Successful mismatched hematopoietic stem cell transplantation for pediatric hemoglobinopathy by using ATG and post-transplant cyclophosphamide

Oostenbrink, Lisa V. E.; Pool, Emma S.; Zijde, Cornelia M. Jol–van der; Jansen-Hoogendijk, Anja M.; Vervat, Carly; Halteren, Astrid G. S. van; Bredius, Robbert G. M.; Smiers, Frans J.; Tol, Maarten J.D. van; Schilham, Marco W.; Lankester, Arjan C.; Mohseny, Alexander B.

doi:10.1038/s41409-021-01302-0

Cited by 19 publications

(11 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Engraftment was robust in our trial with the median time to myeloid and platelet engraftment of 9 and 19 days, respectively. In contrast, protocols using PTCy reported slower engraftment with a median time to neutrophil engraftment of 26 (range 21-31) days (47). Additionally, de la Fuente et al reported that the median time to neutrophil and platelet engraftment was 22 days and 28 days, respectively in SCD patients following haplo-BMT with post-transplantation cyclophosphamide and thiotepa treatment, which is significantly delayed compared to our approach (37).…”

Section: Discussionmentioning

confidence: 63%

“…The recovery of CD19 cells in our trial was quicker compared to CD3/CD19 depletion 86 days vs 60 days (28), and similar to abT/CD19 depleted grafts (46 days). Oostenbrink reported on 14 patients who received a mismatched MUD or haploidentical transplant for hemoglobinopathies (47). NK-cell recovery and Bcell recovery in the mismatched PTCy group was significantly slower compared to our approach (47).…”

Section: Discussionmentioning

confidence: 63%

See 1 more Smart Citation

Donor chimerism and immune reconstitution following haploidentical transplantation in sickle cell disease

et al. 2022

View full text Add to dashboard Cite

IntroductionWe previously reported the initial results of a phase II multicenter transplant trial using haploidentical parental donors for children and aolescents with high-risk sickle cell disease achieving excellent survival with exceptionally low rates of graft-versus-host disease and resolution of sickle cell disease symptoms. To investigate human leukocyte antigen (HLA) sensitization, graft characteristics, donor chimerism, and immune reconstitution in these recipients.MethodsCD34 cells were enriched using the CliniMACS® system with a target dose of 10 x 106 CD34+ cells/kg with a peripheral blood mononuclear cell (PBMNC) addback dose of 2x105 CD3/kg in the final product. Pre-transplant HLA antibodies were characterized. Donor chimerism was monitored 1-24 months post-transplant. Comprehensive assessment of immune reconstitution included lymphocyte subsets, plasma cytokines, complement levels, anti-viral T-cell responses, activation markers, and cytokine production. Infections were monitored.ResultsHLA antibodies were detected in 7 of 11 (64%) evaluable patients but rarely were against donor antigens. Myeloid engraftment was rapid (100%) at a median of 9 days. At 30 days, donor chimerism was 93-99% and natural killer cell levels were restored. By 60 days, CD19 B cells were normal. CD8 and CD4 T-cells levels were normal by 279 and 365 days, respectively. Activated CD4 and CD8 T-cells were elevated at 100-365 days post-transplant while naïve cells remained below baseline. Tregs were elevated at 100-270 days post-transplant, returning to baseline levels at one year. At one year, C3 and C4 levels were above baseline and CH50 levels were near baseline. At one year, cytokine levels were not significantly different from baseline.DiscussionThese results suggest that haploidentical transplantation with CD34-enriched cells and peripheral blood mononuclear cell addback results in rapid engraftment, sustained donor chimerism and broad-based immune reconstitution.

show abstract

Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 63%

Donor chimerism and immune reconstitution following haploidentical transplantation in sickle cell disease

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Haplo‐identical HSCT is an almost universally available alternative donor source with increasing acceptance for malignant and non‐malignant diseases, with a variety of techniques for T‐cell depletion and tolerance induction. Graft manipulation with combined negative selection of αβ + T cells and CD19 + lymphocytes was designed to achieve an ideal graft composition in vitro , 28–31 whilst post‐transplant cyclophosphamide (PTCy) is used for in vivo lympho‐depletion, optionally in combination with serotherapy and T‐cell add‐back procedures 32–34 …”

