Chimeric antigen receptor (CAR) T-cells targeting CD19 mediate potent effects in relapsed/refractory pre-B cell acute lymphoblastic leukemia (B-ALL) but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed on most B-ALL and usually retained following CD19 loss. We report results from a phase I trial testing a novel CD22-CAR in twenty-one children and adults, including 17 previously treated with CD19-directed immunotherapy. Dose dependent anti-leukemic activity was observed with complete remission in 73% (11/15) of patients receiving ≥ 1 × 106 CD22-CART cells/kg, including 5/5 patients with CD19dim/neg B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted escape from killing by CD22-CART cells. These results are the first to eastablish the clinical activity of a CD22-CAR in pre-B cell ALL, including in leukemia resistant to anti-CD19 immunotherapy, demonstrating comparable potency to CD19-CART at biologically active doses in B-ALL. They also highlight the critical role played by antigen density in regulating CAR function. (Funded by NCI Intramural Research Program)
PURPOSE Patients with B-cell acute lymphoblastic leukemia who experience relapse after or are resistant to CD19-targeted immunotherapies have limited treatment options. Targeting CD22, an alternative B-cell antigen, represents an alternate strategy. We report outcomes on the largest patient cohort treated with CD22 chimeric antigen receptor (CAR) T cells. PATIENTS AND METHODS We conducted a single-center, phase I, 3 + 3 dose-escalation trial with a large expansion cohort that tested CD22-targeted CAR T cells for children and young adults with relapsed/refractory CD22+ malignancies. Primary objectives were to assess the safety, toxicity, and feasibility. Secondary objectives included efficacy, CD22 CAR T-cell persistence, and cytokine profiling. RESULTS Fifty-eight participants were infused; 51 (87.9%) after prior CD19-targeted therapy. Cytokine release syndrome occurred in 50 participants (86.2%) and was grade 1-2 in 45 (90%). Symptoms of neurotoxicity were minimal and transient. Hemophagocytic lymphohistiocytosis–like manifestations were seen in 19/58 (32.8%) of subjects, prompting utilization of anakinra. CD4/CD8 T-cell selection of the apheresis product improved CAR T-cell manufacturing feasibility as well as heightened inflammatory toxicities, leading to dose de-escalation. The complete remission rate was 70%. The median overall survival was 13.4 months (95% CI, 7.7 to 20.3 months). Among those who achieved a complete response, the median relapse-free survival was 6.0 months (95% CI, 4.1 to 6.5 months). Thirteen participants proceeded to stem-cell transplantation. CONCLUSION In the largest experience of CD22 CAR T-cells to our knowledge, we provide novel information on the impact of manufacturing changes on clinical outcomes and report on unique CD22 CAR T-cell toxicities and toxicity mitigation strategies. The remission induction rate supports further development of CD22 CAR T cells as a therapeutic option in patients resistant to CD19-targeted immunotherapy.
PURPOSE CD19 chimeric antigen receptor (CD19-CAR) T cells induce high response rates in children and young adults (CAYAs) with B-cell acute lymphoblastic leukemia (B-ALL), but relapse rates are high. The role for allogeneic hematopoietic stem-cell transplant (alloHSCT) following CD19-CAR T-cell therapy to improve long-term outcomes in CAYAs has not been examined. METHODS We conducted a phase I trial of autologous CD19.28ζ-CAR T cells in CAYAs with relapsed or refractory B-ALL. Response and long-term clinical outcomes were assessed in relation to disease and treatment variables. RESULTS Fifty CAYAs with B-ALL were treated (median age, 13.5 years; range, 4.3-30.4). Thirty-one (62.0%) patients achieved a complete remission (CR), 28 (90.3%) of whom were minimal residual disease−negative by flow cytometry. Utilization of fludarabine/cyclophosphamide–based lymphodepletion was associated with improved CR rates (29/42, 69%) compared with non–fludarabine/cyclophosphamide–based lymphodepletion (2/8, 25%; P = .041). With median follow-up of 4.8 years, median overall survival was 10.5 months (95% CI, 6.3 to 29.2 months). Twenty-one of 28 (75.0%) patients achieving a minimal residual disease−negative CR proceeded to alloHSCT. For those proceeding to alloHSCT, median overall survival was 70.2 months (95% CI, 10.4 months to not estimable). The cumulative incidence of relapse after alloHSCT was 9.5% (95% CI, 1.5 to 26.8) at 24 months; 5-year EFS following alloHSCT was 61.9% (95% CI, 38.1 to 78.8). CONCLUSION We provide the longest follow-up in CAYAs with B-ALL after CD19-CAR T-cell therapy reported to date and demonstrate that sequential therapy with CD19.28ζ-CAR T cells followed by alloHSCT can mediate durable disease control in a sizable fraction of CAYAs with relapsed or refractory B-ALL (ClinicalTrials.gov identifier: NCT01593696 ).
