CAR-T cells for the treatment of pediatric chronic myeloid leukemia in repeatedly relapsed lymphoid blast phase.

Chronic myeloid leukemia presenting de novo in the blast phase (CML-BP) is a rare diagnosis among pediatric malignancies. We report on a 16-year-old male who presented with CML-BP lymphoid at diagnosis. He was treated with shortened acute lymphoblastic leukemia induction plus the tyrosine kinase inhibitor (TKI) imatinib followed by dasatinib. After achieving molecular remission (MR), hematopoietic stem cell transplantation (HSCT) was performed early after diagnosis. Despite prophylactic dasatinib, he relapsed 3 months later with the kinase domain mutation T315I. Multiple therapeutic approaches including ponatinib, blinatumomab, a 2nd HSCT from a different donor, donor lymphocyte infusions, and high-dose asciminib all resulted in subsequent relapse. Another molecular response was achieved by combining ponatinib plus asciminib with chemotherapy. In this situation, CD19-directed CAR-T cells (Kymriah®) were administered for compassionate use and tolerated without adverse events. Compared to all prior therapies, CAR T-cells maintained remission. After 12 months of follow-up, complete B-cell aplasia and low numbers of CAR-T cells are detectable in the peripheral blood, potentially mediating long-term disease control.

The Mechanisms of Altered Blood-Brain Barrier Permeability in CD19 CAR T-Cell Recipients.

Cluster of differentiation 19 (CD19) chimeric antigen receptor (CAR) T cells are a highly effective immunotherapy for relapsed and refractory B-cell malignancies, but their utility can be limited by the development of immune effector cell-associated neurotoxicity syndrome (ICANS). The recent discovery of CD19 expression on the pericytes in the blood-brain barrier (BBB) suggests an important off-target mechanism for ICANS development. In addition, the release of systemic cytokines stimulated by the engagement of CD19 with the CAR T cells can cause endothelial activation and decreased expression of tight junction molecules, further damaging the integrity of the BBB. Once within the brain microenvironment, cytokines trigger a cytokine-specific cascade of neuroinflammatory responses, which manifest clinically as a spectrum of neurological changes. Brain imaging is frequently negative or nonspecific, and treatment involves close neurologic monitoring, supportive care, interleukin antagonists, and steroids. The goal of this review is to inform readers about the normal development and microstructure of the BBB, its unique susceptibility to CD19 CAR T cells, the role of individual cytokines on specific elements of the brain's microstructural environment, and the clinical and imaging manifestations of ICANS. Our review will link cellular pathophysiology with the clinical and radiological manifestations of a complex clinical entity.

[Management of children and adolescents receiving CAR-T cell therapy for acute lymphoblastic leukemia].

Tisagenlecleucel, a commercially available CD19-targeted CAR-T cell product, has dramatically changed the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Tisagenlecleucel infusion has been linked to distinct acute adverse events, including cytokine release syndrome, neurotoxicity, hemophagocytic lymphohistiocytosis and prolonged pancytopenia, which are rare with cytocidal chemotherapy. In addition, recent retrospective studies have revealed pre-infusion prognostic factors including high tumor burden (bone marrow leukemia cell fraction ≥5%) and non-response to blinatumomab, another CD19-targeting agent. Not only physicians providing CAR-T cell therapy but also those referring patients for this therapy should thoroughly understand the indications and limitations, characteristic acute complications, pre-treatment factors affecting prognosis, and late complications. This article outlines the current understanding regarding the use of tisagenlecleucel in children and adolescents with B-ALL.

CAR T in patients with large B-cell lymphoma not fit for autologous transplant.

