First name
Stephan
Middle name
A
Last name
Grupp

Title

Impact of poverty and neighborhood opportunity on outcomes for children treated with CD19-directed CAR T-cell therapy.

Year of Publication

2022

Date Published

11/2022

ISSN Number

1528-0020

Abstract

Children living in poverty experience excess relapse and death from newly diagnosed acute lymphoblastic leukemia (ALL). The influence of household poverty and neighborhood social determinants on outcomes from CAR T-cell therapy for relapsed/refractory (r/r) leukemia is poorly described. We identified patients with r/r CD19+ ALL/lymphoblastic lymphoma treated on CD19-directed CAR T-cell clinical trials or with commercial tisagenlecleucel from 2012 to 2020. Socioeconomic status (SES) was proxied at the household-level, with poverty-exposure defined as Medicaid-only insurance. Low neighborhood opportunity was defined by the Childhood Opportunity Index. Among 206 patients aged 1-29, 35.9% were household-poverty exposed, and 24.9% had low neighborhood opportunity. Patients unexposed to household-poverty or low-opportunity neighborhoods were more likely to receive CAR T-cell therapy with high disease burden (>25%)-a disease characteristic associated with inferior outcomes-as compared to less advantaged patients (38% vs 30%; 37% vs 26%). Complete remission (CR) rate was 93% with no significant differences by household-poverty (P = 0.334) or neighborhood opportunity (P = 0.504). In multivariate analysis, patients from low-opportunity neighborhoods experienced increased hazard of relapse as compared to others (P = 0.006, adjusted HR 2.3, 95% CI 1.3-4.1). There was no difference in hazard of death (P = 0.545, adjusted HR 1.2, 95% CI 0.6-2.4). Among children who successfully receive CAR T-cell therapy, CR and OS is equitable regardless of proxied SES and neighborhood opportunity. Children from more advantaged households and neighborhoods receive CAR T-cell therapy with higher disease burden. Investigation of multicenter outcomes and access disparities outside of clinical-trial settings is warranted. Clinical trials: NCT01626495; NCT02435849 ; NCT02374333; NCT02228096; NCT02906371.

DOI

10.1182/blood.2022017866

Alternate Title

Blood

PMID

36351239

Title

Immune Reconstitution Following TCRαβ/CD19-Depleted Hematopoietic Cell Transplantation for Hematologic Malignancy in Pediatric Patients.

Year of Publication

2021

Number of Pages

169.e1-169.e9

Date Published

2021 Feb

ISSN Number

2666-6367

Abstract

TCRαβ/CD19-depleted HCT has been used with excellent outcomes in pediatric patients with hematologic malignancies, and several studies have demonstrated rapid immune reconstitution in the nonmalignant setting. However, immune recovery following TCRαβ/CD19-depleted hematopoietic cell transplantation (HCT) for malignancy remains incompletely elucidated. Furthermore, the majority of studies to date have used haploidentical and matched unrelated donors. Here we report results of immune reconstitution following TCRαβ/CD19-depleted HCT for hematologic malignancy in 51 pediatric patients with hematologic malignancies, the majority of whom received grafts from unrelated donors. Grafts were from matched unrelated (n = 20), mismatched unrelated (n = 20), and haploidentical (n = 11) donors. The median CD34 cell dose was 10.2 × 10/kg (range, 4.54 to 20 × 10/kg), and the median TCRαβ cell dose was 2.53 × 10/kg (range, 0 to 44.9 × 10/kg). Conditioning was myeloablative with either busulfan or total body irradiation, cyclophosphamide, and thiotepa. Thirty-three patients also received rabbit antithymocyte globulin. No prophylactic post-transplantation immune suppression was routinely given. Forty-three patients received rituximab on day +1 for recipient positive Epstein-Barr virus serology. Forty-nine patients (96%) engrafted with a median time to neutrophil recovery of 13 days (range, 8 to 30 days). Thirty-seven patients (73%) are alive at a median follow-up of 25 months (range, 6 to 50 months). Nine patients (18%) developed grade II-IV acute graft-versus-host disease (GVHD), and 5 patients (11%) developed extensive chronic GVHD. Twenty-six patients (51%) experienced viral reactivation. T cell reconstitution was rapid with significant numbers of CD3, CD4, and CD8 T cells present on first assessment at 4 months post-HCT, and significant numbers of naïve CD4 T cells were present by 8 months post-HCT. Chronic GVHD was associated with delayed T cell recovery; however, T cell reconstitution was not affected by underlying diagnosis, donor source, TCRαβ T cell dose, conditioning regimen, or use of antithymocyte globulin. B cell recovery mirrored T cell recovery, and i.v. Ig was discontinued at a median of 8 months (range, 4 to 22 months) post-HCT in patients alive and relapse-free at last follow-up. Immune reconstitution is rapid following TCRαβ/CD19-depleted HCT in pediatric patients with hematologic malignancies. Donor graft source, haploidentical or unrelated, did not affect immune reconstitution. Viral reactivation is common in the first 100 days post-HCT, indicating that improved T cell defense is needed in the early post-HCT period.

