B-cell Recovery Research Articles

#3280 B-CELL RECOVERY IN A RANDOMIZED CONTROLLED TRIAL OF B-CELL DEPLETION WITH OBINUTUZUMAB FOR THE TREATMENT OF PROLIFERATIVE LUPUS NEPHRITIS (NOBILITY)

Abstract Background and Aims B cells are central to the pathogenesis of systemic lupus erythematosus and lupus nephritis (LN). Obinutuzumab, a humanized type II anti-CD20 monoclonal antibody, induces more potent B-cell depletion than rituximab. Patients with LN who received obinutuzumab with standard-of-care (mycophenolate mofetil [MMF]) immunosuppression (Phase II NOBILITY study; NCT02550652) showed improved clinical responses through Week 104 compared with those who received MMF alone. Further, sustained as opposed to unsustained B-cell depletion up to Week 52 in those who received obinutuzumab was associated with a higher incidence of complete renal response (CRR) at Week 76.1,2 This analysis aims to characterize the kinetics of B-cell recovery after the last dose of obinutuzumab in NOBILITY and the impact of these kinetics on response and safety. Method A total of 125 patients with active Class III/IV LN receiving MMF and corticosteroids were randomized and received either obinutuzumab 1000 mg (n = 63) or placebo (n = 62) on Day 1 and Weeks 2, 24 and 26, and followed through Week 104 or to B-cell recovery, whichever was longer.1 B cells were measured using both a T and B natural killer cell (TBNK) assay with a lower limit of quantification (LLoQ) of 10 CD19+ cells/µL and a high-sensitivity minimal residual B-cell 1.1 (MRB1.1) assay with an LLoQ of 0.4 cells/µL. Peripheral B-cell depletion was defined as ≤0.4 cells/µL. Peripheral B-cell recovery was defined as ≥20 cells/µL or the patient's predose baseline, whichever was lower. Time to peripheral B-cell recovery after the last dose of obinutuzumab (Week 26 in 57 of 63 patients), the relationship of time to recovery to efficacy at Week 104 and safety throughout the main study and follow-up period were evaluated (severe adverse event [SAE] and infectious SAE rates, adjusted for patient-years [PY] at risk). Results Of 63 patients who received obinutuzumab, 4 did not achieve full B-cell depletion during the study. By Week 24, 59 patients (93.7%) achieved B-cell depletion (before obinutuzumab redosing); of those, 4 discontinued prior to B-cell recovery, and 4 completed the study at or after Week 104 but before achieving B-cell recovery. The remaining 51 patients constitute the population for this analysis. Based on the distribution of time to B-cell recovery, 93 weeks after the last obinutuzumab infusion was used to group patients (Figure 1). Of the 51 patients, 3 (5.9%) recovered B cells before redosing at Week 26; 1 of the 3 achieved CRR at Week 104. A total of 37 patients (72.5%) attained B-cell recovery within 93 weeks of their last dose of obinutuzumab (median time to B-cell recovery, 78.1 weeks), 18 of 37 (48.6%) and 23 of 37 (62.2%) achieved CRR and overall renal response (ORR) at Week 104, respectively. In these 37 patients, SAE and infectious SAE rates per 100 PY were 13 and 8, respectively. In 11 patients (21.6%), >93 weeks passed after their last dose to achieve B-cell recovery. Nine of 11 patients achieved B-cell recovery with a median time of 102 weeks, and 2 of 11 had not yet achieved B-cell recovery at the time of writing. Five of 11 patients (45.5%) achieved CRR, and 8/11 (72.7%) achieved ORR at Week 104. In these 11 patients, SAE and infectious SAE rates per 100 PY were 10 and 0, respectively. Conclusion Most patients in NOBILITY recovered peripheral B cells within 80 weeks after the last obinutuzumab dose. In 5.9% of patients, recovery occurred very rapidly, even before redosing at 26 weeks, whereas in ≈20%, recovery took >2 years (Figure 2). Renal response rates at Week 104 were similar among patients who recovered B cells within 2 years of their final obinutuzumab infusion, those who recovered later and those who are still depleted, suggesting a greater mechanistic effect of early sustained depletion vs duration of depletion. Within the limitation of small sample size, the SAE and infectious SAE rates appear to be similar regardless of duration of B-cell depletion.

Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma

AbstractIn phase 2 of ZUMA-1, a single-arm, multicenter, registrational trial, axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL). Here, we assessed outcomes in ZUMA-1 after 5 years of follow-up. Eligible adults received lymphodepleting chemotherapy followed by axi-cel (2 × 106 cells per kg). Investigator-assessed response, survival, safety, and pharmacokinetics were assessed in patients who had received treatment. The objective response rate in these 101 patients was 83% (58% complete response rate); with a median follow-up of 63.1 months, responses were ongoing in 31% of patients at data cutoff. Median overall survival (OS) was 25.8 months, and the estimated 5-year OS rate was 42.6%. Disease-specific survival (excluding deaths unrelated to disease progression) estimated at 5 years was 51.0%. No new serious adverse events or deaths related to axi-cel were observed after additional follow-up. Peripheral blood B cells were detectable in all evaluable patients at 3 years with polyclonal B-cell recovery in 91% of patients. Ongoing responses at 60 months were associated with early CAR T-cell expansion. In conclusion, this 5-year follow-up analysis of ZUMA-1 demonstrates sustained overall and disease-specific survival, with no new safety signals in patients with refractory LBCL. Protracted B-cell aplasia was not required for durable responses. These findings support the curative potential of axi-cel in a subset of patients with aggressive B-cell lymphomas. This trial was registered at ClinicalTrials.gov, as #NCT02348216.

Impact of Hematopoietic Cell Transplantation after CAR T-Cell Therapy for B-ALL: Comparison of Statistical Models and Survival Curves By a Novel R Shiny Tool