Large B-cell lymphoma (LBCL) patients with comorbidities and/or advanced age are increasingly considered for treatment with CD19 CAR T, but data on the clinical benefit of CAR T in the less fit patient population are still limited. We analysed outcomes of consecutive patients approved for treatment with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) by the UK National CAR T Clinical Panel, according to fitness for autologous stem cell transplant (ASCT). 81/404 (20%) of approved patients were deemed unfit for ASCT. Unfit patients were more likely to receive tisa-cel versus axi-cel (52% vs. 48%) compared to 20% versus 80% in ASCT-fit patients; p < 0.0001. The drop-out rate from approval to infusion was significantly higher in the ASCT-unfit group (34.6% vs. 23.5%; p = 0.042). Among infused patients, response rate, progression-free and overall survival were similar in both cohorts. CAR T was well-tolerated in ASCT-unfit patients with an incidence of grade ≥3 cytokine release syndrome and neurotoxicity of 2% and 11%, respectively. Results from this multicentre real-world cohort demonstrate that CD19 CAR T can be safely delivered in carefully selected older patients and patients with comorbidities who are not deemed suitable for transplant.

Comparing the efficacy of salvage regimens for relapsed/refractory B-cell acute lymphoblastic leukaemia: a systematic review and network meta-analysis.

The complete remission (CR) rate and overall survival (OS) of relapsed/refractory (R/R) B-cell acute lymphoblastic leukaemia (B-ALL) are not satisfactory. The available salvage regimens include standard chemotherapy, inotuzumab ozogamicin, blinatumomab and cluster of differentiation (CD)19 chimeric antigen receptor T cells (CAR T), and the NCCN guidelines recommend all of these therapies with no preference. Dual CD19/CD22 CAR T-cells have emerged as new treatments and have shown some efficacy, with high CR rates and preventing CD19-negative relapse. However, direct comparisons of the CR rate and long-term survival among the different salvage therapies are lacking. Databases including PubMed, Embase, Web of Science and Cochrane were searched from inception to January 31, 2022, for relevant studies. The outcomes of interest were complete remission/complete remission with incomplete haematologic recovery (CR/CRi) rates and 1-year overall survival (OS) rates. Odds ratios (ORs) were generated for binary outcomes, and the mean difference (MD) was generated for consecutive outcomes by network meta-analysis. CD19 CAR T-cells demonstrated a significantly better effect in improving the CR/CRi rate than blinatumomab (OR = 8.32, 95% CI: 1.18 to 58.44) and chemotherapy (OR = 16.4, 95% CI: 2.76 to 97.45). In terms of OS, CD19 CAR T-cells and dual CD19/CD22 CAR T-cells both had a higher 1-year OS rate than blinatumomab, inotuzumab ozogamicin and chemotherapy. There was no significant difference between CD19 CAR T-cells and dual CD19/CD22 CAR T-cells in terms of 1-year OS and CR/CRi rates. CD19 CAR T-cells are effective in inducing CR, and CD19 CAR T-cells and dual CD19/CD22 CAR T-cells show benefits for overall survival. More high-quality randomized controlled trials and longer follow-ups are needed to confirm and update the results of this analysis in the future.

Infectious complications among CD19 CAR-T cell therapy recipients: A single-center experience.

BACKGROUND: CD19 chimeric antigen receptor (CAR)-T cell therapy has emerged as an effective treatment in those with refractory or relapsed lymphoma. CD19 CAR-T cell therapy can cause direct and indirect toxic adverse effects and increased risk for infection. Infectious complications and optimal antimicrobial prophylaxis strategies are an ongoing area of investigation. METHODS: A single-center retrospective cohort study was conducted to review recipients of CD19 CAR-T cell therapy between April 2018 and December 2020. Patient characteristics and clinical outcomes were extracted from the electronic health records. RESULTS: Infectious complications were identified in 18/50 (36%) recipients with 31 episodes of infection. The median time to infection was 225 days (range 0-614). Bacterial infections were most common with bloodstream infection followed by sinusitis and skin and soft tissue infection. Eight viral infections were identified, most being respiratory viral illnesses. Two fungal infections were identified: Pneumocystis jirovecii pneumonia (PJP) and disseminated fusariosis. Seventeen infections (54.8%) were classified as severe: leading to death, requiring hospitalization, need for empiric intravenous antibiotics, or significant alteration in hospital course. No characteristics were found to be statistically significant risks for infection, although a trend toward significance was seen in prior autologous stem cell transplant recipients (p = .12) and those with recurrent neutropenia (p = .14). Three patients (6%) died from infection. CONCLUSION: Infections were common after CD19 CAR-T cell therapy and occurred beyond the first year. Further multicenter studies are needed to define infectious risks and optimize antimicrobial prophylaxis recommendations in recipients of CD19 CAR-T cell therapy.

