Dual targeting of CD19 and CD22 with Bicistronic CAR-T cells in Patients with Relapsed/Refractory Large B Cell Lymphoma

Relapse following CD19-directed chimeric antigen receptor T-cells (CAR-T) for relapsed/refractory large B-cell lymphoma (r/r LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multi-antigen targeting and PD-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in r/r LBCL as inpatient or outpatient therapy (NCT03289455, https://clinicaltrials.gov/ct2/show/NCT03289455). Endpoints include toxicity (primary) and response rates (secondary). AUTO3 was manufactured for 62 patients using autologous leukapheresis, modified with a bicistronic transgene. 52 patients received AUTO3 (7/52,50x106; 45/52,150-450x106) and 48/52 received pembrolizumab. Median age was 59 years (range,27-83) and 46/52 had stage III/IV disease. Median follow-up was 21.6 months (range,15.1-51.3) at last data cut (Feb 28, 2022). AUTO3 was safe: grade 1-2 and grade 3 CRS affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), HLH affected 2 patients, and no Pembrolizumab-associated autoimmune sequalae were observed. On this basis, outpatient administration was tested in 20 patients, saving a median of 14 hospital days/patient. AUTO3 was effective: overall response rates were 66% (48.9%, CR; 17%, PR). For patients with CR, median DOR was not reached, with 54.4% (CI: 32.8, 71.7) projected to remain progression-free beyond 12 months after onset of remission. DOR for all responding patients was 8.3 months (95% CI: 3.0, NE) with 42.6% projected to remain progression-free beyond 12 months after onset of remission. Overall, AUTO3 +/- pembrolizumab for r/r LBCL was safe, lending itself to outpatient administration, and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation-AUTO3, engineered for superior expansion/persistence in vivo, and selection of CAR binders active at low antigen densities

Bridging Therapy With Axicabtagene Ciloleucel for Large B-Cell Lymphoma: Results From the US Lymphoma Car-T Consortium

During the manufacturing period of autologous chimeric antigen receptor (CAR) T-cell therapy, patients may experience a decline in their condition due to cancer progression. In this study, we investigated the impact of bridging therapy (BT) on the outcome of patients with relapsed/refractory large B-cell lymphoma who received antilymphoma treatment between leukapheresis and axicabtagene ciloleucel (axi-cel) infusion. We conducted our analysis using data from the multicenter US Lymphoma CAR-T Consortium, with a median follow-up of 33 months (range, 4.3-42.1). Out of the 298 patients who underwent leukapheresis, 275 patients received axi-cel. A total 52% of patients (n = 143) who received BT had a higher baseline risk profile than patients who did not receive BT, and these patients, as a group, had inferior outcomes compared with those who did not receive BT. However, after propensity score matching between the 2 groups, there were no statistically significant differences in overall response rate (77% vs 87%; P = .13), complete response rate (58% vs 70%; P = .1), progression-free survival (hazard ratio [HR], 1.25; P = .23), and overall survival (HR, 1.39; P=.09) between the BT group and the no-BT group, respectively. Analyzing the effects of BT in the whole cohort that underwent leukapheresis regardless of receiving axi-cel (intention-to-treat analysis) showed similar results. Radiation BT resulted in outcomes similar to those observed with nonradiation BT. Our findings suggest that BT may be safe without a significant impact on long-term survival for patients who require disease stabilization during the manufacturing period. Moreover, our results suggest that there is no clear advantage to using radiation-based BT over nonradiation-based BT

Hematopoietic Cell Transplant compared with Standard Care in Adolescents and Young Adults with Sickle Cell Disease.

Disease-modifying therapies are standard of care (SOC) for sickle cell disease (SCD), but hematopoietic cell transplantation (HCT) has curative potential. We compared outcomes prospectively through 2-years after biologic assignment to a Donor or No Donor (SOC) Arm based on the availability of an HLA-matched sibling or unrelated donor (BMTCTN 1503; NCT02766465). A donor search was commenced after eligibility confirmation. The primary endpoint was the comparison of survival 2 years after biologic assignment between treatment arms. Power calculations required 60 participants on the Donor Arm and 140 on the No Donor Arm to determine if early transplant-related mortality might be balanced by disease-related mortality over a longer period of follow-up. Secondary objectives compared changes in SCD-related events, functional outcomes, and organ function. Data were analyzed by the intent-to-treat principle. A total of 113 participants were enrolled, 28 on the Donor and 85 on the No Donor Arm The 2-year probabilities of survival were 89% and 93%, on the Donor and No Donor Arms, respectively. Vaso-occlusive pain (VOC) was less frequent on the Donor Arm in the second year after biologic assignment (p < 0.001). On PROMIS-57 surveys there was decreased fatigue (p=0.003) and an increased ability to participate in social roles and activities (p=0.003) on the Donor Arm 2-years after biologic assignment. Differences in other secondary outcomes did not reach statistical significance. Barriers to accrual prevented an objective comparison of survival. Assignment to the Donor Arm led to improvements in VOC, fatigue, and social function

