Hurdles to the Adoption of Gene Therapy as a Curative Option for Transfusion-Dependent Thalassemia
Isabelle Thuret, et al
Stem Cells Transl Med. 2022 Apr; doi: 10.1093/stcltm/szac007
Stem cell transplantation (SCT) for transfusion dependent thalassemia (TDT) clearly demonstrated its efficacy and safety as a curative option for one of the most common monogenic disorders worldwide. The major indicator – in fact – for both most prevalent hemoglobinopathies, including sickle cell disease, is age at time of transplant. With this denominator in mind the currently achieved overall survival at least in matched sibling donor transplantation is nearing 100%. You might ask, what is now the benefit of a gene therapy medicinal product (GTMP) that is for sure innovative, but potentially insecure and clearly very expensive but scientifically attractive treatment option? What is its role in industrialized countries? Is it superior to a matched donor SCT? What about the majority of patients residing in low- and middle-income countries, who most probably will not find an unrelated matched donor?
Thuret et al nicely summarized the pros’ and con’s of available curative options and discuss concisely the different genomic manipulation based treatment options including the vector based gene addition strategy and the CRISPR-Cas9 (and its alike) based genomic modification strategies. They correctly state that ‘The results described (…) represent a remarkable achievement, and potentially offer new hope to patients affected with TDT as heralded by the conditional approval of the first-in-class GTMP.’ Whereas in the ‘old days’ nothing or little could be done the financial burden of what can be done is increasingly the major denominator. In that regard numerous health authorities recommend using cost-utility analyses for the economic evaluation of new treatments based on not just the quantity but also the QOL gained from healthcare interventions.
In conclusion, while gene therapies appear to represent a major therapeutic advancement in the treatment of thalassemia, they raise the critical issues of long-term efficacy and safety, accessibility, and affordability.
Mother Donors Improve Outcomes after HLA Haploidentical Transplantation: A Study by the Cellular Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation
Loredana Ruggeri, et al
Transplant Cell Ther. 2022 Apr; doi: 10.1016/j.jtct.2022.01.001
There were times where the donor selection consisted of an HLA match, CMV status and age. Any further sophistication would have left most of us without a suitable donor. ‘Luxury’ discussions on more detailed selection criteria such as donor specific antibodies (DSA), parental choices and blood group were redundant due to the absence of several alternative donors. But DSA are clearly associated with a high of rate graft rejection and Guru Subramian Guru Murthy et al demonstrated that the pre-transplant ABO status is an independent predictor of survival and other post-transplant outcome parameters in leukemia (ASH, #907, session 721).
With the emergence of in-vitro T cell depleted haploidentical SCT, developed and promoted by pediatric transplant physicians eventually allowed sophisticated discussion on transplacental trafficking of maternal and fetal cells during pregnancy establishing long-term reciprocal microchimerism in both mother and child. It has been hypothesized that mother's "exposure" to paternal HLA haplotype antigens during pregnancy may affect the outcome of hematopoietic stem cell transplantation (HSCT) when sensitized to paternal histocompatibility antigens. Consequently, it was demonstrated that in T cell-depleted HLA haploidentical HSCT, maternal donors have been associated with improved transplantation outcomes.
The retrospective multicenter study, conducted on behalf of the Cellular Therapy and Immunobiology Working Party of the European Society of Blood and Marrow Transplantation, involved 409 patients with acute leukemia who underwent HLA-haploidentical HSCT to evaluate the role of maternal donors in a large cohort of haploidentical transplantation recipients. In this analysis transplantation from maternal donors was associated with a lower relapse incidence in T cell-depleted HSCTs along with better graft-versus-host disease/relapse-free survival (GRFS) in T cell-depleted HSCT.
In conclusion, the availability of several potential donors and effective preventive measures for viral infections will change our donor selection process towards a stronger consideration of parameters that were inevitably ignored in the past. The exact hierarchy regarding the respective relevance is to be defined.
Hematopoietic stem cell transplantation for Wiskott-Aldrich syndrome: an EBMT Inborn Errors Working Party analysis
Michael H Albert, et al
Blood. 2022 Mar 31; doi: 10.1182/blood.2021014687
Wiskott-Aldrich syndrome is an X-linked disorder caused by mutations in the gene that encodes the Wiskott-Aldrich syndrome protein (WASP). The hallmark features of WAS include susceptibility to infections (associated with adaptive and innate immunodeficiency), microthrombocytopenia, and eczema. However, disease severity due to WAS gene mutations ranges from the classic severe form to milder forms.
The Inborn Errors Working Party (IEWP) analyzed 197 patients undergoing transplant at EBMT centers between 2006 and 2017. The recommendation of the WP is to use a myeloablative regimen consisting of either busulfan (n = 103) or treosulfan (n = 94) combined with fludarabine ± thiotepa. The median follow-up post-HSCT of this cohort was 44.9 months. The outcome was remarkable with a 3-year overall survival of 88.7% and chronic graft-versus-host disease (GVHD)-free survival of 81.7%. Neither alkylator choice nor donor type or period of HSCT (2006-2013 vs 2014-2017) had a significant impact. As expected, age <5 yrs was a major predictor of a better overall survival.
As pointed out by Susanne Prockop the IEWP demonstrated that in rare populations, even in the absence of prospective trials, a uniform adoption of a limited number of regimens combined with the use of novel composite end points allows a meaningful analysis that establishes a standard of care (Prockop SE. Towards a standard of care in transplant for WAS. Blood. 2022 Mar 31;139(13):1935-1936. doi: 10.1182/blood.2022015612. PMID: 35357483.).
Defibrotide-treated patients with anicteric or icteric veno-occlusive disease/sinusoidal obstruction syndrome after hematopoietic cell transplantation: an EBMT study.
Mohty M, et al
Bone Marrow Transplant. 2022 Apr; doi: 10.1038/s41409-022-01588-8
Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after hematopoietic cell transplantation remains one of the major post-transplant complications with a persistently high morbidity and mortality if not treated adequately and timely. The only licensed drug for the treatment of severe VOD/SOS is defibrotide. Several criteria for the diagnosis of VOD/SOS have been published over the last decades. Most of these criteria lack the sensitivity that is necessary to trigger early intervention. Obligatory hyperbilirubinemia is one of the major pitfalls since it was clearly shown that incidence of MOD/MOF and lower survival rates have been observed in patients with versus without hyperbilirubinemia at diagnosis. Several pediatric trials starting almost a decade ago defined the incidence of anicteric VOD/SOS in children at 30% which was confirmed in a large post-hoc analysis most recently. This analysis also identified a 15% incidence of anicteric VOD/SOS in adults.
The prospective post-authorization safety study (PASS) collected real-world data on defibrotide use in EBMT-member centers. This post hoc analysis of data from EBMT PASS examined the incidence of VOD/SOS without hyperbilirubinemia and assessed
post-HCT outcomes in defibrotide-treated patients by bilirubin levels at diagnosis.
Overall, 30/104 (29%) patients with VOD/SOS post-HCT had bilirubin ≤2 mg/dL at diagnosis. VOD/SOS resolution rates by day 100 post-HCT and Kaplan–Meier–estimated day 100 post-HCT survival rates were both lower in patients with bilirubin >2 mg/dL in severe but also on non-severe VOD/SOS. The authors summarize that these data corroborate the presence of anicteric VOD/SOS also in adults.
In conclusion, it might be time for a general adjustment of the current diagnostic criteria in adults.