Section: Mechanistic Aspectsmentioning

confidence: 99%

“…Graft manipulation with combined negative selection of αβ + T cells and CD19 + lymphocytes was designed to achieve an ideal graft composition in vitro, [28][29][30][31] whilst post-transplant cyclophosphamide (PTCy) is used for in vivo lympho-depletion, optionally in combination with serotherapy and T-cell add-back procedures. [32][33][34]…”

Section: Ech a N Istic Aspec Tsmentioning

confidence: 99%

Haematopoietic stem cell transplantation for severe autoimmune diseases in children: A review of current literature, registry activity and future directions on behalf of the autoimmune diseases and paediatric diseases working parties of the European Society for Blood and Marrow Transplantation

et al. 2022

View full text Add to dashboard Cite

Although modern clinical management strategies have improved the outcome of paediatric patients with severe autoimmune and inflammatory diseases over recent decades, a proportion will experience ongoing or recurrent/relapsing disease activity despite multiple therapies often leading to irreversible organ damage, and compromised quality of life, growth/development and long-term survival. Autologous and allogeneic haematopoietic stem cell transplantation (HSCT) have been used successfully to induce disease control and often apparent cure of severe treatment-refractory autoimmune diseases (ADs) in children. However, transplant-related outcomes are disease-dependent and long-term outcome data are limited in respect to efficacy and safety. Moreover, balancing risks of HSCT against AD prognosis with continually evolving non-transplant options is challenging. This review appraises published literature on HSCT strategies and outcomes in individual paediatric ADs. We also provide a summary of the European Society for Blood and Marrow Transplantation (EBMT) Registry, where 343 HSCT procedures (176 autologous and 167 allogeneic) have been reported in 326 children (<18 years) for a range of AD indications. HSCT is a promising treatment modality, with potential long-term disease control or cure, but therapy-related morbidity and mortality need to be reduced. Further research is warranted to establish the position of HSCT in paediatric ADs via registries and prospective clinical studies to support evidence-based interspeciality guidelines and recommendations. K E Y W O R D S autoimmune diseases, haematopoietic stem cell transplantation, paediatric Selim Corbacioglu and Raffaella Greco contributed equally.

show abstract

“…Clinical trials are ongoing to determine the best approaches to optimize efficacy and minimize toxicity, especially using alternative donor strategies, which are necessary to expand transplant availability. Pre-transplant immunosuppression has been employed to suppress endogenous hematopoiesis, overcome the engraftment barrier, and improve graft failure rates in the haploidentical setting [43,93]. Strategies include pentostatin and cyclophosphamide (NCT# 03077542), dexamethasone and fludarabine [43], and hydroxyurea and azathioprine [94].…”

Section: Toward the Futurementioning

confidence: 99%

Across the Myeloablative Spectrum: Hematopoietic Cell Transplant Conditioning Regimens for Pediatric Patients with Sickle Cell Disease

Limerick

Abraham

2022

JCM

View full text Add to dashboard Cite

One out of every five hundred African American children in the United States has sickle cell disease (SCD). While multiple disease-modifying therapies are available, hematopoietic cell transplantation (HCT) remains the only curative option for children with SCD. HLA-matched sibling HCT has demonstrated excellent efficacy, but its availability remains limited; alternative donor strategies are increasingly explored. While Busulfan-Cyclophosphamide has become the most widespread conditioning regimen employed in HCT for pediatric SCD, many other regimens have been examined. This review explores different conditioning regimens across the intensity spectrum: from myeloablative to non-myeloablative. We describe survival and organ function outcomes in pediatric SCD patients who have received HCT and discuss the strengths and weaknesses of the various conditioning intensities. Finally, we posit novel directions in allogeneic HCT for SCD.

show abstract

Successful mismatched hematopoietic stem cell transplantation for pediatric hemoglobinopathy by using ATG and post-transplant cyclophosphamide

Cited by 19 publications

References 39 publications

Donor chimerism and immune reconstitution following haploidentical transplantation in sickle cell disease

Donor chimerism and immune reconstitution following haploidentical transplantation in sickle cell disease

Haematopoietic stem cell transplantation for severe autoimmune diseases in children: A review of current literature, registry activity and future directions on behalf of the autoimmune diseases and paediatric diseases working parties of the European Society for Blood and Marrow Transplantation

Across the Myeloablative Spectrum: Hematopoietic Cell Transplant Conditioning Regimens for Pediatric Patients with Sickle Cell Disease

Contact Info

Product

Resources

About