Haploidentical stem cell transplantation for children with high‐risk leukemia

Palma, Julia; Salas, Lucia; Carrión, Flavio; Sotomayor, Cristián; Catalán, Paula; Paris, Claudia; Turner, Victoria; Jorquera, Hugo; Handgretinger, Rupert; Rivera, Gaston K.

doi:10.1002/pbc.24022

Cited by 29 publications

(23 citation statements)

References 41 publications

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“…1,2 Because the donor graft for such haploidentical transplants (haplo-HSCT) has a high frequency of alloreactive T cells, recognizing the non-shared HLA haplotype, extensive T-cell depletion (usually by positive selection of HSCs), remains a fundamental prerequisite if the graft is not to cause fatal acute graft-versushost-disease (GvHD). Although extensive T-cell removal of the graft effectively prevents GvHD, the process also causes prolonged and profound posttransplant immunodeficiency for a year or more, 3,4 with compromised antiviral immunity. [5][6][7] As a consequence, infectious morbidity and mortality remain high and are a frequent cause of treatment failure.…”

Section: Introductionmentioning

confidence: 99%

Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene

Zhou

Stasi

Tey

et al. 2014

Blood

153

133

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Section: Introductionmentioning

confidence: 99%

Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene

Zhou

Stasi

Tey

et al. 2014

Blood

153

133

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“…[1][2][3] Removal of all T cells increases the risk of graft rejection, relapse, and viral and other opportunistic infections. [4][5][6] Consequently, efforts have been made to retain the desired T-cell subsets while selectively depleting alloreactive T cells [7][8][9] or enriching for the cells that are directed to pathogens or malignancies, or that are enriched for GVHD-suppressive regulatory T cells.…”

Section: Introductionmentioning

confidence: 99%

Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation

Zhou

Dotti

Krance

et al. 2015

Blood

183

172

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• Alloreplete iC9-T cells can promote immune recovery posttransplant and protect patients against viral infections.• iC9-T cells can be eliminated from both peripheral blood and CNS by administration of AP1903 leading to a rapid resolution of GVHD.To test the feasibility of a single T-cell manipulation to eliminate alloreactivity while sparing antiviral and antitumor T cells, we infused 12 haploidentical hematopoietic stem cell transplant patients with increasing numbers of alloreplete haploidentical T cells expressing the inducible caspase 9 suicide gene (iC9-T cells). We determined whether the iC9-T cells produced immune reconstitution and if any resultant graft-versus-host disease (GVHD) could be controlled by administration of a chemical inducer of dimerization (CID; AP1903/ Rimiducid). All patients receiving >10 4 alloreplete iC9-T lymphocytes per kilogram achieved rapid reconstitution of immune responses toward 5 major pathogenic viruses and concomitant control of active infections. Four patients received a single AP1903 dose. CID infusion eliminated 85% to 95% of circulating CD3 1 CD19 1 T cells within 30 minutes, with no recurrence of GVHD within 90 days. In one patient, symptoms and signs of GVHDassociated cytokine release syndrome (CRS-hyperpyrexia, high levels of proinflammatory cytokines, and rash) resolved within 2 hours of AP1903 infusion. One patient with varicella zoster virus meningitis and acute GVHD had iC9-T cells present in the cerebrospinal fluid, which were reduced by >90% after CID. Notably, virus-specific T cells recovered even after AP1903 administration and continued to protect against infection. Hence, alloreplete iC9-T cells can reconstitute immunity posttransplant and administration of CID can eliminate them from both peripheral blood and the central nervous system (CNS), leading to rapid resolution of GVHD and CRS. The approach may therefore be useful for the rapid and effective treatment of toxicities associated with infusion of engineered T lymphocytes. This trial was registered at www.clinicaltrials.gov as #NCT01494103. (Blood. 2015;125(26):4103-4113)

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“…[10][11][12][13][14] Although all of our patients received GVHD prophylaxis with calcineurin inhibitors and mycophenolate mofetil, the incidences of severe acute and chronic GVHD were acceptable for our partial depletion of T cells.…”

Section: Discussionmentioning

confidence: 99%

“…There have been several reports on HHCT using CD3-depleted grafts in pediatric patients. 2,[10][11][12][13][14] The Tübingen group reported their experience with CD3/19-depleted HHCT using reduced-intensity conditioning in 38 pediatric patients. 2 The authors reported a primary engraftment rate of 83%, with GR occurring in 17% of patients.…”

Section: Discussionmentioning

confidence: 99%

Refinement of treatment strategies in ex vivo T-cell-depleted haploidentical SCT for pediatric patients

Koh

et al. 2014

Bone Marrow Transplant

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We evaluated the feasibility of T-cell-depleted haploidentical hematopoietic SCT (HHCT) in pediatric patients. Between July 2008 and January 2013, 28 patients underwent ex vivo T-cell-depleted HHCT; 9 had hematologic malignancy, 18 had nonmalignant hematologic disease, and 1 had refractory neuroblastoma. Twenty-six patients achieved neutrophil engraftment at a median of 11 days (range, 9-15 days). Two patients failed to achieve primary engraftment and five experienced graft rejection after primary engraftment. These seven patients achieved stable engraftment after a second HHCT. The cumulative incidences (CIs) of ⩾ grade II and ⩾ grade III acute GVHD were 33.3% and 14.3%, respectively, and the 1-year CI of extensive chronic GVHD was 11.1%. Four patients died of non-relapse-related causes (two of CMV disease, one of encephalopathy and one of autoimmune hemolytic anemia) and one of leukemia relapse. Non-relapse mortality at 100 days, 1 year and 2 years was 0.0%, 10.7% and 14.3%, respectively. At a median follow-up of 32.8 months (range, 17.0-72.5 months), the 2-year OS was 82.1%. OSs for nonmalignant diseases and malignant diseases were 94.4% and 60.0%, respectively (P = 0.019). Thus, HHCT is a realistic alternative for patients with malignant or nonmalignant diseases who lack a suitable donor.Bone Marrow Transplantation (2015) 50, 225-231; doi:10.1038/bmt.2014.232; published online 13 October 2014 INTRODUCTION Recent advances in haploidentical hematopoietic SCT (HHCT) have improved outcomes and enabled the use of haploidentical relatives as donors for children and adults with diseases that are curable with hematopoietic cell transplantation (HCT).A recently developed transplant strategy using a CD3/CD19-depleted graft instead of CD34 + cell selection has shown improved results. [1][2][3] Depleting CD3 + cells is superior to selecting CD34 + cells in terms of rapid engraftment and immune reconstitution. 2,3 Depletion of CD3 + T cells also has the advantage of increasing the number of natural killer cells, monocytes and other immunomodulating cells. 4 We recently completed our prospective study of in vitro CD3-depleted HHCT for pediatric patients lacking suitable related or unrelated donors. We reported our experience with CD3-depleted HHCT for patients with acquired SAA and patients with graft failure (GF) after allogeneic HCT. 5,6 These patients constitute part of the current patient cohort: of 28 patients in the present cohort, 17 were included in the previous two reports. The purpose of the present study was to assess the efficacy and feasibility of CD3-depleted HHCT in the children and adolescents of our cohort with an additional 11 patients and with an extended follow-up of previously reported cases.

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Haploidentical stem cell transplantation for children with high‐risk leukemia

Cited by 29 publications

References 41 publications

Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene

Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene

Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation

Refinement of treatment strategies in ex vivo T-cell-depleted haploidentical SCT for pediatric patients

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