Introduction Consolidative hematopoietic cell transplantation (cHCT) after CAR-T is frequently performed for patients with acute lymphoblastic leukemia (ALL) but the role of HCT is debated. To estimate the association between receipt of HCT and survival, HCT should be considered as a time-varying covariate (TVC), because HCT can occur later after CAR-T infusion. Cox models and Kaplan Meier (KM) curves that treat the TVC (HCT vs no) as known at study entry (Naïve methods) are not appropriate. Ignoring the time from day 0 to the day of TVC status change may lead to immortal person-time bias. Landmark analysis is a popular alternative that chooses a time (3 months after CAR-T) as a new start time and use the TVC status by landmark for Cox model/KM curve. However, patients who had events or were censored before landmark will be excluded and change in TVC after landmark is ignored. Also, results could be sensitive to the choice of landmark times (3 or 9 months). Time-dependent (TD) Cox are recommended to analyze TVC but constructing survival curves with TVC is not straightforward. Recently, a new visualization method was proposed by Smith et al., 2019 (Smith-Zee). Based on a TD Cox model, Smith-Zee constructs survival curves by mimicking new patients with TVC status change at different times, which overcomes drawbacks of the Naïve and Landmark methods. There is un urgent need to guide both clinicians and statisticians on how to analyze TVC using appropriate models and curves. Methods We developed a R Shiny tool, called TimeDep_survival_curvesTM, with different models (Naïve, Landmark, TD Cox) and curves (Naïve KM, Landmark KM, Smith-Zee) for TVC analysis https://samplen.shinyapps.io/TimeDep_survival_curves/. The tool includes several unique features: 1) protects data privacy yet allows users to upload data directly 2) applies different methods on the same data and shows potential biases of inappropriate methods 3) contains a simulation panel that allow users to specify the parameters based on various study settings. Results Individual trials showed conflicting results as to whether HCT benefit patients with B-ALL after CAR-T. The finding divergence might be related to the different statistical methods used (TD Cox vs Naïve). Here,we re-analyzed two CAR-T trials (Fred Hutch: NCT01865617, Seattle Children's (SC): NCT02028455) using Naïve, Landmark, and TD Cox models to evaluate the impact of HCT after CAR-T with leukemia-free survival (LFS). For SC trial, the estimated hazard ratio (HR) and p-value for HCT from the Naïve method are similar to those from the TD Cox (Table 1: Naïve HR=0.28/p<0.01 and TD Cox HR=0.31/p=0.01). For landmark analysis, as we expected, different landmark times (3 vs 9 months) showed different results (Table 1: HR=0.34/p=0.07 for 3 vs HR=0.57/p=0.26 for 9 months) as well as the curves (Figure 1). For Hutch trial, we obtained the same conclusions: HRs and p-values are similar across different models (Table 1). The consistent results from both trials provide reassurance that the impact of HCT may not be specific to the methods used for analysis. However, to understand when the bias from the Naïve method might lead differences in conclusion, we performed simulation (Simulation on R Shiny) and observed the bias from Naïve methods is greater if more patients received HCT later after CAR-T, or if more patients have an event (LFS or OS) sooner (i.e., the shape parameter k of Weibull distribution for time to TVC, ktvc > 1 or for time to event, kevent < 1). When more patients' events occur later (kevent > 1) and undergo HCT sooner (ktvc < 1), the bias from Naïve method is minimal, like what we observed in two CAR-T studies. Conclusion For these two studies, the effect of HCT seems to be consistent across methods, however, this is not generally true. Based on simulation, significant bias might be generated when using Naïve methods for TVC analysis. We recommend to use TD Cox model and Smith-Zee curve. Our R Shiny tool can analyze different TVCs, e.g., HCT (vs no), MRD-CR (vs no), B-cell recovery (vs B-cell aplasia). More importantly, our tool breaks collaboration barriers since it does not require data sharing between institutions. Users can upload data and download results independently without technical coding skills. It critically expands upon the limited tool available, in turn leads to better understandings of the efficacy of immunotherapies, and no doubt will benefit the statistical and medical communities worldwide. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-term Follow-up of CD20-directed Chimeric Antigen Receptor Adoptive T-cell Therapy

Chimeric antigen receptor (CAR) T cell therapy targeting B-cell antigens has led to unprecedented success in inducing complete response (CR) rates in refractory B-cell non-Hodgkin lymphomas (NHLs). We previously reported the results of a pilot trial testing a 3rd generation CAR with 4-1BB and CD28 costimulatory domains targeting CD20 in patients (pts) with relapsed B-cell lymphomas (NCT00621452). 3 pts received cyclophosphamide (CY) 1 g/m2 IV for lymphodepletion 2 days prior to a series of 3 CAR T cell infusions 2 to 5 days apart in escalating doses followed by 2 weeks of low-dose IL-2. Here, we report the long term follow up of 2 of these pts. The third pt, UPN-02, died of progressive mantle cell lymphoma (MCL) and myelodysplastic syndrome at ~26 months (mos) post-treatment. Pt UPN-03, with relapsed MCL, had no evaluable disease after an excisional biopsy following protocol therapy. He relapsed after 2 years with a left flank mass, which was then radiated. He was re-treated with CY lymphodepletion, a dose of 1.8 x 109 CAR T cells/m2, and low-dose IL-2. At 6 weeks post infusion, he developed a small mass at the margin of his previous radiation field suspected to be recurrent MCL. This mass spontaneously regressed 1 mo later. Subsequent CT scans showed a residual soft tissue mass that gradually decreased over time and met criteria for CR by CT criteria. He remained in remission, albeit with detectable minimal residual disease (MRD) by ClonoSEQ assay, for the next 8.4 years until developing a subcutaneous chest mass and axillary adenopathy with biopsy showing recurrent MCL. Pt UPN-04, with relapsed follicular lymphoma (FL), had stable disease by CT at 1 mo but went on to have a partial response at ~3 mos. By 12 mos post-CAR T treatment there was evidence of progressive disease. However, between 2.5 and 3 years post-treatment he experienced resolution of all palpable nodes, and a near-CR was confirmed by CT at 35 mos after treatment. He remained without any clinical signs of progression with low level MRD by ClonoSEQ for the next 4 years. At 7.2 years post-CAR T cell treatment, he was found to have recurrent FL. CAR T cells were detectable for up to 12 mos in UPN-03 and 9 mos in UPN-04 by qPCR assay. B-cell recovery over time in both pts confirmed a lack of functional CAR T cell persistence. Given these findings, along with the durable responses observed in both pts, we hypothesized that these late remissions were caused by endogenous immune responses triggered by CAR T cell therapy. To evaluate this, we performed western blot assays incubating post-infusion serum with autologous tumor cell lysates followed by incubation with an anti-human IgG antibody, which showed new bands at post clinical response timepoints in both pts. ELISPOT assays with PBMCs co-incubated with autologous tumor cells exhibited spikes in IFN-γ secreting cells compared with control cells at timepoints proximal to their clinical responses. These findings suggested the occurrence of both humoral and cellular anti-tumor responses. To better characterize the T-cell response, we performed high-throughput TCR-β sequencing (Adaptive ImmunoSEQ) for UPN-04. We conducted a differential abundance analysis to identify possible tumor-reactive T cells, with the hypothesis that tumor-reactive T cell clones would be increased near the timepoints with clinical responses at ~3 and 35 mos. We identified 12 and 7 sequences, respectively, at these timepoints that were significantly increased compared to baseline (FDR < 0.05) and not present in the CAR-T product; 3 sequences were present at both 3 and 35 mos, and 1 of these was also significantly enriched in a post-infusion tumor biopsy, suggesting possible tumor-specificity. These results support the hypothesis that the late responses were mediated by endogenous T cells rather than CAR T cells. In summary, we report long-term remissions in 2 of 3 pts treated with CD20-targeted CAR T cell therapy, with evidence of endogenous anti-tumor immune responses. Together with previously published reports of epitope spreading after CAR-T for solid tumors, and in mouse models of lymphoma, these results suggest that CAR T cells have the capacity to elicit endogenous anti-tumor immune responses in lymphoma. Our use of CY without fludarabine as lymphodepletion may have facilitated such responses. Future research is warranted to enhance epitope spreading after CAR-T therapy as a bulwark against escape by antigen loss or loss of CAR-T persistence.