Impact of Second Primary Malignancy Post–Autologous Transplantation on Outcomes of Multiple Myeloma: A CIBMTR Analysis

The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P \u3c .001 and HR 5.01, P \u3c .001, respectively) and OS (HR 3.85, P \u3c .001 and HR 8.13, P \u3c .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post-auto-HSCT

Allogeneic Hematopoietic Cell Transplantation for Blastic Plasmacytoid Dendritic Cell Neoplasm: A CIBMTR Analysis

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes

Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide

Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival

Immunologic Outcomes of Allogeneic Stem Cell Transplantation: Graft-Versus-Host and Graft-Versus-Leukemia Responses and Implications for Future Therapy

Allogeneic stem cell transplantation (allo-HCT) is a procedure with the potential to cure many malignant and nonmalignant diseases. The adoptive transfer of a donor immune system into a transplant recipient can result in allorecognition and reactivity of donor immune cells against host target tissues. This can lead to an immune attack against normal tissues in the recipient (graft-versus-host disease, GVHD) but also against the neoplastic cells themselves (graft-versus-tumor effect, GVT). While GVHD has long been recognized as a significant cause of morbidity and mortality after allo-HCT, there has been little progress in advancing the standards of care for GVHD prophylaxis and therapy, which have remain unchanged for more than two decades. Given the more recent recognition that much of the curative benefit of allo-HCT results from the GVT effect, rather than from the cytoreductive effects of conditioning chemotherapy, multiple strategies to take advantage of the GVT effect that aim to limit morbidity and mortality due to GVHD are under investigation, including cellular therapies employing the use of native or engineered graft populations enriched for antitumor responses, and employing donor lymphocyte infusions. Another critical question is how strategies to prevent and/or treat GVHD may be designed to limit the suppression of beneficial T cell responses against pathogens critical to limiting infections in the post-HCT setting. Research in murine models and human subjects has uncovered a great deal regarding the mechanisms of GVHD initiation and persistence, including clinical factors and graft constituents responsible for the acute and chronic forms of GVHD. A variety of cellular mediators, from antigen-presenting cells to effectors, including alloreactive T cells and B cells, have been characterized. Regulatory populations, including CD4+ regulatory T cells and invariant NKT cells, have also been shown to be capable of ameliorating GVHD intensity and survival in model systems. Given this clearer understanding of GVHD pathophysiology, a variety of novel clinical strategies are in development, from those utilizing classical inhibitors of T cell reactivity, to monoclonal antibody therapies to more novel approaches targeting specific signaling pathways in T cells and other mediators of inflammation. Recent meaningful progress has also been made in approaches using adoptive cellular therapies to decrease GVHD while maintaining or specifically augmenting GVT responses. These strategies bring promise for a future wherein more patients can receive allo-HCT for both malignant and nonmalignant diseases, with reduced rates of complications and improved overall survival

Increased polyclonal CD5+ B1a lymphocytes in a haploidentical stem cell transplant recipient

Atypical lymphocyte populations may be seen in the peritransplant setting. In this case report, we describe an unusually high number of CD5+ B-cells (B1a cells) following transplant. B1a cells identified during routine follow-up by immunophenotypic analysis in a middle-aged man who had a haploidentical stem cell transplant for acute myeloid leukemia were compared with a reference set of post-transplant samples. Increased but polyclonal B1a cells were identified with 100% donor chimerism. Our case demonstrates that a high absolute number of B1a cells may be seen post-transplant and should not be confused with an atypical CD5+ lymphoproliferative disorder. Furthermore, the population of polyclonal CD5+ B lymphocytes from the patient's donor is prominent 7 months post-transplant. This suggests that the maintenance of CD5+ B1 cells prior to conversion to adult-type CD5⁻ B2 cells is not hindered by the recipient adult stromal environment

New prospects for drug development: the hedgehog pathway revealed. Focus on hematologic malignancies

The hedgehog (Hh) pathway is a critical regulator of vertebrate embryonic development and is involved in the function of processes such as stem cell maintenance and differentiation, tissue polarity and cell proliferation. Given how critical these functions are, it is not surprising that mutations in Hh pathway components are often implicated in the tumorigenesis of a variety of human cancers. Promotion of tumor growth has recently been shown by activated Hh signaling in the tumor itself, as well as by pathway activation within surrounding cells comprising the tumor microenvironment. Targeted disruption of various Hh pathway proteins has been successfully employed as an anticancer strategy with several synthetic Hh antagonists now available. Here, the molecular basis of Hh signaling, the therapeutic rationales for targeting this pathway and the current status of Hh pathway inhibitors in the clinic are reviewed