PURPOSE CD19-targeted chimeric antigen receptor T cells (CD19-CAR) and blinatumomab effectively induce remission in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) but are also associated with CD19 antigen modulation. There are limited data regarding the impact of prior blinatumomab exposure on subsequent CD19-CAR outcomes. PATIENTS AND METHODS We conducted a multicenter, retrospective review of children and young adults with relapsed or refractory ALL who received CD19-CAR between 2012 and 2019. Primary objectives addressed 6-month relapse-free survival (RFS) and event-free survival (EFS), stratified by blinatumomab use. Secondary objectives included comparison of longer-term survival outcomes, complete remission rates, CD19 modulation, and identification of factors associated with EFS. RESULTS Of 420 patients (median age, 12.7 years; interquartile range, 7.1-17.5) treated with commercial tisagenlecleucel or one of three investigational CD19-CAR constructs, 77 (18.3%) received prior blinatumomab. Blinatumomab-exposed patients more frequently harbored KMT2A rearrangements and underwent a prior stem-cell transplant than blinatumomab-naïve patients. Among patients evaluable for CD19-CAR response (n = 412), blinatumomab nonresponders had lower complete remission rates to CD19-CAR (20 of 31, 64.5%) than blinatumomab responders (39 of 42, 92.9%) or blinatumomab-naive patients (317 of 339, 93.5%), P < .0001. Following CD19-CAR, blinatumomab nonresponders had worse 6-month EFS (27.3%; 95% CI, 13.6 to 43.0) compared with blinatumomab responders (66.9%; 95% CI, 50.6 to 78.9; P < .0001) or blinatumomab-naïve patients (72.6%; 95% CI, 67.5 to 77; P < .0001) and worse RFS. High-disease burden independently associated with inferior EFS. CD19-dim or partial expression (preinfusion) was more frequently seen in blinatumomab-exposed patients (13.3% v 6.5%; P = .06) and associated with lower EFS and RFS. CONCLUSION With the largest series to date in pediatric CD19-CAR, and, to our knowledge, the first to study the impact of sequential CD19 targeting, we demonstrate that blinatumomab nonresponse and high-disease burden were independently associated with worse RFS and EFS, identifying important indicators of long-term outcomes following CD19-CAR.
. Sequential loss of tumor surface antigens following chimeric antigen receptor T-cell therapies in diffuse large B-cell lymphoma.
CAR T-cell toxicities resembling hemophagocytic lymphohistiocytosis (HLH) occur in a subset of patients with cytokine release syndrome (CRS). As a variant of conventional CRS, a comprehensive characterization of CAR T-cell associated HLH (carHLH) and investigations into associated risk factors are lacking. In the context of 59 patients infused with CD22 CAR T-cells where a substantial proportion developed carHLH, we comprehensively describe the manifestations and timing of carHLH as a CRS variant and explore factors associated with this clinical profile. Amongst 52 subjects with CRS, 21 (40.4%) developed carHLH. Clinical features of carHLH included hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, coagulopathy, hepatic transaminitis, hyperbilirubinemia, severe neutropenia, elevated lactate dehydrogenase and occasionally hemophagocytosis. Development of carHLH was associated with pre-infusion NK-cell lymphopenia and higher bone marrow T/NK-cell ratio, which was further amplified with CAR T-cell expansion. Following CRS, more robust CAR T-cell and CD8 T-cell expansion in concert with pronounced NK-cell lymphopenia amplified pre-infusion differences in those with carHLH without evidence for defects in NK-cell mediated cytotoxicity. CarHLH was further characterized by persistent elevation of HLH-associated inflammatory cytokines, which contrasted with declining levels in those without carHLH. In the setting of CAR T-cell mediated expansion, clinical manifestations and immunophenotypic profiling in those with carHLH overlap with features of secondary HLH, prompting consideration of an alternative framework for identification and management of this toxicity profile to optimize outcomes following CAR T-cell infusion.
