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Emapalumab, a fully human anti-IFNγ monoclonal antibody, has been approved in the US as second-line treatment of primary hemophagocytic lymphohistiocytosis (HLH) patients and has shown promise in patients with graft failure (GF) requiring a second allogeneic hematopoietic stem cell transplantation (HSCT). The blockade of IFNγ activity may increase the risk of severe infections, including fatal mycobacteriosis. We report a case of secondary HLH-related GF in the context of HLA-haploidentical HSCT successfully treated with emapalumab in the presence of concomitant life-threatening infections, including disseminated tuberculosis (TB). A 4 years old girl with Adenosine Deaminase-Severe Combined Immunodeficiency complicated by disseminated TB came to our attention for ex-vivo hematopoietic stem cell-gene therapy. After engraftment failure of gene corrected cells, she received two HLA-haploidentical T-cell depleted HSCT from the father, both failed due to GF related to concomitant multiple infections and secondary HLH. Emapalumab administration allowed to control HLH, as well as to prevent GF after a third haplo-HSCT from the mother. Remarkably, all infections improved with antimicrobial medications and disseminated TB did not show any reactivation. This seminal case supports emapalumab use for treatment of secondary HLH and prevention of GF in patients undergoing haplo-HSCT even in the presence of multiple infections, including TB.

Collection of an adequate amount of autologous haematopoietic stem progenitor cells (HSPC) is required for ex vivo manipulation and successful engraftment for certain inherited disorders. Fifty-seven paediatric patients (age 0.5–11.4 years) underwent a bone marrow harvest for the purpose of HSPC gene therapy (GT), including adenosine deaminase-severe combined immunodeficiency (ADA-SCID), Wiskott–Aldrich syndrome (WAS) and metachromatic leukodystrophy (MLD) patients. Total nucleated cells and the percentage and absolute counts of CD34+ cells were calculated at defined steps of the procedure (harvest, CD34+ cell purification, transduction with the gene transfer vector and infusion of the medicinal product). A minimum CD34+ cell dose for infusion was 2 × 106/kg, with an optimal target at 5–10 × 106/kg. Median volume of bone marrow harvested was 34.2 ml/kg (range 14.2–56.6). The number of CD34+ cells collected correlated inversely with weight and age in all patients and particularly in the MLD children group. All patients reached the minimum target dose for infusion: median dose of CD34+ cells/kg infused was 10.3 × 106/kg (3.7–25.9), with no difference among the three groups. Bone marrow harvest of volumes > 30 ml/kg in infants and children with ADA-SCID, WAS and MLD is well tolerated and allows obtaining an adequate dose of a medicinal product for HSPC-GT.

For decades, bone marrow (BM) has been the preferred source of hematopoietic stem and progenitor cells (HSPCs) for transplants following myeloablative conditioning. At present, mobilized peripheral blood stem cells are commonly used for transplantation, particularly in the autologous setting.[1][1

