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Background B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T-cell therapy is an emerging treatment option for multiple myeloma. The aim of this systematic review and meta-analysis was to determine its safety and clinical activity and to identify factors influencing these outcomes. Methods We performed a database search using the terms “BCMA,” “CAR,” and “multiple myeloma” for clinical studies published between 01/01/2015 and 01/01/2020. The methodology is further detailed in PROSPERO (CRD42020125332). Results Twenty-three different CAR-T-cell products have been used so far in 640 patients. Cytokine release syndrome was observed in 80.3% (69.0–88.2); 10.5% (6.8–16.0) had neurotoxicity. A higher neurotoxicity rate was reported in studies that included more heavily pretreated patients: 19.1% (13.3–26.7; I 2  = 45%) versus 2.8% (1.3–6.1; I 2  = 0%) ( p  < 0.0001). The pooled overall response rate was 80.5% (73.5–85.9); complete responses (CR) were observed in 44.8% (35.3–54.6). A pooled CR rate of 71.9% (62.8–79.6; I 2  = 0%) was noted in studies using alpaca/llama-based constructs, whereas it was only 18.0% (6.5–41.1; I 2  = 67%) in studies that used retroviral vectors for CAR transduction. Median progression-free survival (PFS) was 12.2 (11.4–17.4) months, which compared favorably to the expected PFS of 1.9 (1.5–3.7) months (HR 0.14; p  < 0.0001). Conclusions Although considerable toxicity was observed, BCMA-targeted CAR-T-cell therapy is highly efficacious even in advanced multiple myeloma. Subgroup analysis confirmed the anticipated inter-study heterogeneity and identified potential factors contributing to safety and efficacy. The results of this meta-analysis may assist the future design of CAR-T-cell studies and lead to optimized BCMA CAR-T-cell products.

JAK1/2 inhibitor ruxolitinib (RUX) is approved in patients with myelofibrosis but the impact of pretreatment with RUX on outcome after allogeneic hematopoietic stem cell transplantation (HSCT) remains to be determined. We evaluated the impact of RUX on outcome in 551 myelofibrosis patients who received HSCT without ( n  = 274) or with ( n  = 277) RUX pretreatment. The overall leukocyte engraftment on day 45 was 92% and significantly higher in RUX responsive patients than those who had no or lost response to RUX (94% vs. 85%, p  = 0.05). The 1-year non-relapse mortality was 22% without significant difference between the arms. In a multivariate analysis (MVA) RUX pretreated patients with ongoing spleen response at transplant had a significantly lower risk of relapse (8.1% vs. 19.1%; p  = 0.04)] and better 2-year event-free survival (68.9% vs. 53.7%; p  = 0.02) in comparison to patients without RUX pretreatment. For overall survival the only significant factors were age > 58 years ( p  = 0.03) and HLA mismatch donor ( p  = 0.001). RUX prior to HSCT did not negatively impact outcome after transplantation and patients with ongoing spleen response at time of transplantation had best outcome.

Active immunization using tumor antigen-loaded dendritic cells holds promise for the adjuvant treatment of cancer to eradicate or control residual disease, but so far, most dendritic cell trials have been performed in end-stage cancer patients with high tumor loads. Here, in a phase I/II trial, we investigated the effect of autologous dendritic cell vaccination in 10 patients with acute myeloid leukemia (AML). The Wilms' tumor 1 protein (WT1), a nearly universal tumor antigen, was chosen as an immunotherapeutic target because of its established role in leukemogenesis and superior immunogenic characteristics. Two patients in partial remission after chemotherapy were brought into complete remission after intradermal administration of full-length WT1 mRNA-electroporated dendritic cells. In these two patients and three other patients who were in complete remission, the AML-associated tumor marker returned to normal after dendritic cell vaccination, compatible with the induction of molecular remission. Clinical responses were correlated with vaccine-associated increases in WT1-specific CD8⁺ T cell frequencies, as detected by peptide/HLA-A*0201 tetramer staining, and elevated levels of activated natural killer cells postvaccination. Furthermore, vaccinated patients showed increased levels of WT1-specific IFN-γ–producing CD8⁺ T cells and features of general immune activation. These data support the further development of vaccination with WT1 mRNA-loaded dendritic cells as a postremission treatment to prevent full relapse in AML patients.