DOI

10.1016/j.jtct.2020.10.006

Alternate Title

Transplant Cell Ther

PMID

33830028

Title

Unrelated donor α/β T cell- and B cell-depleted HSCT for the treatment of pediatric acute leukemia.

Year of Publication

2022

Number of Pages

1175-1185

Date Published

2022 Feb 22

ISSN Number

2473-9537

Abstract

Unrelated donor (URD) hematopoietic stem cell transplant (HSCT) is associated with an increased risk of severe graft-versus-host disease (GVHD). TCRαβ/CD19 depletion may reduce this risk, whereas maintaining graft-versus-leukemia. Outcome data with TCRαβ/CD19 depletion generally describe haploidentical donors, with relatively few URDs. We hypothesized that TCRαβ/CD19-depletion would attenuate the risks of GVHD and relapse for URD HSCT. Sixty pediatric and young adult (YA) patients with hematologic malignancies who lacked a matched-related donor were enrolled at 2 large pediatric transplantation centers between October 2014 and September 2019. All patients with acute leukemia had minimal residual disease testing, and DP typing was available for 77%. All patients received myeloablative total body irradiation- or busulfan-based conditioning with no posttransplant immune suppression. Engraftment occurred in 98%. Four-year overall survival was 69% (95% confidence interval [CI], 52%-81%), and leukemia-free survival was 64% (95% CI, 48%-76%), with no difference between lymphoid and myeloid malignancies (P = .6297 and P = .5441, respectively). One patient (1.7%) experienced primary graft failure. Relapse occurred in 11 patients (3-year cumulative incidence, 21%; 95% CI, 11-34), and 8 patients (cumulative incidence, 15%; 95% CI, 6.7-26) experienced nonrelapse mortality. Grade III to IV acute GVHD was seen in 8 patients (13%), and 14 patients (26%) developed chronic GVHD, of which 6 (11%) had extensive disease. Nonpermissive DP mismatch was associated with higher likelihood of acute GVHD (odds ratio, 16.50; 95% CI, 1.67-163.42; P = .0166) but not with the development of chronic GVHD. URD TCRαβ/CD19-depleted peripheral HSCT is a safe and effective approach to transplantation for children/YAs with leukemia. This trial was registered at www.clinicaltrials.gov as #NCT02323867.

DOI

10.1182/bloodadvances.2021005492

Alternate Title

Blood Adv

PMID

34872106

Title

Impact of high-risk cytogenetics on outcomes for children and young adults receiving CD19-directed CAR T-cell therapy.

Year of Publication

2022

Number of Pages

2173-2185

Date Published

2022 Apr 07

ISSN Number

1528-0020

Abstract

Chimeric antigen receptor (CAR) T-cell therapy can induce durable remissions of relapsed/refractory B-acute lymphoblastic leukemia (ALL). However, case reports suggested differential outcomes mediated by leukemia cytogenetics. We identified children and young adults with relapsed/refractory CD19+ ALL/lymphoblastic lymphoma treated on 5 CD19-directed CAR T-cell (CTL019 or humanized CART19) clinical trials or with commercial tisagenlecleucel from April 2012 to April 2019. Patients were hierarchically categorized according to leukemia cytogenetics: High-risk lesions were defined as KMT2A (MLL) rearrangements, Philadelphia chromosome (Ph+), Ph-like, hypodiploidy, or TCF3/HLF; favorable as hyperdiploidy or ETV6/RUNX1; and intermediate as iAMP21, IKZF1 deletion, or TCF3/PBX1. Of 231 patients aged 1 to 29, 74 (32%) were categorized as high risk, 28 (12%) as intermediate, 43 (19%) as favorable, and 86 (37%) as uninformative. Overall complete remission rate was 94%, with no difference between strata. There was no difference in relapse-free survival (RFS; P = .8112), with 2-year RFS for the high-risk group of 63% (95% confidence interval [CI], 52-77). There was similarly no difference seen in overall survival (OS) (P = .5488), with 2-year OS for the high-risk group of 70% (95% CI, 60-82). For patients with KMT2A-rearranged infant ALL (n = 13), 2-year RFS was 67% (95% CI, 45-99), and OS was 62% (95% CI, 40-95), with multivariable analysis demonstrating no increased risk of relapse (hazard ratio, 0.70; 95% CI, 0.21-2.90; P = .7040) but a higher proportion of relapses associated with myeloid lineage switch and a 3.6-fold increased risk of all-cause death (95% CI, 1.04-12.75; P = .0434). CTL019/huCART19/tisagenlecleucel are effective at achieving durable remissions across cytogenetic categories. Relapsed/refractory patients with high-risk cytogenetics, including KMT2A-rearranged infant ALL, demonstrated high RFS and OS probabilities at 2 years.