Administration of Obinutuzumab, and Not Rituximab, during Induction and Maintenance for Follicular Lymphoma Increases the Likelihood of Developing Delayed Neutropenia

The results of the PRIMA trial published a decade ago, substantiated the benefit of maintenance therapy with anti-CD20 monoclonal antibodies (MoAb), following chemo-immunotherapeutic induction, for prolongation of the progression-free survival (PFS) of patients with high-tumor- burden follicular lymphoma (FL). Rituximab-associated delayed neutropenia, defined as an event occurring after recovery of cytopenias related to the chemotherapy backbone, has been reported in lymphoma patients, with the prevalence varying between 8-27%. Several mechanisms have been implicated in its pathogenesis, mainly related to B-cell recovery, such as a disrupted stromal-derived factor-1 gradient and the generation of anti-neutrophil antibodies. The available data associated with anti-CD20 MoAb-mediated delayed neutropenia during the prolonged (2-year) maintenance treatment in FL are limited, and the consequences of its occurrence remain unclear. The aims of this study were to assess the prevalence of neutropenia and risk factors for its development in FL patients during maintenance therapy as well as to evaluate its severity and impact on decisions regarding modification of the original treatment protocol. In this retrospective study, clinical data were retrieved from electronic medical records of FL patients treated at the Rambam Health Care Campus between 2006 (when maintenance therapy was first applied) and 2021. Continuous variables were statistically processed using the Mann Whitney U test and categorical variables - using Fisher exact tests. Statistical significance was defined as p <0.05. During the study period, a total of 305 patients treated for high-tumor-burden FL were identified in the institutional database; 164 of these patients (53.8%) also received maintenance therapy with anti-CD20 MoAb (rituximab or obinutuzumab). Data on 157/164 patients were included in the final analysis after the exclusion of 7 patients due to their concomitant autoimmune disease. During maintenance therapy, 37/157 (23.6%) patients developed delayed neutropenia, with 4/37 (11%) of them experiencing at least one recurrent event. This relatively high percentage of delayed events is comparable only to that observed in a study which evaluated heavily pretreated lymphoma patients (Cattaneo C et al. Leuk Lymphoma, 2006), exposed to highly myelotoxic regimens or fludarabine and did not include a maintenance phase. Median time from the start of maintenance to the first neutropenic episode in the current study was 5 (range 1.5-12) months and the majority of these events were of high grade (III and IV in 24% and 38% of patients, respectively). Despite the fact that 15/37 (40%) patients who developed this complication were hospitalized with neutropenic fever, the occurrence of neutropenia led to early discontinuation of maintenance treatment solely in 14% of the cohort and had no effect on PFS, measured at a median follow-up of 91.5 months. Univariate and multivariate analyses identified the use of the obinutuzumab/bendamustine (O/B) combination for induction therapy, or maintenance with obinutuzumab (O) as the only risk factors of delayed neutropenia development in patients on maintenance therapy (odds ratios in case of O/B induction followed by O maintenance: 4.433 [95%CI=1.387-14.17, p=0.012]; in case of O maintenance: 3.048 [95%CI=1.207-7.697, p=0.018]). All other laboratory and clinical factors examined did not impact late neutropenia occurrence (Table 1). The current study demonstrates that the administration of obinutuzumab both as part of induction with bendamustine and as maintenance therapy increases the likelihood of developing anti-CD20 MoAb-induced delayed neutropenia, suggesting that pharmacokinetic differences between type I and type II MoAb are partly responsible for this effect. Moreover, the findings regarding the prevalence of neutropenia and time to its first episode in this study cohort do not support the involvement of processes related to B-cell recovery in the pathogenesis of this complication during maintenance treatment, and warrant investigation of alternative mechanisms. The risk factors for delayed neutropenia in FL patients on maintenance therapy, identified in this study, should be considered in the treatment paradigm for older frail patients who are more prone to complications of neutropenic fever. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Acquired B-cell deficiency secondary to B-cell-depleting therapies

The advantage of the newer biological therapies is that the immunosuppressive effect is targeted, in contrast, to the standard, traditional immunomodulatory agents, which have a more global effect. However, there are unintended targets and consequences, even to these “precise” therapeutics, leading to acquired or secondary immunodeficiencies. Besides depleting specific cellular immune subsets, these biological agents, which include monoclonal antibodies against biologically relevant molecules, often have broader functional immune consequences, which become apparent over time. This review focuses on acquired B-cell immunodeficiency, secondary to the use of B-cell depleting therapeutic agents. Among the many adverse consequences of B-cell depletion is the risk of hypogammaglobulinemia, failure of B-cell recovery, impaired B-cell differentiation, and risk of infections. Factors, which modulate the outcomes of B-cell depleting therapies, include the intrinsic nature of the underlying disease, the concomitant use of other immunomodulatory agents, and the clinical status of the patient and other co-existing morbidities. This article seeks to explore the mechanism of action of B-cell depleting agents, the clinical utility and adverse effects of these therapies, and the relevance of systematic and serial laboratory immune monitoring in identifying patients at risk for developing immunological complications, and who may benefit from early intervention to mitigate the secondary consequences. Though these biological drugs are gaining widespread use, a harmonized approach to immune evaluation pre-and post-treatment has not yet gained traction across multiple clinical specialties, because of which, the true prevalence of these adverse events cannot be determined in the treated population, and a systematic and evidence-based dosing schedule cannot be developed. The aim of this review is to bring these issues into focus, and initiate a multi-specialty, data-driven approach to immune monitoring.

