Fanconi Anemia: Hematopoietic Stem Cell Transplant or Gene Therapy?

FA is a rare, multi-organ cancer-prone IBMFS associated with hematological malignancies and STs. The androgen therapy, hematopoietic growth factors, HSCT, and GT, still in the clinical trial, are various treatments for this disease. Here, we aimed to compare the advantages and disadvantages of HSCT and GT in FA cures. We perform an advanced electronic search of “FA” AND (genetics OR treatment OR HSCT OR GT OR Mosaicism), and “Allo-HSCT” AND (conditioning regimen OR complications OR GvHD OR infection OR cost) MeSH terms in non-citation and citation databases. Besides, the gray literature was searched too. This article will provide a summary of the advantages and disadvantages of HSCT and GT of FA disease. Our results show that GT has a good potential in FA treatments in the future. Furthermore, it has higher advantages and fewer disadvantages in comparison with HSCT. Systematic Review Registration: CRD42021247364 ID on PROSPERO database.

Case Report: Graft Versus Tumor Effect After Non-Myeloablative Allogeneic Stem-Cell Transplantation in a Patient With Brentuximab-Vedotin Refractory Sezary Syndrome

Sezary Syndrome (SS) is a rare leukemic variant of primary cutaneous T-cell lymphoma. Relapsed or refractory disease is generally considered incurable by conventional therapeutic approaches, although durable responses can be achieved with novel monoclonal antibodies. Allogeneic hematopoietic stem cell transplantation (alloHSCT) may have potential value by inducing graft vs-lymphoma (GvL) effects, but there is currently no consensus regarding the timing of alloHSCT or type of conditioning regimen. Here we present the case of a male patient who achieved a complete remission (CR) of primary refractory SS after non-myeloablative alloHSCT. Patient: Two years prior to HSCT, the patient had been refractory to CHOEP-based chemotherapy, interferon, extracorporeal photopheresis (ECP), and bexarotene. Directly prior to alloHSCT brentuximab-vedotin (BV) was applied resulting in a partial remission of the skin compartment and overall in a stable disease. Prior to HSCT, flow cytometry of the bone marrow and peripheral blood showed an infiltration with T-cells positive for CD5, CD4, low CD3, low CD2 and negative for CD7, CD38, HLA-DR and CD8. The trephine biopsy showed a 7% infiltration of SS cells. The CD4:CD8 ratio in peripheral blood (pb) was massively increased at 76.67, with 63.5% of white blood cells expressing a SS immune phenotype. The conditioning regimen included 30 mg/m2 fludarabine on days -5, -4 and -3 and total body irradiation with 2 Gy on day -1. Immunosuppression consisted of cyclosporine A from day-1 and mycophenolate mofetil from day 0. The patient received 6.55x106 CD34+ cells and 1.11x108 CD3+ cells/kg body weight. Bone marrow evaluation on day 28 still showed persistent SS cells by flow cytometry. After tapering immunosuppression until day 169, the CD4:CD8 ratio in pb normalized. CR was documented on day 169 after alloHSCT and is now ongoing for almost 3 years after alloHSCT. Conclusions: We confirm that an alloHSCT can be a curative option for refractory patients with SS. The achievement of a CR after tapering the immunosuppressive therapy indicates a significant role of the GvL effect. In present treatment algorithms for patients with SS, the timing of an alloHSCT and the intensity of conditioning should be further explored.

Fanconi Anemia: Hematopoietic Stem Cell Transplant or Gene Therapy?

FA is a rare, multi-organ cancer-prone IBMFS associated with hematological malignancies and STs. The androgen therapy, hematopoietic growth factors, HSCT, and GT, still in the clinical trial, are various treatments for this disease. Here, we aimed to compare the advantages and disadvantages of HSCT and GT in FA cures. We perform an advanced electronic search of “FA” AND (genetics OR treatment OR HSCT OR GT OR Mosaicism), and “Allo-HSCT” AND (conditioning regimen OR complications OR GvHD OR infection OR cost) MeSH terms in non-citation and citation databases. Besides, the gray literature was searched too. This article will provide a summary of the advantages and disadvantages of HSCT and GT of FA disease. Our results show that GT has a good potential in FA treatments in the future. Furthermore, it has higher advantages and fewer disadvantages in comparison with HSCT. Systematic Review Registration: CRD42021247364 ID on PROSPERO database.

