Longitudinal analysis of gut microbiome and metabolome correlates of response and toxicity with idecabtagene vicleucel.

Increasing evidence suggests that the gut microbiome may influence the responses and toxicities associated with chimeric antigen receptor T-cell (CAR-T) therapy. We conducted whole-genome shotgun sequencing on stool samples (N = 117) collected at various times from patients with multiple myeloma (n = 33) who underwent idecabtagene vicleucel (ide-cel) anti-B-cell maturation antigen CAR-T therapy. We observed a significant decrease in bacterial diversity after ide-cel infusion, along with significant differences in the bacterial composition linked to therapy response and toxicities.

Antibiotic-induced loss of gut microbiome metabolic output correlates with clinical responses to CAR T-cell therapy.

Antibiotic (ABX)-induced microbiome dysbiosis is widespread in oncology, adversely affecting outcomes and side effects of various cancer treatments, including immune checkpoint inhibitors and chimeric antigen receptor T-cell (CAR-T) therapies. In this study, we observed that prior exposure to broad-spectrum ABXs with extended anaerobic coverage such as piperacillin-tazobactam and meropenem was associated with worse anti-CD19 CAR-T therapy survival outcomes in patients with large B-cell lymphoma (N = 422) than other ABX classes. In a discovery subset of these patients (n = 67), we found that the use of these ABXs was in turn associated with substantial dysbiosis of gut microbiome function, resulting in significant alterations of the gut and blood metabolome, including microbial effectors such as short-chain fatty acids (SCFAs) and other anionic metabolites, findings that were largely reproduced in an external validation cohort (n = 58).

Transplantation Outcomes of Myelofibrosis with Busulfan and Fludarabine Myeloablative Conditioning.

Outcomes of myelofibrosis (MF) with allogeneic stem cell transplantation (allo-SCT) have improved over the past decade, related in part to advances in supportive treatments and conditioning regimens. Several factors are known to predict transplantation outcomes. However, most studies lack homogeneity in conditioning regimens used, limiting their ability to assess prognostic factors on transplantation outcomes.

A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy.

Increasing evidence suggests that the gut microbiome may modulate the efficacy of cancer immunotherapy. In a B cell lymphoma patient cohort from five centers in Germany and the United States (Germany, n = 66; United States, n = 106; total, n = 172), we demonstrate that wide-spectrum antibiotics treatment ('high-risk antibiotics') prior to CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is associated with adverse outcomes, but this effect is likely to be confounded by an increased pretreatment tumor burden and systemic inflammation in patients pretreated with high-risk antibiotics. To resolve this confounding effect and gain insights into antibiotics-masked microbiome signals impacting CAR-T efficacy, we focused on the high-risk antibiotics non-exposed patient population.

A polyamine-centric, blood-based metabolite panel predictive of poor response to CAR-T cell therapy in large B cell lymphoma.

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy for relapsed or refractory (r/r) large B cell lymphoma (LBCL) results in durable response in only a subset of patients. MYC overexpression in LBCL tumors is associated with poor response to treatment. We tested whether an MYC-driven polyamine signature, as a liquid biopsy, is predictive of response to anti-CD19 CAR-T therapy in patients with r/r LBCL.

Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma.

Unlabelled: To explore the role of clonal hematopoiesis (CH) in chimeric antigen receptor (CAR) T-cell therapy outcomes, we performed targeted deep sequencing on buffy coats collected during the 21 days before lymphodepleting chemotherapy from 114 large B-cell lymphoma patients treated with anti-CD19 CAR T cells. We detected CH in 42 (36.8%) pretreatment samples, most frequently in PPM1D (19/114) and TP53 (13/114) genes.

Real-world long-term outcomes in multiple myeloma with VRD induction, Mel200-conditioned auto-HCT, and lenalidomide maintenance.

Standard-of-care for newly-diagnosed, autologous hematopoietic stem cell transplantation (auto-HCT)-eligible, multiple myeloma (MM) patients includes bortezomib, lenalidomide, and dexamethasone (VRD) induction followed by melphalan 200 mg/m (Mel200)-conditioned auto-HCT and lenalidomide maintenance. We completed a retrospective case series assessing outcomes of 187 MM patients who received this regimen at our institution. The 100-day non-relapse mortality incidence was zero.

Allogeneic hematopoietic cell transplantation for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN).