To the Editor: The description of a man with erythrocytosis and perinephric fluid collections recently appeared in the Case Records of the Massachusetts General Hospital 1 (Patient 1 in Table 1), and the authors of that article appealed to readers to share similar cases. Two additional patients were identified (Patients 2 and 3), and a review of the literature identified three more patients with similar findings 2 – 4 (Patients 4, 5, and 6). These six patients shared five characteristics — telangiectasias, elevated erythropoietin level and erythrocytosis, monoclonal gammopathy, perinephric-fluid collections, and intrapulmonary shunting — defining a syndrome that we have termed the TEMPI . . .

Abstract Background There is currently no consensus on optimal duration of antibiotic treatment in febrile neutropenia. We report on the clinical impact of implementation of antibiotic de-escalation and discontinuation strategies based on the Fourth European Conference on Infections in Leukaemia (ECIL-4) recommendations in high-risk hematological patients. Methods We studied 446 admissions after introduction of an ECIL-4–based protocol (hereafter “ECIL-4 group”) in comparison to a historic cohort of 512 admissions. Primary clinical endpoints were the incidence of infectious complications including septic shock, infection-related intensive care unit (ICU) admission, and overall mortality. Secondary endpoints included the incidence of recurrent fever, bacteremia, and antibiotic consumption. Results Bacteremia occurred more frequently in the ECIL-4 group (46.9% [209/446] vs 30.5% [156/512]; P < .001), without an associated increase in septic shock (4.7% [21/446] vs 4.5% [23/512]; P = .878) or infection-related ICU admission (4.9% [22/446] vs 4.1% [21/512]; P = .424). Overall mortality was significantly lower in the ECIL-4 group (0.7% [3/446] vs 2.7% [14/512]; P = .016), resulting mainly from a decrease in infection-related mortality (0.4% [2/446] vs 1.8% [9/512]; P = .058). Antibiotic consumption was significantly reduced by a median of 2 days on antibiotic therapy (12 vs 14; P = .001) and 7 daily antibiotic doses (17 vs 24; P < .001) per admission period. Conclusions Our results support implementation of ECIL-4 recommendations to be both safe and effective based on real-world data in a large high-risk patient population. We found no increase in infectious complications and total antibiotic exposure was significantly reduced. Implementation of antibiotic de-escalation and discontinuation prior to neutrophil recovery did not lead to an increase in infectious complications. Total antibiotic exposure was significantly reduced by a median of 7 daily doses.

Additional cases are reported in which bortezomib reverses many of the manifestations of the TEMPI syndrome. To the Editor: We recently described the TEMPI syndrome (Aug. 4, 2011), 1 which is characterized by the pentad of telangiectasias, elevated erythropoietin level and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting. One of the patients (Patient 2) had a dramatic response to treatment with the proteasome inhibitor bortezomib, and we hypothesized that the paraprotein may play a role in the pathophysiology of the TEMPI syndrome. Patient 2, a 48-year-old woman, received a total of eight cycles of intravenous bortezomib (four doses of 1.3 mg per square meter of body-surface area per cycle). Her telangiectasias disappeared (Figure 1, Panels . . .