Glucagon-Like Peptide-1 Is Associated With Systemic Inflammation in Pediatric Patients Treated With Hematopoietic Stem Cell Transplantation

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are challenged with severe side effects, which are propagated by mucosal barrier disruption, and the related microbial translocation and systemic inflammation. Glucagon-like peptide-1 (GLP-1), a well-known incretin hormone, possesses anti-inflammatory properties and promotes regeneration of damaged intestinal epithelium in animal studies. We hypothesized that the immense inter-individual variation in the degree of mucosal damage and systemic inflammation, seen after HSCT is influenced by endogenous GLP-1 and could be related to acute post-transplant complications. In this prospective study we measured serial weekly fasting plasma GLP-1, along with C-reactive protein (CRP), and citrulline in 82 pediatric patients during allogeneic HSCT together with a fasting plasma GLP-1 in sex- and age-matched healthy controls. Overall, GLP-1 levels were increased in the patients during the course of HSCT compared with the controls, but tended to decrease post-transplant, most pronounced in patients receiving high-intensity conditioning regimen. The increase in CRP seen in the early post-transplant phase was significantly lower from day +8 to +13 in patients with GLP-1 above the upper quartile (>10 pmol/L) at day 0 (all P ≤ 0.03). Similar findings were seen for peak CRP levels after adjusting for type of conditioning (-47.0%; 95% CI, -8.1 – -69.4%, P = 0.02). Citrulline declined significantly following the transplantation illustrating a decrease in viable enterocytes, most evident in patients receiving high-intensity conditioning regimen. GLP-1 levels at day 0 associated with the recovery rate of citrulline from day 0 to +21 (34 percentage points (pp)/GLP-1 doubling; 95% CI, 10 – 58pp; P = 0. 008) and day 0 to day +90 (48 pp/GLP-1 doubling; 95% CI, 17 – 79pp; P = 0. 004), also after adjustment for type of conditioning. This translated into a reduced risk of acute graft-versus-host disease (aGvHD) in patients with highest day 0 GLP-1 levels (>10 pmol/L) (cause-specific HR: 0.3; 95% CI, 0.2 – 0.9, P = 0.02). In conclusion, this study strongly suggests that GLP-1 influences regeneration of injured epithelial barriers and ameliorates inflammatory responses in the early post-transplant phase.

Total Body Irradiation in Haematopoietic Stem Cell Transplantation for Paediatric Acute Lymphoblastic Leukaemia: Review of the Literature and Future Directions

Total body irradiation (TBI) has been a pivotal component of the conditioning regimen for allogeneic myeloablative haematopoietic stem cell transplantation (HSCT) in very-high-risk acute lymphoblastic leukaemia (ALL) for decades, especially in children and young adults. The myeloablative conditioning regimen has two aims: (1) to eradicate leukaemic cells, and (2) to prevent rejection of the graft through suppression of the recipient's immune system. Radiotherapy has the advantage of achieving an adequate dose effect in sanctuary sites and in areas with poor blood supply. However, radiotherapy is subject to radiobiological trade-offs between ALL cell destruction, immune and haematopoietic stem cell survival, and various adverse effects in normal tissue. To diminish toxicity, a shift from single-fraction to fractionated TBI has taken place. However, HSCT and TBI are still associated with multiple late sequelae, leaving room for improvement. This review discusses the past developments of TBI and considerations for dose, fractionation and dose-rate, as well as issues regarding TBI setup performance, limitations and possibilities for improvement. TBI is typically delivered using conventional irradiation techniques and centres have locally developed heterogeneous treatment methods and ways to achieve reduced doses in several organs. There are, however, limitations in options to shield organs at risk without compromising the anti-leukaemic and immunosuppressive effects of conventional TBI. Technological improvements in radiotherapy planning and delivery with highly conformal TBI or total marrow irradiation (TMI), and total marrow and lymphoid irradiation (TMLI) have opened the way to investigate the potential reduction of radiotherapy-related toxicities without jeopardising efficacy. The demonstration of the superiority of TBI compared with chemotherapy-only conditioning regimens for event-free and overall survival in the randomised For Omitting Radiation Under Majority age (FORUM) trial in children with high-risk ALL makes exploration of the optimal use of TBI delivery mandatory. Standardisation and comprehensive reporting of conventional TBI techniques as well as cooperation between radiotherapy centres may help to increase the ratio between treatment outcomes and toxicity, and future studies must determine potential added benefit of innovative conformal techniques to ultimately improve quality of life for paediatric ALL patients receiving TBI-conditioned HSCT.