DOI

10.1182/blood.2021012727

Alternate Title

Blood

PMID

34871373

Title

CD19-targeted chimeric antigen receptor T-cell therapy for CNS relapsed or refractory acute lymphocytic leukaemia: a post-hoc analysis of pooled data from five clinical trials.

Year of Publication

2021

Number of Pages

e711-e722

Date Published

2021 Oct

ISSN Number

2352-3026

Abstract

<p><strong>BACKGROUND: </strong>CNS relapse of acute lymphocytic leukaemia is difficult to treat. Durable remissions of relapsed or refractory B-cell acute lymphocytic leukaemia have been observed following treatment with CD19-directed chimeric antigen receptor (CAR) T cells; however, most trials have excluded patients with active CNS disease. We aimed to assess the safety and activity of CAR T-cell therapy in patients with a history of CNS relapsed or refractory B-cell acute lymphocytic leukaemia.</p>

<p><strong>METHODS: </strong>In this post-hoc analysis, we included 195 patients (aged 1-29 years; 110 [56%] male and 85 [44%] female) with relapsed or refractory CD19-positive acute lymphocytic leukaemia or lymphocytic lymphoma from five clinical trials (Pedi CART19, 13BT022, ENSIGN, ELIANA, and 16CT022) done at the Children's Hospital of Philadelphia (Philadelphia, PA, USA), in which participants received CD19-directed CAR T-cell therapy between April 17, 2012, and April 16, 2019. The trials required control of CNS disease at enrolment and infusion and excluded treatment in the setting of acute neurological toxic effects (&gt;grade 1 in severity) or parenchymal lesions deemed to increase the risk of neurotoxicity. 154 patients from Pedi CART19, ELIANA, ENSIGN, and 16CT022 received tisagenlecleucel and 41 patients from the 13BT022 trial received the humanised CD19-directed CAR, huCART19. We categorised patients into two strata on the basis of CNS status at relapse or within the 12 months preceding CAR T-cell infusion-either CNS-positive or CNS-negative disease. Patients with CNS-positive disease were further divided on the basis of morphological bone marrow involvement-either combined bone marrow and CNS involvement, or isolated CNS involvement. Endpoints were the proportion of patients with complete response at 28 days after infusion, Kaplan-Meier analysis of relapse-free survival and overall survival, and the incidence of cytokine release syndrome and neurotoxicity.</p>

<p><strong>FINDINGS: </strong>Of all 195 patients, 66 (34%) were categorised as having CNS-positive disease and 129 (66%) as having CNS-negative disease, and 43 (22%) were categorised as having isolated CNS involvement. The median length of follow-up was 39 months (IQR 25-49) in the CNS-positive stratum and 36 months (18-49) in the CNS-negative stratum. The proportion of patients in the CNS-positive stratum with a complete response at 28 days after infusion was similar to that in the CNS-negative stratum (64 [97%] of 66 vs 121 [94%] of 129; p=0·74), with no significant difference in relapse-free survival (60% [95% CI 49-74] vs 60% [51-71]; p=0·50) or overall survival (83% [75-93] vs 71% [64-79]; p=0·39) at 2 years between the two groups. Overall survival at 2 years was significantly higher in patients with isolated CNS involvement compared with those with bone marrow involvement (91% [82-100] vs 71% [64-78]; p=0·046). The incidence and severity of neurotoxicity (any grade, 53 [41%] vs 38 [58%]; grade 1, 24 [19%] vs 20 [30%]; grade 2, 14 [11%] vs 10 [15%]; grade 3, 12 [9%] vs 6 [9%], and grade 4, 3 [2%] vs 2 [3%]; p=0·20) and cytokine release syndrome (any grade, 110 [85%] vs 53 [80%]; grade 1, 12 [9%] vs 2 [3%]; grade 2, 61 [47%] vs 38 [58%]; grade 3, 18 [14%] vs 7 [11%] and grade 4, 19 [15%] vs 6 [9%]; p=0·26) did not differ between the CNS-negative and the CNS-positive disease strata.</p>