ANALYSIS OF B-LYMPHOCYTE MATURATION KINETICS WITH A 10-COLOR BCP-ALL MINIMAL RESIDUAL DISEASE DETECTION TUBE BY FLOW CYTOMETRY: A COMPARISON OF REGENERATING BONE MARROW BEFORE AND AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION

Minimal residual disease (MRD) measurement in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has been consolidated in the literature as the strongest adverse prognostic factor for overall and disease-free survival in both child and adult studies. However, only recently has multiparametric flow cytometry (MFC) been fully standardized with the addition of new markers and acquisition of a higher number of cellular events, which can improve the objectivity and sensitivity of the test. This prospective study aims to test a single 10-color flow cytometric assay compared to standardized 8-color two tubes in patients with BCP-ALL before bone marrow transplantation, follow by analysis of the kinetic of medullary B-cell recovery after transplant. Prospective analysis of 75 consecutive patients (pcts) transplanted between 2019/January and 2022/May, with MRD evaluation in the month before HSCT, day30, day100 and day360. Flow cytometry was performed on bone marrow samples after bulk-lysis with ammonium chloride when necessary, and subsequent staining with antibody panels. A 10-color tube included the backbone markers CD19, CD45, CD34, CD10, and CD20, in addition to CD38 and CD81 to improve separation between normal/reactive and malignant BCP, and four discriminatory markers placed in the same tube (CD66c and CD123 in PE, CD73 in BV605, and CD304 in APC-R700). This tube was compared to the standardized EuroFlow®method, which was composed of two 8-color tubes previously described. FACSCantoII™and FACSLyric™flow cytometry's were used. Data were analyzed with Infinicyt. The achieved sensitivity and percentages of lymphoblasts, normal mature and precursor B-cells, plasmatic cells and stromal cells were compared before and after transplantation. Statistical analyses were performed in SPSS Statistics v.20.0 software. 34 ALL (42.6%), being 26 BCP-ALL and 8 high-risk T-ALL, and 41 AML (57.4%), median age 31.6 (4.1-62.5 years) for ALL and 42.9 (0.6-74.2 years) for AML; 45(60%) in first complete remission (CR1), 21 CR2 (28%), one CR3 and 7 active diseases. Among 64 patients in morphologic remission, we found 38(59.4%) MRD negative and 26(40.6%) MRD positive before transplant. Pos-transplantation MRD and maturation analysis was possible in 26 pcts at d30, 24 at d60, 57 at d100 and 18 at d360. All but two samples had more than 9.000.000 cell events acquired, median lower limit of detection (LoD) was 0,0002% and lower limit of quantification (LoQ) was 0,0005% in both assays. All patients had the same percentages of lymphoblasts, normal mature and precursor B-cells, plasmatic cells, in the two different assays. The posttransplant B-cell recovery kinetic was similar between BCP-ALL, T-cell ALL and myeloid leukemia recovery after transplantation, and different between adults and children at day100 and day360, but not in day30. This study showed that this 10-color single tube strategy achieves the same sensitivity as the 8-color assay and allows correct identification of MRD, achieving maximum sensitivities and specificities in a single tube, and still maintaining the best discrimination between pathological B cells and normal B cell precursors. B-cell maturation kinetics were similar between leukemia types, and slightly different between adults and children. Additional studies and a larger sample size are needed to confirm these findings.

Response to SARS-CoV-2 vaccines in patients receiving B-cell modulating antibodies for renal autoimmune disease

BackgroundEffective SARS-CoV-2 vaccination in patients receiving treatment with B-cell depleting agents is challenging. Information on vaccination responses in these patients are a valuable tool to develop efficient vaccination regimens.MethodsIn this single-center retrospective observational study, we report the humoral and cellular response in 34 patients receiving anti-CD20 antibody treatment for renal immune disease.ResultsAfter base immunization with SARS-CoV-2-vaccines, 92.0% developed a cellular, 32.4% a humoral response. Humoral immunity correlated with B-cell counts and the timespan between anti-CD20 antibody treatment and vaccination. All patients with > 21/µl B-cells, or > 197 days after treatment showed humoral response.ConclusionsAdequate timing of SARS-CoV-2-vaccinations after anti-CD20 antibody treatment and CD19 measurements are crucial to generate immunity. Awaiting partial B-cell recovery by postponing regularly scheduled anti-CD20 treatment should be considered in patients with stable immune disease.Trial registration: This study has been retrospectively registered in the German Clinical Trials Register (DRKS00027049) on 29/10/2021.

Randomized controlled trial to compare safety and efficacy of mycophenolate vs. cyclosporine after rituximab in children with steroid-resistant nephrotic syndrome.

The comparative safety and efficacy of maintenance mycophenolate mofetil (MMF) and cyclosporine (CYC) following rituximab (RTX) in children with steroid-resistance nephrotic syndrome are uncertain. Multicenter randomized controlled trial. Sixty-six children between 2 and 6 years of age with SRNS. Patients were randomized to receive either MMF 1000 mg/m2 /day (n=32) or CYC 5mg/kg/day (n=34) for 12months following RTX induction therapy (375 mg/m2 ) given as needed for B-cell count. Complete remission and adverse events (AEs). Complete remission was observed in 26 patients (83.1%) in the MMF group compared with 21 patients (61.7%) in the CYC group (p=0.02). The median time to remission was shorter in the MMF group than in the CYC group (2.64 vs. 3.4 months; hazard ratio [HR], 0.61; 95% CI, 0.74-0.90, p=0.03). The median time to first relapse was longer in the MMF group compared with the CYC group (10.8 vs. 8.0 months; HR, 1.12; 95% CI, 1.31-1.54, p=0.01), and this was significantly correlated with the median time to B-cell recovery in the two groups (8.6 vs. 5.2 months in MMF and CYC, respectively, p=0.02). The overall incidence of adverse drug events was lower in the MMF group compared with the CYC group (59.3% vs. 76.4%, p=0.03). MMF-RTX is superior to CYC-RTX in maintaining remission with fewer AEs in children with initial SRNS. Additional high-quality randomized control trials with long-term follow-up are needed to identify the long-term potential complications.

P673: DEPLETION AND RECOVERY OF NORMAL B-CELLS DURING AND AFTER TREATMENT WITH CHEMOIMMUNOTHERAPY, IBRUTINIB OR VENETOCLAX.