CD26 CAR-T cells have attenuated mitochondrial and glycolytic metabolic profiling.

BACKGROUND: Multiple targets of chimeric antigen receptor T cells (CAR-T cells) are shared expressed by tumor cells and T cells, these self-antigens may stimulate CAR-T cells continuously during the expansion. Persistent exposure to antigens is considered to cause metabolic reprogramming of T cells and the metabolic profiling is critical in determining the cell fate and effector function of CAR-T cells. However, whether the stimulation of self-antigens during CAR-T cell generation could remodel the metabolic profiling is unclear. In this study, we aim to investigate the metabolic characteristics of CD26 CAR-T cells, which expressed CD26 antigens themselves. METHODS: The mitochondrial biogenesis of CD26 and CD19 CAR-T cells during expansion was evaluated by the mitochondrial content, mitochondrial DNA copy numbers and genes involved in mitochondrial regulation. The metabolic profiling was investigated by the ATP production, mitochondrial quality and the expression of metabolism-related genes. Furthermore, we assessed the phenotypes of CAR-T cells through memory-related markers. RESULTS: We reported that CD26 CAR-T cells had elevated mitochondrial biogenesis, ATP production and oxidative phosphorylation at early expansion stage. However, the mitochondrial biogenesis, mitochondrial quality, oxidative phosphorylation and glycolytic activity were all weakened at later expansion stage. On the contrary, CD19 CAR-T cells did not exhibit such characteristics. CONCLUSION: CD26 CAR-T cells showed distinctive metabolic profiling during expansion that was extremely unfavorable to cell persistence and function. These findings may provide new insights for the optimization of CD26 CAR-T cells in terms of metabolism.

Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: A Work Group Report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees.

Secondary hypogammaglobulinemia (SHG) is characterized by reduced immunoglobulin levels due to acquired causes of decreased antibody production or increased antibody loss. Clarification regarding whether the hypogammaglobulinemia is secondary or primary is important because this has implications for evaluation and management. Prior receipt of immunosuppressive medications and/or presence of conditions associated with SHG development, including protein loss syndromes, are histories that raise suspicion for SHG. In patients with these histories, a thorough investigation of potential etiologies of SHG reviewed in this report is needed to devise an effective treatment plan focused on removal of iatrogenic causes (eg, discontinuation of an offending drug) or treatment of the underlying condition (eg, management of nephrotic syndrome). When iatrogenic causes cannot be removed or underlying conditions cannot be reversed, therapeutic options are not clearly delineated but include heightened monitoring for clinical infections, supportive antimicrobials, and in some cases, immunoglobulin replacement therapy. This report serves to summarize the existing literature regarding immunosuppressive medications and populations (autoimmune, neurologic, hematologic/oncologic, pulmonary, posttransplant, protein-losing) associated with SHG and highlights key areas for future investigation.

A durable 4-1BB-based CD19 CAR-T cell for treatment of relapsed or refractory non-Hodgkin lymphoma.

