First name
Nancy
Middle name
J
Last name
Bunin

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

Partially CD3-depleted unrelated and haploidentical donor PSCT has favorable GVHD and survival rates in pediatric hematologic malignancy.

Year of Publication

2019

Date Published

2019 Nov 22

ISSN Number

1523-6536

Abstract

<p>Most children who may benefit from stem cell transplantation lack matched related donors. Alternative donor transplantations with unrelated (URD) or partially matched related donors (PMRD) carry increased risks of graft-versus-host-disease (GVHD) and mortality compared to matched related donor transplants. We hypothesized a strategy of partial CD3/CD19-depletion for URD or PMRD peripheral stem cell transplantation (PSCT) would attenuate risks of GVHD and mortality. We enrolled 84 pediatric patients with hematologic malignancies at the Children's Hospital of Philadelphia and the Children's Hospital of Wisconsin between April 2005 and February 2015 (NCT00579124: https://clinicaltrials.gov/ct2/show/NCT00579124; NCT01071226: https://clinicaltrials.gov/ct2/show/NCT01071226). Two (2.4%) experienced primary graft failure. Relapse occurred in 23 patients (27.4%; cumulative incidence 26.3%), and 17 patients (20.2%) experienced non-relapse mortality (NRM). Grade III-IV acute GVHD was observed in 18 patients (21.4%), and chronic GVHD was observed and graded as limited in 24 (35.3%) and extensive in 8 (11.7%). Three-year OS was 61.8% (95% CI 50.2 -71.4%) and EFS 52.0% (95% CI 40.3 - 62.4%). Age ≥15 years was associated with decreased OS (p=0.05) and EFS (p=0.05). Relapse was more common in children in second complete remission (p=0.03). Partially CD3-depleted alternative donor PSCT NRM, OS, and EFS compare favorably with previously published studies of T cell-replete PSCT. Historically, T cell-replete PSCTs have had a high ratio of extensive compared to limited chronic GVHD, which may explain the comparatively low relapse and NRM rates in our study despite similar overall rates of chronic GVHD. Partial T cell-depletion may expand donor options for children with malignant transplant indications lacking matched related donors by mitigating but not eliminating chronic GVHD.</p>

DOI

10.1016/j.bbmt.2019.11.022

Alternate Title

Biol. Blood Marrow Transplant.

PMID

31765697

Title

Chimeric antigen receptor T cells for sustained remissions in leukemia.

Year of Publication

2014

Number of Pages

1507-17

Date Published

2014 Oct 16

ISSN Number

1533-4406

Abstract

<p><strong>BACKGROUND: </strong>Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease.</p>

<p><strong>METHODS: </strong>We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76×10(6) to 20.6×10(6) CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells.</p>

<p><strong>RESULTS: </strong>A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab.</p>

<p><strong>CONCLUSIONS: </strong>Chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 ClinicalTrials.gov numbers, NCT01626495 and NCT01029366.).</p>

DOI

10.1056/NEJMoa1407222

Alternate Title

N. Engl. J. Med.

PMID

25317870

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