-cells could potentially enhance immunological protection without increasing the risk of eliciting acute graft-versus-host disease, which is mainly induced by naïve T-cells. Here, we performed longitudinal analysis of the lymphocyte compartment in 19 patients who underwent haplo-HSCT previously enrolled in a phase II prospective clinical trial (www.clinicaltrials.gov as #NCT04687982), in which they received post-transplant CD45RA-depleted donor lymphocyte infusions (DLI). T-cell receptor sequencing analysis showed that, surprisingly, CD45RA-depleted DLI do not increase T-cell clonal diversity, but lead to prominent expansion of a selected number of infused memory T-cell clones, suggesting recruitment of these cells in the immune response. Pathogen-specific memory T-cells, including cytomegalovirus (CMV)-specific cells, were engrafted and were able to persist for at least 1 month. Deep immunophenotyping revealed strong polyfunctional effector CMV-specific T-cell responses in the majority of patients, with their expansion correlating with the frequency of CMV-specific cells in the donor. These findings provide a rationale behind the suggested improved protection against viral infections in patients receiving CD45RA-depleted DLI.

Feasibility and Efficacy of CD45RA+ Depleted Donor Lymphocytes Infusion After Haploidentical Transplantation With Post-Transplantation Cyclophosphamide in Patients With Hematological Malignancies.

Allogeneic stem cell transplantation from haploidentical donor using post-transplantation cyclophosphamide has been used to cure hematological diseases. Because of slow immunological reconstitution, there is an increased incidence of viral infection. The aim of our study was to prospectively evaluate the efficacy and the feasibility of a CD45RA+ depleted donor lymphocytes infusion (DLI) in terms of reduction of viral infection early after haploidentical transplantation. This a prospective single-center study. We enrolled 23 patients, of whom 19 were evaluable. Graft-versus-host disease (GVHD) prophylaxis was the same for all patients. The primary endpoint was 100-day cumulative incidence of viral infections. The primary endpoint was met, because the 100-day cumulative incidence of viral infection was 32%. The median time from transplantation to first CD45RA+ depleted DLI was 55 days (range, 46-63). 28% of patients had cytomegalovirus reactivation, no patients reactivated human herpesvirus-6; 1 patient developed BK virus related hemorrhagic cystitis. Most of the patients received the planned 3 infusions. Only 1 patient had development of grade 2 acute GVHD, and 2 patients had moderate chronic GVHD. All evaluable patients were off immunosuppressive therapy at last follow-up. The median follow-up was 12 months (range, 3-23), the 1-year overall survival and progression-free survival were 79% and 75%, respectively; the 100-day and 1-year non-relapse mortality were 5% and 12%, respectively. CD45RA+ depleted DLI are feasible in patients treated with haploidentical transplantation. The toxic profile is good with a low risk for development of both acute and chronic GVHD.

Desensitization with plasma exchange in a patient with human leukocyte antigen donor-specific antibodies before T-cell-replete haploidentical transplantation.

BACKGROUND: The presence of human leukocyte antigen donor-specific antibodies (DSAs) increases the risk of graft failure in T-cell-replete haploidentical hematopoietic stem cell transplantation (haplo-HSCT) CASE REPORT: A 49-year-old female with high-risk acute myeloid leukemia in first complete remission received a haplo-HSCT from her daughter. Pretransplant recipient screening examination showed high DSAs levels against unshared class I leukocyte antigens. RESULTS: The patient underwent a desensitization program consisting of plasma exchange (PEX), polyvalent intravenous (IV) immunoglobulins, and IV tacrolimus and mycophenolate mofetil (MMF). This protocol resulted in the disappearance of the DSA anti HLA B41. Engraftment was prompt with stable full donor chimerism. CONCLUSIONS: This case report suggests that the adopted scheme is safe for reducing DSA levels and facilitating donor engraftment in patients scheduled for haplo-HSCT.

Role of naive-derived T memory stem cells in T-cell reconstitution following allogeneic transplantation.

Early T-cell reconstitution following allogeneic transplantation depends on the persistence and function of T cells that are adoptively transferred with the graft. Posttransplant cyclophosphamide (pt-Cy) effectively prevents alloreactive responses from unmanipulated grafts, but its effect on subsequent immune reconstitution remains undetermined. Here, we show that T memory stem cells (TSCM), which demonstrated superior reconstitution capacity in preclinical models, are the most abundant circulating T-cell population in the early days following haploidentical transplantation combined with pt-Cy and precede the expansion of effector cells. Transferred naive, but not TSCM or conventional memory cells preferentially survive cyclophosphamide, thus suggesting that posttransplant TSCM originate from naive precursors. Moreover, donor naive T cells specific for exogenous and self/tumor antigens persist in the host and contribute to peripheral reconstitution by differentiating into effectors. Similarly, pathogen-specific memory T cells generate detectable recall responses, but only in the presence of the cognate antigen. We thus define the cellular basis of T-cell reconstitution following pt-Cy at the antigen-specific level and propose to explore naive-derived TSCM in the clinical setting to overcome immunodeficiency. These trials were registered at www.clinicaltrials.gov as #NCT02049424 and #NCT02049580.

CD34+ dose-driven administration of granulocyte colony-stimulating factor after high-dose chemotherapy in lymphoma patients.