Background: Infectious complications are a major cause of morbidity and mortality in Chronic Lymphocytic Leukaemia (CLL). Therapeutic approaches that deplete CLL cells also affect normal B-cells. Optimal treatment would result in eradication of CLL cells and recovery of normal immune function. FLAIR (ISRCTN01844152) is a phase III trial for previously untreated CLL comparing ibrutinib plus rituximab (IR) with fludarabine, cyclophosphamide and rituximab (FCR) and subsequently amended to also compare ibrutinib plus venetoclax (I+V) and ibrutinib alone (I) with FCR. Measurable residual disease (MRD) and normal B-cell levels were assessed at multiple timepoints. Aims: To assess the depletion of normal B-cells during treatment and recovery after end of treatment. Methods: Participants aged under 75 years with <20% TP53-deleted cells were initially randomised to FCR or IR and subsequently to FCR, IR, I+V or I with the IR arm closed after randomisation of 771 participants to FCR/IR. FCR was given for 6 cycles, while treatment in the IR, I and I+V arms continued for up to 6 years except in participants attaining <0.01% MRD who continued treatment for the time taken to achieved MRD <0.01% and then stopped if MRD remained <0.01%. Month (M) 24 was earliest permitted stopping point. MRD flow cytometry was performed according to ERIC guidelines (panel: CD19/5/20/43/79/81+ROR1, acquisition of 0.5–2.2 million cells, BD Biosciences Lyric). Additional analysis of normal B-cell subsets was performed in a cohort of >500 patients (panel: CD19 to identify B-cells, CD20/5/79b+ROR1 and CD3 to exclude CLL & contaminating cells, with CD27/ 38/IgD/IgM to characterise normal B-cell subsets using a Coulter Cytoflex LX). Results: Normal B-cells were undetectable during FCR treatment and only rarely detectable until 12 months after last FCR cycle. Circulating normal B-cells were reduced in number or undetectable in participants receiving ibrutinib-containing regimens with greater depletion in the I+V and IR arms relative to I monotherapy. B-progenitors persist through FCR treatment but were depleted during I, I+R or I+V treatment. Normal B-cell levels at 24 and 36 months after randomisation, with time off-treatment if applicable, are shown in Figure 1. In the ibrutinib-containing arms (IR, I, and I+V), there was a trend towards fewer COVID-associated SAE at any time point for participants with detectable B-cells at 24M (4/181, 2.2%) compared to those with no detectable B-cells (14/344, 4.1%) and COVID-associated SAEs were not observed in FCR-treated participants who had recovered any level of normal B-cells by 24M (0/215). However, the data on COVID infections are limited and there was no apparent association between normal B-cell levels at 24M with the proportion of participants experiencing an infectious SAE overall. Assessment of normal B-cell subsets during ibrutinib-based treatment demonstrated a mix of naïve and memory B-cells. Serological response to COVID infection/vaccination in this cohort is currently being performed. Participants stopping I+V treatment at 24-30 months post-randomisation due to MRD eradication showed rapid recovery of normal naive B-cells within 6-12 months after end of treatment in the vast majority (>95%) of evaluable cases. Image:Summary/Conclusion: Normal circulating B-cells are depleted during treatment with rituximab but can persist at a low level during I, IR or I+V treatment. Most patients in remission after treatment with FCR or I+V show recovery of normal B-cells at 12 months of stopping treatment.

S112: TISAGENLECLEUCEL IN PEDIATRIC AND YOUNG ADULT PATIENTS (PTS) WITH RELAPSED/REFRACTORY (R/R) B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL): FINAL ANALYSES FROM THE ELIANA STUDY

Background: Pediatric and young adult pts with R/R B-ALL experience a treatment journey characterized by diminishing likelihood of cure and increasing morbidity. Tisagenlecleucel is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for use in pediatric and young adults with B-ALL and adults with B-cell lymphomas. Tisagenlecleucel provided high rates of remission (>80%) in children and young adults with R/R B-ALL in ELIANA, with 62% of responders remaining relapse-free at 24 mo (Grupp et al, Blood, 2018). Aims: Here, we report the final efficacy and safety analyses in pts followed up to 5.9 years post-tisagenlecleucel infusion. Methods: ELIANA (NCT02435849) was a pivotal, Phase II, open-label, multicenter, global study of tisagenlecleucel in pediatric and young adult pts with R/R B-ALL. Pts received a single infusion of tisagenlecleucel at 0.2-5.0×106 CAR+ viable T cells/kg body weight for pts ≤50 kg and 0.1-2.5×108 CAR+ viable T cells for pts >50 kg. Endpoints included overall remission rate (ORR) within 3 mo, relapse-free survival (RFS), duration of remission (DOR), overall survival (OS), persistence of B-cell aplasia, and short- and long-term safety events. Results:Results: As of September 24, 2021, 97 pts were enrolled and 79 pts (81%) received tisagenlecleucel. Median time from infusion to data cutoff was 5.5 y; 64 pts had ≥5 y of follow-up. At study entry, the median age was 11 y (range, 3-24). Pts were heavily pretreated with a median of 3 prior lines of therapy (range, 1-8) and 61% had a history of prior stem cell transplant (SCT). ORR (complete remission [CR] or CR with incomplete hematologic recovery within 3 mo after infusion) was 82% (95% CI, 72-90). Among pts in remission (CR/CRi), the 5y RFS rate was 49% (95% CI, 34-62), and the median RFS was not reached (Figure, 46.8 mo when censoring for SCT; n=15). The median time to B-cell recovery was 38.6 mo (95% CI, 23-not reached) and the probability of B-cell aplasia at 6 mo and 12 mo was 83% (95% CI, 71-91) and 71% (95% CI, 57-82), respectively. Pts with B-cell recovery (<6 mo, n=10; 6-12 mo, n=4; >12 mo, n=7) experienced a 2y cumulative incidence of relapse of 25.2% (with SCT treated as a competing risk). Among all pts, the 5y EFS and OS rates were 42% (95%CI, 29-54) and 55% (95% CI, 43-66), respectively. There were no significant differences in any efficacy endpoint between pediatric (<18 y; n=65) and young adult (≥18 y; n=14) pts. No new or unexpected AEs were reported during long-term follow-up. Among pts in remission, the most commonly reported grade ≥3 AEs occurring >1 y post-infusion were infection (20%) and cytopenias (6%). Ten (14%) pts in remission experienced long-term cytopenias persisting for >1 y; however, none of these pts experienced cytopenias persisting for >5 y (median 2 y; range, 1.1-5y). Eighty-two percent of pts received IVIG any time post-infusion. Image:Summary/Conclusion: This >5 y follow-up study demonstrates continued durable efficacy of tisagenlecleucel without late adverse effects in heavily pretreated pediatric and young adult pts with R/R B-ALL. Tisagenlecleucel continues to be a potentially curative treatment option for pediatric and young adult patients with R/R B-ALL.