Steroid-resistant intestinal aGVHD and refractory CMV and EBV infections complicated by haplo-HSCT were successfully rescued by FMT and CTL infusion

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) produces similar survival outcomes as HLA-matched sibling donor allogeneic HCST in younger patients with acquired severe aplastic anemia (SAA). This study reported a 29-years-old man with SAA and intracranial hemorrhage who underwent haplo-HSCT with a modified BU/CY + ATG conditioning regimen. Neutrophil and platelet engraftment were both achieved on day 14 after HSCT. The patient developed grade IV acute graft-versus-host disease (aGVHD) on day 20 and acquired cytomegalovirus (CMV) and Epstein–Barr virus (EBV) infections on day 47. After the failure of methylprednisolone, basiliximab, ruxolitinib, and antiviral treatment, the patient was diagnosed with steroid-resistant grade IV aGVHD and refractory CMV and EBV infections. We performed fecal microbiota transplantation and infused CMV- and EBV-specific cytotoxic T lymphocytes. After that the stool volume and frequency gradually decreased, and viral DNA was undetectable on day 80. This report provides helpful clinical experience for treating steroid-resistant aGVHD and refractory viral infections.

CONDITIONING REGIMEN FOR LANGERHANS HISTIOCYTOSIS

Langerhans cell histiocytosis (LCH) is a rare disease, with an estimated incidence of 0.5 per 100,000 children in the United States of America1. HCL occurs due to differentiation of myeloid precursors into CD1a+ / CD207+ cells and is characterized by constitutional activation of the MAPK2 signaling pathway, leading to a spectrum of organ involvement and dysfunction. Treatment of HCL is risk-adjusted: single lesions may respond to local treatment whereas multisystem disease requires systemic therapy. Although survival for patients without organ dysfunction is excellent3, mortality in those with compromised organs at risk (hematopoietic system, liver, and/or spleen) reaches 20%2,4. Despite the progress made in the treatment of HCL, disease reactivation rates remain above 30% and the best second-line treatment has not yet been established. Treatment failure is associated with increased morbidity and mortality, including an association with neurodegeneration2. As it is a rare disease and generally has a good prognosis, few scientific studies are evaluating the role of allogeneic hematopoietic stem cell transplantation (HSCT) in the treatment of this disease. In 2015 Veys et al5 published retrospective results of 87 high-risk patients transplanted between 1990 and 2013. Myeloablative conditioning regimens (MAC) based on total body irradiation or busulfan6 were the most used until the 2000s, and reduced-intensity conditioning regimens (RIC) – predominantly a combination of Melphalan and Fludarabine – were most used between 2000 and 2013. Transplant-associated mortality rates in 3 years were similar between RIC and MAC conditioning regimens (21% versus 15%, respectively). Recurrence was higher in the RIC group compared to the MAC group (28% versus 8%, respectively), however, the 3-year overall survival (OS) was similar (77% versus 71%, respectively), since the patients who relapsed after RIC transplantation could be rescued with chemotherapy. More recently, Kudo et al7 published a retrospective study with 30 patients with refractory LCH who underwent HSCT between 1996 and 2014. Eleven patients received myeloablative conditioning regimen based on total body radiotherapy (RCT) with a dose equal to or greater than 8 Gy or busulfan, and 19 of reduced intensity based on Fludarabine and Melphalan, associated or not with low dose of RCT. There was no significant difference between the conditioning regimen modalities, with OS of 56.8% for the RIC group and 63.6% for the MAC group. Disease status was the main prognostic factor, with a 5-year OS of 100% for patients who arrived at HSCT with disease in remission or with partial remission, versus 54.5% for those who had active disease at the time of the procedure. Regarding the type of donor used and the source of stem cells, there is great variation, with greater frequency for unrelated and extensive use of bone marrow and umbilical cord, and apparently, there is no impact on survival rates.5, 6 There are few case reports and extremely restricted performance of autologous HSCT in HCL.