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is an aggressive hematological malignancy; however, some patients achieve durable remission with allogeneic hematopoietic cell transplantation (allo-HCT). We report on all 17 patients with BPDCN who underwent allo-HCT at our center between 2000 and 2020. The median age was 39 (18-67) years.

A randomized phase 2 trial of idiotype vaccination and adoptive autologous T-cell transfer in patients with multiple myeloma.

We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding antimyeloma idiotype (Id)-keyhole limpet hemocyanin (KLH) vaccine to vaccine-specific costimulated T cells. In this randomized phase 2 trial, patients received either control (KLH only) or Id-KLH vaccine, autologous transplantation, vaccine-specific costimulated T cells expanded ex vivo, and 2 booster doses of assigned vaccine. In 36 patients (KLH, n = 20; Id-KLH, n = 16), no dose-limiting toxicity was seen.

Chimeric Antigen Receptor T-Cells in B-Acute Lymphoblastic Leukemia: State of the Art and Future Directions.

Use of adoptive T-cell therapy modified with chimeric antigen receptor (CAR-T) has revolutionized treatment of patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). CAR-T cells directed against CD19 antigen have produced response rates as high as 90% in clinical trials for r/r B-ALL. Despite high rates of complete remissions, the durability of responses has been sub-optimal with frequent relapses, especially in adult B-ALL population.

Idiopathic refractory ascites after allogeneic stem cell transplantation: a previously unrecognized entity.

At our center, we observed a series of patients who developed transudative refractory ascites secondary to noncirrhotic, non-veno-occlusive disease (VOD)-related portal hypertension after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients were considered to have idiopathic portal hypertension-related refractory ascites (IRA) if they developed ascites secondary to intrahepatic portal hypertension (serum ascites albumin gradient ≥1.1 g/dL or hepatic venous pressure gradient [HVPG] >5 mm Hg), but did not meet the clinical criteria for classical VOD/sinusoidal obstructive syndrome (SOS) and did not have any alternate etiology of portal hypertension.

Postrelapse survival in diffuse large B-cell lymphoma after therapy failure following autologous transplantation.

Outcomes for diffuse large B-cell lymphoma (DLBCL) patients relapsing after autologous hematopoietic cell transplantation (auto-HCT) have been historically poor. We studied outcomes of such patients using data from 4 transplantation centers. Eligibility criteria included adult patients (age ≥18 years) with DLBCL experiencing disease relapse after auto-HCT performed during 2006 to 2015.

Impact of Donor Type and Melphalan Dose on Allogeneic Transplantation Outcomes for Patients with Lymphoma.

We analyzed 186 patients with lymphoma who underwent allogeneic stem cell transplantation (ASCT) with fludarabine-melphalan (FM) conditioning and different types of donors (25 haploidentical [HD], 98 matched unrelated [MUD], and 63 matched related [MRD]) at our institution between September 2009 and January 2018. Patients received fludarabine 160 mg/m (40 mg/m/day for 4 days) in combination with 1 dose of melphalan 140 mg/m (FM140) or 100 mg/m (FM100). Engraftment was similar among the 3 groups (92%, 89%, and 98%, respectively; P = .

Elderly do benefit from induction chemotherapy: High dose mitoxantrone-based ("5 + 1") induction chemotherapy regimen in newly diagnosed acute myeloid leukemia.

An intensive "5 + 1" regimen, which included bolus high dose cytarabine (HiDAC) at 3 g/m once daily over 3 hours on days 1-5 and high dose mitoxantrone (HDM) 80 mg/m on day 2, was evaluated in 101 consecutively treated newly diagnosed acute myeloid leukemia (AML) patients at a single center since 2009. The median age was 65 (range 18-90) years. The 4 and 8-week mortality in our cohort was 3/101 (2.

Rare gene fusion rearrangement SPTNB1-PDGFRB in an atypical myeloproliferative neoplasm.

The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia recognizes a distinct class of myeloid and lymphoid tumors with eosinophilia-related proliferations associated with specific gene rearrangements, one of which involves rearrangements of platelet-derived growth factor receptor B (PDGFRB) gene. We report a case of a rare PDGFRB rearrangement with SPTNB1 (spectrin beta, nonerythrocytic 1) that presented as atypical myeloproliferative neoplasm.