PB2110: PHARMACOKINETICS AND PHARMACODYNAMICS IN FIRST-MIND: A PHASE IB, OPEN-LABEL, RANDOMIZED STUDY OF TAFASITAMAB ± LENALIDOMIDE + R-CHOP IN PATIENTS WITH NEWLY DIAGNOSED DIFFUSE LARGE B-CELL LYMPHOMA

Background: The combination of tafasitamab + lenalidomide (LEN) has been granted accelerated approval in the United States (2020) and is conditionally approved in Canada and Europe (2021) for R/R DLBCL in autologous stem-cell transplant-ineligible adult patients. A tolerable safety profile for rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) + tafasitamab ± LEN in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) in the Phase Ib First-MIND study (NCT04134936) was previously reported, with clinically meaningful efficacy for R-CHOP + tafasitamab + LEN compared to R-CHOP + LEN (ASH 2021; #3556). Aims: To report pharmacokinetics, pharmacodynamics, and immunogenicity in patients with newly diagnosed DLBCL after adding tafasitamab ± LEN to R-CHOP as first-line treatment. Methods: Eligible patients were ≥18 years with treatment-naïve DLBCL, International Prognostic Index 2–5, and Eastern Cooperative Oncology Group performance score 0–2. Patients were randomized 1:1 to either six 21-day (D) cycles (C) of R-CHOP (R-CHO, D1; P, D1–5) + tafasitamab (12 mg/kg IV, D1, 8, 15) (Arm A) or R-CHOP + tafasitamab + LEN (25 mg orally, D1–10) (Arm B). Secondary endpoints included tafasitamab serum concentration and number and percentage of patients developing anti-tafasitamab antibodies. Exploratory endpoints included natural killer (NK) cell, T-cell, and B-cell count in peripheral blood. Results: In total, 83 patients were screened; 66 were randomized (Arm A, n=33; Arm B, n=33). The data cut-off was 13 March 2021 for the safety analysis, including ≥1 month follow-up after end of treatment (EoT) visit for all patients, and 15 September 2021 for the efficacy analysis. Tafasitamab serum concentrations reached steady state by C3 (geometric mean trough concentrations: Arm A, 186.40–216.55 µg/mL; Arm B, 171.77–201.54 µg/mL) and steadily declined after treatment completion. Anti-tafasitamab antibodies were detected in 1/65 (1.5%) patients. This patient showed pre-existing anti-tafasitamab antibodies at baseline, which decreased during treatment. Median NK cell counts decreased from baseline at C1 D8, but were at baseline or higher levels by EoT visit (Arm A) and C1 D15 (Arm B; Table). T-cell counts decreased from baseline at C1 D8 in both arms but were at baseline level or higher by C1 D15 (Arm A) and EoT visit (Arm B). Median B-cell counts decreased from baseline to 0 cells/μL (Arm A, C1 D15; Arm B, C1D8); at 6-month follow-up after EoT visit, B-cell counts had recovered to measurable levels in ~50% of patients. Image:Summary/Conclusion: Tafasitamab serum concentration reached and maintained a therapeutic dose level in this first-line regimen and declined in line with known tafasitamab half-life (~16 days) after treatment completion; tafasitamab levels were comparable between the two treatment arms. No patients developed treatment-induced or treatment-boosted anti-tafasitamab antibodies. Median NK, T-cell, and B-cell counts were comparable between treatment arms in all cycles. NK and T-cell counts recovered to baseline levels by EoT; further follow up on B-cell recovery will be performed.

T Cell Defects: New Insights Into the Primary Resistance Factor to CD19/CD22 Cocktail CAR T-Cell Immunotherapy in Diffuse Large B-Cell Lymphoma.

Despite impressive progress, a significant portion of patients still experience primary or secondary resistance to chimeric antigen receptor (CAR) T-cell immunotherapy for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). The mechanism of primary resistance involves T-cell extrinsic and intrinsic dysfunction. In the present study, a total of 135 patients of DLBCL treated with murine CD19/CD22 cocktail CAR T-therapy were assessed retrospectively. Based on four criteria (maximal expansion of the transgene/CAR-positive T-cell levels post-infusion [Cmax], initial persistence of the transgene by the CAR transgene level at +3 months [Tlast], CD19+ B-cell levels [B-cell recovery], and the initial response to CAR T-cell therapy), 48 patients were included in the research and divided into two groups (a T-normal group [n=22] and a T-defect [n=26] group). According to univariate and multivariate regression analyses, higher lactate dehydrogenase (LDH) levels before leukapheresis (hazard ratio (HR) = 1.922; p = 0.045) and lower cytokine release syndrome (CRS) grade after CAR T-cell infusion (HR = 0.150; p = 0.026) were independent risk factors of T-cell dysfunction. Moreover, using whole-exon sequencing, we found that germline variants in 47 genes were significantly enriched in the T-defect group compared to the T-normal group (96% vs. 41%; p<0.0001), these genes consisted of CAR structure genes (n=3), T-cell signal 1 to signal 3 genes (n=13), T cell immune regulation- and checkpoint-related genes (n=9), cytokine- and chemokine-related genes (n=13), and T-cell metabolism-related genes (n=9). Heterozygous germline UNC13D mutations had the highest intergroup differences (26.9% vs. 0%; p=0.008). Compound heterozygous CX3CR1I249/M280 variants, referred to as pathogenic and risk factors according to the ClinVar database, were enriched in the T-defect group (3 of 26). In summary, the clinical characteristics and T-cell immunodeficiency genetic features may help explain the underlying mechanism of treatment primary resistance and provide novel insights into CAR T-cell immunotherapy.

Impact of donor vaccination on recipient response to early SARS-CoV-2 mRNA vaccination after allogeneic HSCT

Since the emergence of COVID-19 more than 2 years ago, allogeneic haematopoietic stem-cell transplantation (HSCT) recipients have been considered at especially high risk of developing severe forms of the disease. The first studies focusing on COVID-19 after HSCT confirmed the poor prognosis in this population,1 highlighting the urgent need for efficient preventive and curative treatment strategies. In this regard, mRNA vaccines have emerged with the ability to confer a high protection rate, mostly against severe disease, and a good safety profile; however, in post-HSCT vaccination, humoral response might be altered due to intake of immunosuppressive drugs and delay of B-cell recovery.

Antigen Specific Humoral and Cellular Immunity Following SARS-CoV-2 Vaccination in ANCA-Associated Vasculitis Patients Receiving B-Cell Depleting Therapy.