Our goal was to optimize use of granulocyte colony-stimulating factor (G-CSF) after high-dose chemotherapy and autologous peripheral blood stem-cell transplantation in lymphoma patients, limiting G-CSF administration to patients infusing a suboptimal CD34(+) cell number. Of 124 consecutive patients with histologically proven Hodgkin's and non-Hodgkin's lymphoma from January 2001 to June 2004, 60 patients (group 1) given > or = 5 x 10(6)/kg CD34(+) cells received no G-CSF; 64 patients (group 2) given < or = 5 x 10(6)/kg CD34(+) cells received G-CSF from day +5 after stem-cell reinfusion. The median times to reach 0.5 x 10(9)/L and 1.0 x 10(9)/L neutrophils were, respectively, 3 and 4 d shorter in G-CSF group and this difference was statistically significant (P = 0.0014; P = 0.0001). In terms of antibiotic and antimycotic requirements, gastrointestinal toxicity, days of hospitalization, and transfusion requirements, no differences were demonstrated between the two groups. No statistically significant difference was demonstrated for the total number of febrile episodes (52 for group 1; 53 for group 2; P = 0.623) and the median number of febrile days (2 d for both groups). Myeloid reconstitution values for both groups agree with published results for autotransplanted patients treated with G-CSF from 7 to 14 d. Also, major clinical events, antibiotic, antimycotic, and transfusion requirements, and hospital stay were similar to published findings. Our data suggest that G-CSF administration can be safely optimized, used only for patients infused with a suboptimal CD34(+) cell dose.

Tandem high-dose chemotherapy and autologous stem cell transplantation in refractory/relapsed Hodgkin's lymphoma: a monocenter prospective study.

We designed a prospective study to evaluate the feasibility and efficacy of tandem high-dose chemotherapy (HDCT) in the treatment of refractory or relapsed Hodgkin's lymphoma (HL). Thirty-two patients were treated with salvage chemotherapy (IGEV, ifosfamide, gemcitabine, and vinorelbine) and chemo-sensitive patients received a first HDCT course with melphalan 200 mg/m(2) (MEL200) and a second BEAM course. The median time interval between the two HDCT courses was 66 days. The median number of reinfused CD34(+) cells was 4.7 x 10(6)/kg after MEL200 and 5.8 x 10(6)/kg after BEAM. The hematological reconstitution after both HDCT courses did not differ. No grade III or IV renal, hepatic, lung, cardiac, and neurological toxicity was observed. Severe (grade III and IV) oral mucositis was the most prominent complication affecting 60 and 50% of patients after MEL200 and BEAM, respectively. Fever of unknown origin occurred in 65 and 70% of patients after MEL200 and BEAM, respectively. One patient died from septic shock during the aplasia period following BEAM. In an intention-to-treat analysis, the overall response rate increased after each stage of protocol, ranging from 47% to 65% and 75% after IGEV, MEL200, and BEAM, respectively. Tandem HDCT is feasible and effective in patients with relapsed or refractory HL.

Are interleukin-16 and thrombopoietin new tools for the in vitro generation of dendritic cells?

The effects of interleukin 16 (IL-16) on dendritic cell (DC) generation from human CD34(+) progenitor cells are not known. Here, we show that IL-16 added to a basal cocktail comprised of granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-4, Flt-3 ligand (Flt3L), and tumor necrosis factor alpha (TNF-alpha) does induce the CD34(+) hematopoietic cells to proliferate in vitro and to differentiate into phenotypically and functionally mature DCs. IL-16 exerts this function more efficiently than stem cell factor (SCF) as a control, thrombopoietin (TPO), or IL-16 plus TPO. Moreover, we show that the combination of IL-16 plus TPO induces the generation of tolerogenic DCs, able to induce an anergic state in T cells that persists when T cells are rechallenged with immunogenic DCs. An altered pattern of cytokine production, a reduced expression of the C-type lectin DC-SIGN, and an increased surface expression of the inhibitory molecules immunoglobulin-like transcript 2 (ILT-2), ILT-3, and ILT-4 may all contribute to confer the tolerogenic properties of these DCs. Generation of tolerogenic DCs may aid the exploration of new therapeutic strategies to promote tolerance to autoantigens and prevent disease development.

Feasibility and toxicity of high-dose therapy (HDT) supported by peripheral blood stem cells in elderly patients with multiple myeloma and non-Hodgkin's lymphoma: survey from a single institution.

The aim of this retrospective study was to investigate the feasibility of high-dose therapy (HDT) followed by peripheral blood stem cell transplantation (PBSCT) in elderly patients with hematological malignancies. From April 1998 to November 2001, 40 elderly patients (defined as > or =60 years) with non-Hodgkin's lymphoma (12 patients) and multiple myeloma (28 patients) were evaluated. Seven lymphoma and one myeloma patients were in complete remission (CR), 27 in partial remission (PR), two had stable disease (SD), and three progressive disease (PD). The median age was 65 years (range 60-71). Thirty-nine patients were mobilized with chemotherapy plus granulocyte-colony stimulating factor (G-CSF) and one with G-CSF alone. Patients received HDT including melphalan alone in 32 cases or combined with other drugs in six and BEAM in two. The median number of collected CD34(+) cells was 12.4 x 10(6)/kg (range 2.0-68.9). The median number of re-infused CD34(+) cells was 9.9 x 10(6)/kg (range 2.0-68.9). All patients engrafted after PBSC and the median time to neutrophil recovery (N > 500/micro l) and platelet recovery (PLT > 20,000/micro l) was 8 days (range 5-18) and 6 days (range 5-18), respectively. Nonhematological toxicity was mild and no patient died from transplant-related toxicity (TRM). Median duration of hospitalization was 18 days (range 12-24). To date, 32 patients are alive and eight died from disease progression at a median follow-up interval of 24 months. HDT supported by PBSC is a feasible procedure in selected elderly patients, and an age of more than 60 years should not be considered a contraindication for HDT.