Donor cell leukaemia (DCL) is a rare complication of allogeneic haematopoietic cell transplantation (HCT). We have investigated the prevalence and outcome of donor cell haematology malignancies within centres registered with the European Society of Blood and Marrow transplantation (EBMT). We have sought to identify risk factors to shed light on the pathogenesis of DCL as a model for leukaemogenesis. DCL cases were identified by questionnaire and a follow-up questionnaire requested detailed data. Control subjects from the EBMT registry who had not developed DCL were used for a matched pair analysis to identify risk factors. We identified 38 patients with DCL; the estimated prevalence was 80.5/100,000 transplants. Patients were predominantly treated for haematological malignancy. A clone was retrospectively identified in 7/25 (28%) donors for whom data was available. Overall survival was poor with 29/38 patients dead a median of 11 (range 0–91) months after DCL diagnosis. Matched case-pair analysis identified three factors on multivariate analysis as significantly associated with an increased risk for DCL: use of growth factors within the first 100 days after transplantation, in vivo T-cell depletion and multiple allografts. The risk factors identified, support reduced immune surveillance and replicative stress as pathogenic in the development of DCL.

The present study aimed at describing the outcome of patients with HIV-associated lymphomas following autologous hematopoietic stem cell transplantation (autoHCT) in the rituximab and combined antiretroviral therapy (cART) era. Eligible for this retrospective study were HIV-positive patients with lymphoma who received autoHCT between 2007 and 2013. A total of 118 patients were included with a median age of 45 years (range 24–66). Underlying diagnoses were diffuse large B cell lymphoma in 47%, Hodgkin lymphoma in 24%, Burkitt lymphoma in 18%, and plasmablastic lymphoma in 7% of patients. Disease status at autoHCT was complete remission in 44%, partial remission (PR) in 38%, and less than PR in 18% of the patients. With a median follow-up of 4 years, 3-year non-relapse mortality, incidence of relapse, progression-free survival (PFS) and overall survival (OS) were 10%, 27%, 63% and 66%, respectively. By multivariate analysis, disease status less than PR but not CD4+ cell count at the time of autoHCT was a significant predictor of unfavorable PFS and OS. In conclusion, in the era of cART and chemoimmunotherapy, the outcome of autoHCT for HIV-related lymphoma is driven by lymphoma-dependent risk factors rather than by characteristics of the HIV infection.

Poor graft function (PGF) is a rare but serious complication of allogeneic hematopoietic cell transplantation (alloHCT). Due to their hematopoietic supporting properties and immune regulatory effects, multipotent mesenchymal stromal cells (MSC) could be considered a good candidate to help to restore bone marrow (BM) niches homeostasis and facilitate hematopoiesis after alloHCT. We prospectively assessed the efficacy and safety of ex-vivo expanded BM-derived MSC from third-party donor in a series of 30 patients with prolonged severe cytopenia and PGF after alloHCT. This multicenter trial was registered at www.clinicaltrials.gov (#NTC00603330). Within 90 days post-MSC infusion, 53% (95% CI, 35 - 71%) of patients improved at least one cytopenia (overall response, OR) and 37% (95% CI, 19 - 54%) achieved a complete hematological response (CR: absolute neutrophil count, ANC >0.5 x 10 /L, Hb > 80g/L and platelet count > 20 x 10 /L with transfusion independence). Corresponding response rates increased to 67% (95% CI, 50 - 84%) OR and 53% (95% CI, 35 - 71%) CR within 180 days after MSC infusion. A significant decrease in red blood cells and platelets transfusion requirement was observed after MSC (median of 30-days transfusion requirement of 0.5 and 0 from d90-120 post-MSC versus 5 and 6.5 before MSC, respectively, p ≤0.001). An increase in ANC was also noted by day +90 and +180, with 3/5 patients with severe neutropenia having recovered an ANC > 1 x 10 /L within the 90-120 days after MSC infusion. Overall survival at 1 year post-MSC was 70% (95% CI, 55.4 - 88.5), with all but one of the patients who achieved CR being alive. A single infusion of third-party MSC appeared to be safe, with the exception of one deep vein thrombotic event possibly related to the intervention. In conclusion, a single i.v. infusion of BM-derived MSC from third party donor seemed to improve hematological function after alloHCT, although spontaneous amelioration cannot be excluded. Comparative studies are warranted to confirm these encouraging results.