Humoral vaccine responses are known to be suboptimal in patients receiving B-cell targeted therapy, and little is known about vaccine induced T-cell immunity in these patients. In this study, we characterized humoral and cellular antigen-specific anti-SARS-CoV2 responses following COVID-19 vaccination in patients with ANCA-associated vasculitis (AAV) receiving anti-CD20 therapy, who were either B-cell depleted, or B-cell recovered at the time of vaccination and in normal control subjects. SARS-CoV-2 anti-spike (S) and anti-nucleocapsid (NC) antibodies were measured using electrochemiluminescence immunoassays, while SARS-CoV-2 specific T-cell responses to S glycoprotein subunits 1 (S1) and 2 (S2) and receptor binding domain peptide pools were measured using interferon-gamma enzyme-linked immunosorbent spot (ELISPOT) assays. In total, 26 recently vaccinated subjects were studied. Despite the lack of a measurable humoral immune response, B-cell depleted patients mounted a similar vaccine induced antigen-specific T-cell response compared to B-cell recovered patients and normal controls. Our data indicate that to assure a humoral response in patients receiving anti-CD20 therapy, SARS-CoV-2 vaccination should ideally be delayed until B-cell recovery (CD-20 positive B-cells > 10/μl). Nevertheless, SARS-CoV-2 vaccination elicits robust, potentially protective cellular immune responses in these subjects. Further research to characterize the durability and protective effect of vaccine-induced anti-SARS-CoV-2 specific T-cell immunity are needed.

Next-Generation Sequencing of Minimal Residual Disease for Predicting Relapse after Tisagenlecleucel in Children and Young Adults with Acute Lymphoblastic Leukemia.

We assessed minimal residual disease (MRD) detection and B-cell aplasia after tisagenlecleucel therapy for acute lymphoblastic leukemia (ALL) to define biomarkers predictive of relapse (N = 143). Next-generation sequencing (NGS) MRD detection >0 in bone marrow (BM) was highly associated with relapse. B-cell recovery [signifying loss of functional chimeric antigen receptor (CAR) T cells] within the first year of treatment was associated with a hazard ratio (HR) for relapse of 4.5 [95% confidence interval (CI), 2.03-9.97; P < 0.001]. Multivariate analysis at day 28 showed independent associations of BMNGS-MRD >0 (HR = 4.87; 95% CI, 2.18-10.8; P < 0.001) and B-cell recovery (HR = 3.33; 95% CI, 1.44-7.69; P = 0.005) with relapse. By 3 months, the BMNGS-MRD HR increased to 12 (95% CI, 2.87-50; P < 0.001), whereas B-cell recovery was not independently predictive (HR = 1.27; 95% CI, 0.33-4.79; P = 0.7). Relapses occurring with persistence of B-cell aplasia were largely CD19- (23/25: 88%). Detectable BMNGS-MRD reliably predicts risk with sufficient time to consider approaches to relapse prevention such as hematopoietic cell transplantation (HCT) or second CAR-T cell infusion. SIGNIFICANCE: Detectable disease by BMNGS-MRD with or without B-cell aplasia is highly predictive of relapse after tisagenlecleucel therapy for ALL. Clonotypic rearrangements used to follow NGS-MRD did not change after loss of CD19 or lineage switch. High-risk patients identified by these biomarkers may benefit from HCT or investigational cell therapies.See related commentary by Ghorashian and Bartram, p. 2.This article is highlighted in the In This Issue feature, p. 1.

Tisagenlecleucel Therapy Is Safe and Effective for Children with Down Syndrome with ALL in First Relapse

Introduction: Children with Down Syndrome (DS) have a 20-fold increased incidence of acute lymphoblastic leukemia (ALL) and a 70% higher risk of relapse than children with ALL and no DS. Treatment for DS children with relapsed ALL is challenging due to the high treatment-related mortality associated with both intensive chemotherapy and hematopoietic stem cell transplantation (HSCT) as well as high rates of second relapse. Outcomes for relapsed ALL in DS are dismal, with recent studies citing an event-free survival (EFS) as low as 17%. Alternative treatment approaches are needed for this patient population. Treatment with anti-CD19 chimeric antigen receptor T-cells (CARTs) have shown high remission rates in patients with multiple relapsed/refractory ALL with an acceptable safety profile. CARTs are generally not indicated for first relapse of ALL; DS-specific indications for CARTs do not exist. In Ontario, due to the specific susceptibility of children with DS-ALL, CARTs were made available to this population upon first relapse. We describe the population-based Canadian experience using CARTs for first relapse of DS-ALL.Methods: Efficacy and safety data on all children referred for CARTs at the Hospital for Sick Children, in Toronto, Canada were retrospectively collected in a central database and validated by treating clinicians. Here we report all patients with DS suffering a first relapse of ALL at age <18 years referred for commercially available CARTs (tisagenlecleucel) between 2019 and 2021.Results: Five patients with DS received tisagenlecleucel for first relapse of ALL during the study period. Median age at original diagnosis was 6.3 years (range 3.4-11.5). Four patients presenting with National Cancer Institute (NCI) standard risk and one with NCI high-risk disease were initially treated on Children's Oncology Group based protocols. Four patients presented with relapse >36 months from diagnosis and one patient with early relapse. Mononuclear cells were successfully collected for all patients on the first attempt. Patients were bridged from collection to infusion with low intensity chemotherapy regimens. Tisagenlecleucel was successfully manufactured for all patients and infused at a median of 69 days (range 56-101) from collection of T cells. Four patients developed CRS: two patients grade 1, one patient grade 2, and one patient grade 4 requiring ICU care and treatment with tocilizumab and steroid. All patients achieved minimal residual disease (MRD) negative remission one month after infusion, with B-cell aplasia. Two patients showed early (< 6months post infusion) B-cell recovery consistent with CAR T-cell loss; both received off-label reinfusions of tisagenlecleucel and again achieved B-cell aplasia. One patient had a seizure with the first Fludarabine dose of lymphodepleting (LD) chemotherapy for re-infusion and was found to have elevated intracranial pressure. After treatment with Topiramate and anti-seizure prophylaxis the patient tolerated LD chemotherapy without further neurological events. No patient received further ALL therapy; none went on to HSCT. One patient suffered a CD19-negative relapse 7 months post infusion and was transitioned to palliative-intent treatment. Two patients developed prolonged neutropenia with one patient showing recovery (ANC>1x10E9/l) at 5 months post infusion and the patient who had relapsed disease remained neutropenic until relapse. Infectious complications in the first 6 months post infusion were rare. One patient, who was not neutropenic, required two hospital admissions for line related sepsis. With a median follow-up time of 519 days (range 197-785), the 1-year estimated EFS and overall survival were both 80% (95 th confidence interval 52-100%; Figure 1).Conclusions: Tisagenlecleucel was safe and effective in a small cohort of children with DS and first relapse of CD19+ ALL, with achievement of long-term remissions without further therapy, and an EFS superior to that seen in historical cohorts. Rate of acute complications were not increased compared with reported outcomes in patients without DS. Further evaluation of tisagenlecleucel in this setting is warranted. [Display omitted] DisclosuresKrueger: KITE/Gilead: Consultancy; Novartis: Consultancy; SOBI: Consultancy. Whitlock: Sobi Pharmaceuticals: Consultancy; Novartis: Research Funding; Amgen; Jazz Pharmaceuticals: Honoraria. Gupta: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure:tisagenlecleucel for early B-cell recovery