Objective: Previous studies reported that 4-1BB-based CD19 chimeric antigen receptor (CAR)-T cells were more beneficial for the clinical outcomes than CD28-based CAR-T cells, especially the lower incidence rate of severe adverse events. However, the median progression-free survival (mPFS) of 4-1BB-based product Kymriah was shorter than that of CD28-based Yescarta (2.9 monthsvs. 5.9 months), suggesting that Kymriah was limited in the long-term efficacy. Thus, a safe and durable 4-1BB-based CD19 CAR-T needs to be developed. Methods: We designed a CD19-targeted CAR-T (named as IM19) which consisted of an FMC63 scFv, 4-1BB and CD3ζ intracellular domain and was manufactured into a memory T-enriched formulation. A phase I/II clinical trial was launched to evaluate the clinical outcomes of IM19 in relapsed or refractory (r/r) B cell non-Hodgkin lymphoma (B-NHL). Dose-escalation investigation (at a dose of 5×105/kg, 1×106/kg and 3×106/kg) was performed in 22 r/r B-NHL patients. All patients received a single infusion of IM19 after 3-day conditional regimen. Results: At month 3, the overall response rate (ORR) was 59.1%, the complete response rate (CRR) was 50.0%. The mPFS was 6 months and the 1-year overall survival rate was 77.8%. Cytokine release syndrome (CRS) occurred in 13 patients (59.1%), with 54.5% of grade 1-2 CRS. Only one patient (4.5%) experienced grade 3 CRS and grade 3 neurotoxicity. Conclusions: These results demonstrated the safety and durable efficacy of a 4-1BB-based CD19 CAR-T, IM19, which is promising for further development and clinical investigation.

Pharmacokinetic and pharmacodynamic studies of CD19 CAR T cell in human leukaemic xenograft models with dual-modality imaging.

In recent years, chimeric antigen receptor T (CAR T)-cell therapy has shown great potential in treating haematologic disease, but no breakthrough has been achieved in solid tumours. In order to clarify the antitumour mechanism of CAR T cell in solid tumours, the pharmacokinetic (PK) and pharmacodynamic (PD) investigations of CD19 CAR T cell were performed in human leukaemic xenograft mouse models. For PK investigation, we radiolabelled CD19 CAR T cell with 89 Zr and used PET imaging in the CD19-positive and the CD19-negative K562-luc animal models. For PD evaluation, optical imaging, tumour volume measurement and DNA copy-number detection were performed. Unfortunately, the qPCR results of the DNA copy number in the blood were below the detection limit. The tumour-specific uptake was higher in the CD19-positive model than in the CD19-negative model, and this was consistent with the PD results. The preliminary PK and PD studies of CD19 CAR T cell in solid tumours are instructive. Considering the less efficiency of CAR T-cell therapy of solid tumours with the limited number of CAR T cells entering the interior of solid tumours, this study is suggestive for the subsequent CAR T-cell design and evaluation of solid tumour therapy.

Toxicity and effectiveness of CD19 CAR T therapy in children with high-burden central nervous system refractory B-ALL.

INTRODUCTION: Although recent clinical trials have demonstrated the efficacy of CD19-directed chimeric antigen receptor (CAR) T-cell therapy for refractory or relapsed B acute lymphoblastic leukemia (r/r B-ALL), most trials exclude patients with high-burden CNS leukemia (CNSL) to avoid the risk of severe neurotoxicity. There were only sparse cases describing the effect of CAR T cells on low-burden CNSL, and the safety and effectiveness of CAR T cells in high-burden CNSL remains unknown. METHODS: Here, we retrospectively analyzed the results of CD19 CAR T-cell therapy in 12 pediatric patients that had low (Blasts < 20/µL in CSF) or high-burdens (Blasts or intracranial solid mass) of CNS B-ALL, that are enrolled in three clinical trials and one pilot study at Beijing Boren Hospital RESULTS: Eleven patients (91.7%) achieved complete remission (CR) on day 30, and one patient got CR on day 90 after infusion. Most patient experienced mild cytokine-release syndrome. However, of the five patients who retained > 5/µL blasts in CSF or a solid mass before CAR T-cell expansion, four developed severe (grade 3-4) neurotoxicity featured by persistent cerebral edema and seizure, and they fully recovered after intensive managements. Sustained remission was achieved in 9 of the 12 patients, resulted in a 6-month leukemia-free survival rate of 81.8% (95% CI 59.0-100). Only one patient has CNS relapse again. CONCLUSION: Our study demonstrates that CAR T cells are effective in clearing both low- and high-burden CNSL, but a high CNSL burden before CAR T-cell expansion may cause severe neurotoxicity requiring intense intervention.

Humanized anti-CD19 chimeric antigen receptor-T cell therapy is safe and effective in lymphoma and leukemia patients with chronic and resolved hepatitis B virus infection.