Relapsed pre-B acute lymphoblastic leukemia (ALL) portends a poor prognosis even with hematopoietic stem cell transplantation (HSCT). CD19 chimeric antigen receptor (CAR) T cells have shown promise in early studies although morbidity related tohigh gradecytokine release syndrome (CRS) and/or neurotoxicity could limit its wide applicability in patients with high disease burden. The lympho depleting chemotherapy regimen may affect both toxicity and response and has not been well studied. Relapse rates among complete responders to CD19 CAR therapy occur in nearly half of patients in the first year. We report outcomes from our completed clinical trial of 53 children and young adults with relapsed/refractory ALL (n=51) or lymphoma (n=2) with a median follow up (mF/U) of 18.7 months. The first 21 patients received a low dose fludarabine (25 mg/m2/day Days -4 to -2) and cyclophosphamide (900 mg/m2 Day -2) preparative regimen (LDflu/cy) and results are reported in Lancet 385:517-28. The regimen for the subsequent 32 patients, who all received 1x106 CAR+ T cells/kg, was stratified based on disease burden. Subjects with low burden ALL (lowALL; <25% marrow blasts) received LDflu/cy while those with high burden disease (highALL; >25% marrow blasts or lymphomatous disease) received an alternative regimen [FLAG (n=6), ifosfamide/etoposide per AALL0031 (n=2) or fludarabine (30mg/m2/day Days -6 to -3) and cyclophosphamide (1200 mg/m2/day Days -4 and -3) (HDflu/cy; n=8)] in an attempt to mitigate severe CRS risk and improve response. Four highALL subjects received LDflu/cy due to comorbidities including Trisomy 21. CRS was graded and anti-cytokine therapy was instituted as per Blood 124:188-95. Date for data cutoff was July 31, 2016. Of the 53 subjects 11 had primary refractory ALL, 5Ph+, 3 with Trisomy 21, 4 with CNS2 and 2 with CNS3 ALL including one with extensive leptomeningeal and parenchymal involvement. Cells were manufactured in 7-11 days and none underwent a test expansion. One patient was not infused due to rapidly progressive fungal pneumonia but was accounted for in all analyses. Of 51 ALL patients, 31 (60.8%) achieved a complete response (CR) with 28/31 (90%) of responders negative for minimal residual disease (MRD-). All 6 subjects with CNS ALL were rendered into CNS1 status with resolution of leptomeningeal enhancement, where appropriate, and CAR cells in CSF. The median leukemia free survival (mLFS) of MRD- CR responders is 18 months with a 49.5% probability of LFS beginning at 18 months (mF/U 22.6 months). Grade 3 (n=5) and 4 (n=2) CRS combined for a severe CRS incidence of 13.5%. Three grade 3 neurotoxicities(1 each: dysphasia, delirium, headache) and 2 seizures (one grade 1, one grade 2) occurred. There were no grade 4 neurotoxicities, even in the subject with extensive CNS disease. Subjects with low ALL had a significantly higher CR rate (18/21; 85.7%) than those with high ALL (13/32; 40.6%) (p=0.0011) and use of a flu/cy regimen correlated with higher response (29/44; 65.9% vs 2/8; 25%; p=0.0301). Overall survival in all subjects receiving a flu/cy regimen was 13.3 months with a 34.7% probability of survival beginning at 38 months (mF/U 18.7 months), which is significantly longer than those who did not receive a flu/cy regimen (5.5 months, no survivors beyond 11 months). The hazard ratio (HR) of not receiving a flu/cy regimen was 6.35 (1.906-21.14; p=0.0026). mLFS of subjects with MRD- CR who received a flu/cy regimen was not reached with a 53.3% probability of LFS beginning at 18 months (mF/U 22.6 months). Of the 28 subjects achieving MRD- CR, 21 had a subsequent HSCT with a median time to HSCT of 54 days from CAR infusion. 