<p><strong>INTERPRETATION: </strong>Tisagenlecleucel and huCART19 are active at clearing CNS disease and maintaining durable remissions in children and young adults with CNS relapsed or refractory B-cell acute lymphocytic leukaemia or lymphocytic lymphoma, without increasing the risk of severe neurotoxicity; although care should be taken in the timing of therapy and disease control to mitigate this risk. These preliminary findings support the use of these CAR T-cell therapies for patients with CNS relapsed or refractory B-cell acute lymphocytic leukaemia.</p>

<p><strong>FUNDING: </strong>Children's Hospital of Philadelphia Frontier Program.</p>

DOI

10.1016/S2352-3026(21)00238-6

Alternate Title

Lancet Haematol

PMID

34560014

Title

Humanized CD19-Targeted Chimeric Antigen Receptor (CAR) T Cells in CAR-Naive and CAR-Exposed Children and Young Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia.

Year of Publication

2021

Number of Pages

JCO2003458

Date Published

2021 Jun 22

ISSN Number

1527-7755

Abstract

<p><strong>PURPOSE: </strong>CD19-targeted chimeric antigen receptor (CAR)-modified T cells demonstrate unprecedented responses in B-cell acute lymphoblastic leukemia (B-ALL); however, relapse remains a substantial challenge. Short CAR T-cell persistence contributes to this risk; therefore, strategies to improve persistence are needed.</p>

<p><strong>METHODS: </strong>We conducted a pilot clinical trial of a humanized CD19 CAR T-cell product (huCART19) in children and young adults with relapsed or refractory B-ALL (n = 72) or B-lymphoblastic lymphoma (n = 2), treated in two cohorts: with (retreatment, n = 33) or without (CAR-naive, n = 41) prior CAR exposure. Patients were monitored for toxicity, response, and persistence of huCART19.</p>

<p><strong>RESULTS: </strong>Seventy-four patients 1-29 years of age received huCART19. Cytokine release syndrome developed in 62 (84%) patients and was grade 4 in five (6.8%). Neurologic toxicities were reported in 29 (39%), three (4%) grade 3 or 4, and fully resolved in all cases. The overall response rate at 1 month after infusion was 98% (100% in B-ALL) in the CAR-naive cohort and 64% in the retreatment cohort. At 6 months, the probability of losing huCART19 persistence was 27% (95% CI, 14 to 41) for CAR-naive and 48% (95% CI, 30 to 64) for retreatment patients, whereas the incidence of B-cell recovery was 15% (95% CI, 6 to 28) and 58% (95% CI, 33 to 77), respectively. Relapse-free survival at 12 and 24 months, respectively, was 84% (95% CI, 72 to 97) and 74% (95% CI, 60 to 90) in CAR-naive and 74% (95% CI, 56 to 97) and 58% (95% CI, 37 to 90) in retreatment cohorts.</p>

<p><strong>CONCLUSION: </strong>HuCART19 achieved durable remissions with long-term persistence in children and young adults with relapsed or refractory B-ALL, including after failure of prior CAR T-cell therapy.</p>

DOI

10.1200/JCO.20.03458

Alternate Title

J Clin Oncol

PMID

34156874

Title

Beyond the storm - subacute toxicities and late effects in children receiving CAR T cells.

Year of Publication

2021

Date Published

2021 Jan 25

ISSN Number

1759-4782

Abstract

<p>As clinical advances with chimeric antigen receptor (CAR) T cells are increasingly described and the potential for extending their therapeutic benefit grows, optimizing the implementation of this therapeutic modality is imperative. The recognition and management of cytokine release syndrome (CRS) marked a milestone in this field; however, beyond the understanding gained in treating CRS, a host of additional toxicities and/or potential late effects of CAR T cell therapy warrant further investigation. A multicentre initiative involving experts in paediatric cell therapy, supportive care and/or study of late effects from cancer and haematopoietic stem cell transplantation was convened to facilitate the comprehensive study of extended CAR&nbsp;T cell-mediated toxicities and establish a framework for new systematic investigations of CAR T cell-related adverse events. Together, this group identified six key focus areas: extended monitoring of neurotoxicity and neurocognitive function, psychosocial considerations, infection and immune reconstitution, other end organ toxicities, evaluation of subsequent neoplasms, and strategies to optimize remission durability. Herein, we present the current understanding, gaps in knowledge and future directions of research addressing these CAR T cell-related outcomes. This systematic framework to study extended toxicities and optimization strategies will facilitate the translation of acquired experience and knowledge for optimal application of CAR T cell therapies.</p>

DOI

10.1038/s41571-020-00456-y

Alternate Title

Nat Rev Clin Oncol

PMID

33495553

Title

Risk-Adapted Preemptive Tocilizumab to Prevent Severe Cytokine Release Syndrome After CTL019 for Pediatric B-Cell Acute Lymphoblastic Leukemia: A Prospective Clinical Trial.