Chimeric antigen receptor-T (CAR-T) cell therapy is a promising treatment for CD19+ B-cell malignancies. However, elimination of B cells by anti-CD19 CAR-T cells may lead to the reactivation of hepatitis B virus (HBV) and related hepatitis in patients with HBV infection. This study aims to evaluate the safety and efficacy of humanized anti-CD19 CAR-T (hCAR-T) therapy in B-cell malignancies with HBV infection. Twenty relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL) patients with HBV infection were treated with hCAR-T therapy. Among them, five hepatitis B antigen-positive patients who received antiviral prophylaxis did not develop HBV reactivation, including two patients who received both hCAR-T and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Among 15 patients with resolved HBV infection, two received antiviral prophylaxis, and the other 13 did not experience HBV reactivation without antiviral prophylaxis. One patient with resolved HBV infection experienced HBV reactivation 6 months after hCAR-T therapy and sequential allo-HSCT. Moreover, HBV infection did not affect in vivo expansion of hCAR-T cells or increase the risk of severe cytokine release syndrome. In conclusion, hCAR-T therapy is safe and effective in DLBCL and ALL patients with chronic and resolved HBV infection under proper antiviral prophylaxis.

[Establishment of a cytokine release syndrome associated with chimeric antigen receptor T cell treatment in SCID/Beige mice model].

Objective: To establish a cytokine release syndrome (CRS) mouse model related to CAR-T cell therapy and provide a research model for the clinical phenomena. Methods: CAR-T cells targeting human CD19 molecule were constructed by molecular cloning and lentiviral transfection. Flow cytometry (FACS) was used to detect the transfection efficiency of CAR-T cells. The tumor-killing efficiency of CAR-T cells was detected by ELISA and flow cytometry. The CAR-T cells were injected into the tumor-bearing SCID/Beige mice through tail vein, and divided into phosphate buffered solution (PBS) group, low-burden group (1×10(5) Raji-Luc2 cells) and high-burden group (5×10(5) Raji-Luc2 cells). The tumor treatment effect was detected by animal in vivo imaging. Serum levels of cytokines including human IFN-γ, human IL-2, mouse IL-6, and mouse GM-CSF were measured by ELISA. The health status of the mice was evaluated by pathological examination. Results: The health scores of T cell group and T cell+ OKT-3 group were (1.15±0.08) and (2.90±0.15), respectively, after the injection of human T cell and T cell + OKT-3 antibody through tail vein, and the difference was statistically significant (P<0.001). The serum levels of human IL-2, human IFN-γ, human IL-15, mouse IL-6 and mouse GM-CSF in T cell+ OKT-3 group were (1 064.00±50.14), (1 285.00±193.90), (202.4±18.76), (1 478.00±289.20) and (350.70±42.27) pg/ml, respectively, higher than (22.67±6.36), (23.67±3.71), (44.33±14.45), (147.30±36.20), (138.00±22.74) pg/ml in T cell group (P<0.05). OKT-3 combined with human T cells caused a rapid increase in serum levels of human IL-2, human IFN-γ, mouse IL-6 and mouse GM-CSF, accompanied by an increase in body temperature and weight loss. CD19-targeting CAR-T cells were successfully constructed, and the positive rate of CAR-T cells was >30% detected by flow cytometry. ELISA results showed that in the presence of CD19 antigen, IL-2 and IFN-γ secreted by CAR-T19 cells co-incubated with Raji and Nalm were (561.00±37.07), (680.30±71.27), (369±25.71) and (523.00±26.31) pg/ml, respectively, higher than (55.00±20.53) and (64.00±7.55) pg/ml in the co-incubated with K562 group (P<0.001). Activated CAR-T19 cells were reinjected through the tail vein on the seventh day after tumor formation. Imaging experiments in mice showed that on the thirteenth day after tumor formation, the fluorescence intensities of tumors in the low-burden and high-burden groups were lower than on the seventh day of tumor inoculation, and the fluorescence intensity of tumors in the high-burden group decreased from 144.00±24.69 to 5.02±2.35 (P=0.005). The fluorescence intensity of low burden group decreased from 58.47±9.36 to 3.48±1.67 (P=0.004). The serum levels of T cell activation related cytokines IL-2, IL-15 and IFN-γ increased rapidly, and the secretion of monocyte related cytokines IL-16 and GM-CSF increased, accompanied by the typical characteristics of CRS such as increased body temperature and weight loss at 72 hours after injection of CAR-T19 cells. Conclusions: CAR-T cells targeting CD19 molecule are successfully constructed, and CRS phenomenon is verified in tumor-bearing mice by CAR-T cell re-infusion, providing an animal model for the mechanism of CAR-T treatment-related CRS and CRS prevention strategies.

Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia.

OPINION STATEMENT: Chimeric receptor antigen (CAR) T cells are an innovative cellular immunotherapeutic approach that involves genetic modification of T cells to express CAR targeting tumor antigen. Prior to the development of CAR-T, the only potential cure for patients with relapsed or refractory (RR) acute lymphoblastic leukemia (ALL) was allogeneic hematopoietic stem cell transplantation (HSCT). Several CAR-T cell products have been studied in prospective clinical trials which ultimately have resulted in the approval of one anti-CD19 CAR-T cell product in pediatric RR ALL: tisagenlecleucel (CD3ζ and 41BB). While some patients achieve durable responses with CAR-T, lack of response and relapse remains clinical challenges. Reasons for sub-optimal response include lack of CAR-T cell persistence and target antigen down-regulation. Future CARs are under development to improve long-term persistence and to be able to overcome resistance mechanisms associated with the disease and the hostile tumor microenvironment. With evolving understanding about CARs and new constructs under investigation, there is optimism that future products will improve the safety and efficacy from the current standard of care.

Chimeric antigen receptor T cell therapy can be administered safely under the real-time monitoring of Th1/Th2 cytokine pattern using the cytometric bead array technology for relapsed and refractory acute lymphoblastic leukemia in children.

CD19 chimeric antigen receptor T (CD19CAR-T) cell therapy has shown striking response in treating relapsed and refractory B-lineage acute lymphoblastic leukemia (r/r B-ALL). However, side-effects including cytokine release syndrome (CRS) and neurotoxicity can be fatal to patients. In this report, five patients with r/r B-ALL were treated with CD19CAR-T cells. Cytokine release syndrome experienced by four patients who achieved complete remission (CR) with minimal residual disease (MRD) negative. One patient who did not response to the treatment had no CRS. Acute toxicities including fever, hypotension and other neurological toxicities occurred in responding patients within 2 weeks post infusion and managed properly with tocilizumab and/or steroids according to the "real-time" monitoring of a simple 6 Th1/Th2 cytokine pattern. In conclusion, our study demonstrates that CD19CAR-T cell therapy can be safely administered for patients with relapsed and refractory leukemia under the "real-time" monitoring of a simple 6-cytokine pattern.

Relapsed Philadelphia Chromosome-Positive Pre-B-ALL after CD19-Directed CAR-T Cell Therapy Successfully Treated with Combination of Blinatumomab and Ponatinib.

Adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with conventional chemotherapy have dismal outcomes. Novel immunotherapies targeting CD19, including the bispecific T-cell engager blinatumomab and chimeric antigen-receptor T (CAR-T) cells, have revolutionized the treatment of R/R B-ALL. Robust response rates to CAR-T cell therapy after blinatumomab have recently been reported, but it is unknown whether blinatumomab can be effective following failure of anti-CD19 CAR-T cell therapy. Herein, we describe a patient with Philadelphia chromosome-positive B-ALL who relapsed after CD19-directed CAR-T therapy, but subsequently responded to the combination of blinatumomab and the tyrosine kinase inhibitor ponatinib, with the achievement of a complete remission lasting 12 months.

Phase I Clinical Trial of CD19 CAR-T Cells Expressing CXCR5 Protein for the Treatment of Relapsed or Refractory B-cell Lymphoma.