8/28 (28.6%) relapsed with CD19+ (n=2), CD19-/dim (n=5), CD19 unknown (n=1) blasts. Relapse was significantly more common in subjects who did not have a HSCT after CAR therapy (6/7; 85.7%) compared to those who did (2/21; 9.5%) (p=0.0001). Even accounting for transplant related mortality, them LFS in the HSCT group was not reached with a 62% probability of LFS beginning at 18 months. This is significantly longer than them LFS of 4.9 months in MRD- CR subjects who did not proceed to HSCT (p=0.0006) with a HR of 16.9 (3.37-85.1) of not having a subsequent HSCT. In all, CD19 CAR T cell therapy was effective and safe with a low incidence of severe CRS and neurotoxicity. In this nonrandomized series, the rate of durable remission was higher when a flu/cy preparative regimen was used and consolidation HSCT was employed. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Lee: Juno: Honoraria. Kochenderfer:bluebird bio: Patents & Royalties, Research Funding; Kite Pharma: Patents & Royalties, Research Funding. Rosenberg:Kite pharma: Research Funding. Mackall:NCI: Patents & Royalties: B7H3 CAR.
BackgroundChimeric antigen receptor (CAR) T-cell-associated cytokine release syndrome (CRS) may present with tachycardia, hemodynamic instability and reduced cardiac function. Pediatric CAR studies examining cardiac toxicity are limited.MethodsWe report on cardiac toxicity observed in children and young adults with hematologic malignancies enrolled in a CD19-28ζ CAR T-cell phase I trial (NCT01593696). All patients had a formal baseline echocardiogram. Real-time studies included echocardiograms on intensive care unit (ICU) transfer, and serial troponin and pro-B-type natriuretic peptide (pro-BNP) in the select patients.ResultsFrom July 2012 to March 2016, 52 patients, with a median age of 13.4 years (range 4.2–30.3) were treated. CRS developed in 37/52 (71%), which was grade 3–4 CRS in nine patients (17%). The median prior anthracycline exposure was 205 mg/m2 (range 70–620 mg/m2) in doxorubicin equivalents. The median baseline left ventricle ejection fraction (LVEF) and baseline LV global longitudinal strain (GLS) were 60% (range 50%–70%) and 16.8% (range 14.1%–23.5%, n=37) respectively. The majority, 78% (29/37), of patients had a reduced GLS <19% at baseline, and 6% (3/52) of patients had baseline LVEF <53%. ICU transfers occurred in 21 patients, with nine requiring vasoactive hemodynamic support and three necessitating >1 vasopressor. Six (12%) patients developed cardiac dysfunction (defined by >10% absolute decrease in LVEF or new-onset grade 2 or higher LV dysfunction, per CTCAE v4), among whom 4 had grade 3–4 CRS. Troponin elevations were seen in 4 of 13 patients, all of whom had low LVEF. Pro-BNP was elevated from baseline in 6/7 patients at the onset of CRS, with higher levels correlating with more severe CRS. Cardiac dysfunction fully resolved in all but two patients by day 28 post-CAR.ConclusionCardiac toxicity related to CD19-28ζ CAR T-cell-associated CRS was generally reversible by day 28 postinfusion. Implementation of more frequent monitoring with formal echocardiograms incorporating systemic analysis of changes in GLS, and cardiac biomarkers (troponin and proBNP) may help to earlier identify those patients at highest risk of severe cardiac systolic dysfunction, facilitating earlier interventions for CRS to potentially mitigate acute cardiac toxicity.
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