Outcomes after Reinfusion of CD19-Specific Chimeric Antigen Receptor (CAR)-Modified T Cells in Children and Young Adults with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

Background: CAR-modified T cells targeting CD19 have produced remarkable responses in relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL); however, relapse continues to be a substantial challenge. CD19+ relapses, which account for 33-78% of relapses, are associated with loss of CAR T-cell surveillance due to short persistence. Thus, strategies to improve functional persistence to prevent and treat CD19+ relapsed disease are crucial. Here, we report our experience administering reinfusions of murine or humanized 4-1BB CD19 CAR T cells in an effort to prolong persistence in patients with demonstrated short persistence to mitigate relapse risk, treat CD19+ relapsed disease, and produce responses after nonresponse to initial CAR infusion.Methods: This analysis included patients aged <30 years treated with a murine CD19 CAR construct, either investigational CTL019 (NCT01626495, NCT02906371) or commercial tisagenlecleucel, or a humanized CD19 CAR construct, huCART19 (NCT02374333), who received ≥1 reinfusion of the same CAR product due to: 1) clinical signs of poor persistence within 6 months (mos) of initial infusion, including peripheral B-cell recovery (BCR) or CD19+ hematogones in the bone marrow, 2) new CD19+ minimal residual disease (MRD) or relapse, or 3) nonresponse to initial infusion. The huCART19 trial included patients who had previously received a CAR T cell product (CAR-exposed), whereas all patients reinfused with CTL019/tisagenlecleucel were CAR-naïve at initial infusion. The primary outcome was complete response (CR) at day 28 after reinfusion, defined as complete remission with establishment or maintenance of B-cell aplasia. Secondary outcomes included CRS incidence, cumulative incidence of relapse (CIR) and overall survival (OS).Results: Among 229 CAR-naïve and 33 CAR-exposed patients treated with CD19 CAR between 2012-2020, 81 received ≥1 reinfusion (investigational CTL019, n=44; commercial tisagenlecleucel, n=11; huCART19, n=13 CAR-naïve and n=13 CAR-exposed). In addition, 18 patients received PD-1 blockade after their first (n=11) or subsequent (n=7) reinfusions. Indications for first reinfusion were peripheral BCR (CAR-naïve, n=32; CAR-exposed, n=6), hematogones (CAR-naïve, n=21; CAR-exposed, n=4), CD19+ MRD/relapse (CAR-naïve, n=10, CAR-exposed, n=0), and nonresponse to initial infusion (CAR-naïve, n=5, CAR-exposed, n=3). CRS grade ≥2 (Penn scale) occurred in 19 patients (grade 2, n=13; grade 3, n=4; grade 4, n=2). Grade 3-4 events only occurred in patients with active disease at time of reinfusion. Twenty-two patients had an inpatient admission within 30 days of first reinfusion, of which 7 required intensive care unit admissionAmong the 63 patients reinfused for relapse prevention, 33 (52%) had a CR at day 28. With a median duration of follow-up of 38 mos, 13 experienced a subsequent relapse (7 CD19+, 4 CD19-, 2 CD19-subset negative), 4 received alternative therapy or allogeneic hematopoietic stem cell transplantation (HSCT) in remission, and 16 remain in remission without further therapy at a median of 39 mos after first reinfusion. The median duration of B-cell aplasia was 8 mos (IQR 2-35) after reinfusion. Of the 30 with no response (NR), 10 had a subsequent CD19+ relapse, 15 received alternative therapy or HSCT, and 5 remain in remission without further therapy at a median of 43 mos after reinfusion. CIR and OS were not statistically significantly different between patients with CR or NR (CIR, p=0.26; OS, p=0.25) (Figure A-B). However, at 24 mos after reinfusion, CIR was 29% (95% CI, 11-44%) for CR compared to 61% (95% CI, 24-80%) for NR; OS was 90% (95% CI, 80-100%) for both groups.Of the 10 patients reinfused for relapse, 5 (50%) had a CR; 2 subsequently experienced a CD19+ relapse, 2 received an HSCT in remission, and 1 remains in remission without further therapy at 18 mos after reinfusion. Of the 8 patients reinfused for nonresponse to initial infusion, 7 were evaluable; none had a CR, and all died at a median of 2.5 mos after reinfusion.Conclusions: Reinfusion of CTL019/tisagenlecleucel or huCART19 is safe, may prolong B-cell aplasia in patients with short CAR persistence and reduce relapse risk, and can induce remissions in patients with CD19+ relapsed disease. Thus, reinfusion may provide an alternative to HSCT for short persistence. However, reinfusion is not effective for patients with nonresponse to initial CAR infusion. [Display omitted] DisclosuresCallahan: Novartis: Speakers Bureau. Rheingold: Optinose: Other: Spouse's current employment; Pfizer: Research Funding. June: Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company; Novartis: Patents & Royalties; AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy. Grupp: Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy; Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards; Novartis, Kite, Vertex, and Servier: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding. Maude: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Wugen: Consultancy.

Impact of Allogeneic Hematopoietic Cell Transplantation (HCT) As Consolidation Following CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy for Treatment of Relapsed Acute Lymphoblastic Leukemia (ALL)

Impact of Allogeneic Hematopoietic Cell Transplantation (HCT) As Consolidation Following CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy for Treatment of Relapsed Acute Lymphoblastic Leukemia (ALL)

M180 PERSISTENT HYPOGAMMAGLOBULINEMIA IN A PEDIATRIC PATIENT FOLLOWING RITUXIMAB TREATMENT FOR AUTOIMMUNE ENCEPHALITIS

Rituximab, a chimeric anti-CD20 monoclonal antibody that depletes pre-plasma B-cells, is used for the treatment of autoimmune disease. While proven effective in disease management, anti-CD20 therapies are also associated with prolonged (>6-9 months) hypogammaglobulinemia and subsequent infectious risk. We describe an adolescent patient with autoimmune encephalitis who experienced prolonged B-cell depletion and persistent hypogammaglobulinemia following Ritixumab, with eventual B-cell recovery but persistent hypogammaglobulinemia and absence of isotype-switched memory B cells(CD19+CD27+IGD-IgM-).