BACKGROUND: It is difficult for CD19 CAR-T cells to enter solid tumors, which is one reason for their poor efficacy in lymphoma treatment. The chemokine CXCL13 secreted by stro-mal cells of the lymph nodes induces the homing of B and T lymphocytes, which express its receptor CXCR5. Preclinical trials have shown that the expression of CXCR5 on CD19 CAR-T cells can increase their migration to the tumor microenvironment and enhance their antitumor function. METHODS: We engineered the CD19 CAR-T cells to express a second receptor, CXCR5. Then, we conducted a phase I clinical trial to evaluate the safety and efficacy of CXCR5 CD19 CAR-T cells in the treatment of relapsed or refractory (R/R) B-cell lymphoma. RESULTS: We recruited 10 patients with R/R B-cell lymphoma undergoing CXCR5 CD19 CAR-T cell therapy. The objective response rate was 80%, and the complete response rate was 50%. The median follow-up time was 15.48 months (3.4-22.3 months), and the median Progression-Free Survival (PFS) time was 8.15 months (1.5-22.33 months). One patient received ASCT at 1.5 months (at PR) after infusion of CAR-T cells. The incidence of grade 1 and grade 2 Cytokine Release Syndrome (CRS) was 70% and 20%, respectively. No patient experienced grade 3 or higher levels of CRS, neurotoxicity, or infusion-related dose toxicity. CONCLUSION: The results obtained in this study suggest that CXCR5 CD19 CAR-T cells should be investigated in a trial with broader patient populations. TRIAL REGISTRATION: The trials were registered at www.chictr.org.cn as ChiCTR2100052677 and ChiCTR1900028692.

Consolidation with First and Second Allogeneic Transplants in Adults with Relapsed/Refractory B-ALL Following Response to CD19CAR T Cell Therapy.

CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy has led to unprecedented rates of complete remission (CR) in children and adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL), yet the majority of adults relapse after initial response. One proposed method to extend the durability of remission in adults following response to CAR-T therapy is consolidation with allogeneic hematopoietic cell transplantation (alloHCT). Considering the limited published data for the utility of post CAR-T therapy consolidative alloHCT in r/r B-ALL, especially data related to patients receiving a second alloHCT, we sought to describe outcomes of patients with r/r B-ALL at our institution who received their first or second alloHCT following response to CAR-T therapy. We performed a retrospective analysis of adult patients with r/r B-ALL who responded to either investigational or standard of care (SOC) CD19-targeted CAR-T therapy and underwent consolidation with alloHCT while in CR without interim therapy. We identified 45 patients, of whom 26 (58%) and 19 (42%) received their first and second alloHCT as consolidation post CAR-T therapy, respectively. The median age was 31 years (range: 19-67) and 31 (69%) patients were Hispanic. Ph-like was the most common genetic subtype and comprised over half of cases (53%; n = 24). The median number of prior therapies pre-transplant was 5 (range: 2-7), and disease status at the time of alloHCT was CR1, CR2 or ≥CR3 in 7 (16%), 22 (49%) and 16 (35%) patients, respectively. The median time from CAR-T therapy until alloHCT was 93 (range: 42-262) days. The conditioning regimen was radiation-based myeloablative (MAC) in 22 (49%) patients. With a median follow-up of 2.47 years (range: 0.13-6.93), 2-year overall survival (OS), relapse free survival (RFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 57.3% (95% CI: 0.432-0.760), 56.2% (95% CI: 0.562-0.745), 23.3% (95% CI: 0.13-0.42), and 20.4% (95% CI: 0.109-0.384), respectively. Two-year OS (52% vs. 68%, P = .641), RFS (54% vs. 59%, P = .820), CIR (33.5% vs. 8.5%, P = .104), and NRM (12.5% vs. 32.2%, P = .120) were not significantly different between patients who underwent their first vs. second transplant, respectively. In univariate analysis, only Ph-like genotype was associated with inferior RFS (P = .03). AlloHCT post CAR-T response is associated with a relatively low early mortality rate and encouraging survival results in high-risk adults with r/r B-ALL, extending to the second alloHCT for fit and eligible patients.