Year of Publication

2021

Number of Pages

JCO2002477

Date Published

2021 Jan 08

ISSN Number

1527-7755

Abstract

<p><strong>PURPOSE: </strong>To prospectively evaluate the effectiveness of risk-adapted preemptive tocilizumab (PT) administration in preventing severe cytokine release syndrome (CRS) after CTL019, a CD19 chimeric antigen receptor T-cell therapy.</p>

<p><strong>METHODS: </strong>Children and young adults with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia were assigned to high- (≥ 40%) or low- (&lt; 40%) tumor burden cohorts (HTBC or LTBC) based on a bone marrow aspirate or biopsy before infusion. HTBC patients received a single dose of tocilizumab (8-12 mg/kg) after development of high, persistent fevers. LTBC patients received standard CRS management. The primary end point was the frequency of grade 4 CRS (Penn scale), with an observed rate of ≤ 5 of 15 patients in the HTBC pre-defined as clinically meaningful. In post hoc analyses, the HTBC was compared with a historical cohort of high-tumor burden patients from the initial phase I CTL019 trial.</p>

<p><strong>RESULTS: </strong>The primary end point was met. Seventy patients were infused with CTL019, 15 in the HTBC and 55 in the LTBC. All HTBC patients received the PT intervention. The incidence of grade 4 CRS was 27% (95% CI, 8 to 55) in the HTBC and 3.6% (95% CI, 0.4 to 13) in the LTBC. The best overall response rate was 87% in the HTBC and 100% in the LTBC. Initial CTL019 expansion was greater in the HTBC than the LTBC ( &lt; .001), but persistence was not different ( = .73). Event-free and overall survival were worse in the HTBC ( = .004, &lt; .001, respectively). In the post hoc analysis, grade 4 CRS was observed in 27% versus 50% of patients in the PT and prior phase I cohorts, respectively ( = .18).</p>

<p><strong>CONCLUSION: </strong>Risk-adapted PT administration resulted in a decrease in the expected incidence of grade 4 CRS, meeting the study end point, without adversely impacting the antitumor efficacy or safety of CTL019.</p>

DOI

10.1200/JCO.20.02477

Alternate Title

J Clin Oncol

PMID

33417474

Title

Diagnostic biomarkers to differentiate sepsis from cytokine release syndrome in critically ill children.

Year of Publication

2020

Number of Pages

5174-5183

Date Published

2020 Oct 27

ISSN Number

2473-9537

Abstract

<p>Chimeric antigen receptor (CAR) T-cells directed against CD19 have drastically altered outcomes for children with relapsed and refractory acute lymphoblastic leukemia (r/r ALL). Pediatric patients with r/r ALL treated with CAR-T are at increased risk of both cytokine release syndrome (CRS) and sepsis. We sought to investigate the biologic differences between CRS and sepsis and to develop predictive models which could accurately differentiate CRS from sepsis at the time of critical illness. We identified 23 different cytokines that were significantly different between patients with sepsis and CRS. Using elastic net prediction modeling and tree classification, we identified cytokines that were able to classify subjects as having CRS or sepsis accurately. A markedly elevated interferon γ (IFNγ) or a mildly elevated IFNγ in combination with a low IL1β were associated with CRS. A normal to mildly elevated IFNγ in combination with an elevated IL1β was associated with sepsis. This combination of IFNγ and IL1β was able to categorize subjects as having CRS or sepsis with 97% accuracy. As CAR-T therapies become more common, these data provide important novel information to better manage potential associated toxicities.</p>

DOI

10.1182/bloodadvances.2020002592

Alternate Title

Blood Adv

PMID

33095872

Title

Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2.

Year of Publication

2020

Date Published

2020 Jul 30

ISSN Number

1558-8238

Abstract

<p><strong>BACKGROUND: </strong>Initial reports from the Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to Coronavirus Disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed Multisystem Inflammatory Syndrome in Children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology.</p>

<p><strong>METHODS: </strong>We prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data. Twenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8 and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. Cts and burr cells on blood smears also differentiated between patients with severe COVID-19 and those with MIS-C.</p>

<p><strong>CONCLUSION: </strong>Pediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and severe COVID-19.</p>

DOI

10.1172/JCI140970

Alternate Title

J. Clin. Invest.

PMID

32730233

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