beta-Thalassemia is a severe inherited anemia caused by insufficient production of beta-globin chains. Allogeneic hematopoietic stem cell (HSC) transplantation is currently the only cure, and is limited by donor availability and regimen-related toxicity and mortality. Gene therapy is a promising therapeutic tool for all thalassemic patients lacking a compatible donor and potentially provides transfusion independence in the absence of transplant-related complications, such as graft rejection and graft-versus-host disease. The issue of HSC procurement is critical in this setting because of the specific features of thalassemic syndromes, which include bone marrow (BM) expansion, ineffective erythropoiesis, and splenomegaly. Little is known about the efficiency of CD34(+) cell yield from steady-state BM harvests from thalassemic patients. We have collected data on safety and cell yield from 20 pediatric patients with beta-thalassemia who underwent autologous BM harvest before allogeneic HSC transplantation, and from 49 age-matched sibling donors who also underwent BM harvest. The procedure was safe, as no significant adverse events occurred. In terms of cell yield, no difference was found between patients and normal donors in the number of CD34(+) cells and total nucleated cells harvested. Most importantly, no difference was found in the proportion of myeloid and erythroid progenitors, suggesting a similar repopulating capacity. On the basis of these results, we conclude that steady-state BM can be used as a safe and efficient source of HSC for gene therapy of b-thalassemia. "beta-Thalassemia is a severe inherited anemia caused by insufficient production of beta-globin chains. Allogeneic hematopoietic stem cell (HSC) transplantation is currently the only cure, and is limited by donor availability and regimen-related toxicity and mortality. Gene therapy is a promising therapeutic tool for all thalassemic patients lacking a compatible donor and potentially provides transfusion independence in the absence of transplant-related complications, such as graft rejection and graft-versus-host disease. The issue of HSC procurement is critical in this setting because of the specific features of thalassemic syndromes, which include bone marrow (BM) expansion, ineffective erythropoiesis, and splenomegaly. Little is known about the efficiency of CD34(+) cell yield from steady-state BM harvests from thalassemic patients. We have collected data on safety and cell yield from 20 pediatric patients with beta-thalassemia who underwent autologous BM harvest before allogeneic HSC transplantation, and from 49 age-matched sibling donors who also underwent BM harvest. The procedure was safe, as no significant adverse events occurred. In terms of cell yield, no difference was found between patients and normal donors in the number of CD34(+) cells and total nucleated cells harvested. Most importantly, no difference was found in the proportion of myeloid and erythroid progenitors, suggesting a similar repopulating capacity. On the basis of these results, we conclude that steady-state BM can be used as a safe and efficient source of HSC for gene therapy of b-thalassemia."

Abstract 4438 BACKGROUND: Graft Failure (GF) occurs in 5–27% of patients (pts) after allogeneic hamatopoietic stem cell transplant (HSCT) and is associated with high morbidity and mortality related to infections and hemorrhagic events. Graft function may be poor as result of graft rejection, primary disease relapse or Poor Graft Function (PGF). The incomplete recovery of blood counts is defined primary PGF and the decreasing blood counts after successful engraftment secondary PGF. Several factors may determine GF: disease risk and status, conditioning regimen, HSC source, HLA compatibility, T cell content, immunosuppression, GvHD, viral infections, drugs. GCSF and Rhu-EPO are readily available and effective in PGF but with no effects on platelets. Second transplantation from the same donor, with or without conditioning therapy, can boost the haematopoietic recovery in pts with GF. Unfortunately, both a second peripheral CD34+ mononuclear cells (MNC) mobilization and a marrow harvest in the operating room may be contraindicated early after the first donation as not safe for donors. Intrabone SCT can overcome the risk of graft failure even with a low number of CD34+ MNC, as it has been demonstrated in cord blood transplant. Here we investigate in three adult pts with GF a bone-to-bone boost (BBB) with a small marrow harvest from respective donors, unfit for a second conventional donation. AIM: to evaluate the feasibility of the BBB technique in 3 pts with graft failure. METHODS: pts were 2 males (57, 53 y) with PGF with a diagnosis of AML and CMML, respectively, and a female (44 y) with graft rejection and AML relapse. In the first two patients prolonged pancytopenia and hypoplastic marrow were documented, with diagnosis of primary PGF and secondary PGF, respectively, donor chimerism ranging from 80–100% (STR and HLA), without evidence of leukemia. In the third patient, after prolonged pancytopenia an AML relapse was documented with 89% blasts on bone marrow aspirate. In PGF patients no conditioning regimen was administered before the boost at day 30 and 72 after SCT, respectively. In the patient with AML relapse Melphalan 200 mg/mq was given 48 h before the infusion, at day 35 after SCT. The 3 donors were related, haploidentical. For the BBB procedure small quantities of bone marrow (< 200ml) were collected from the posterior iliac crest bilaterally of the donors, at the bedside, during deep sedation and analgesya. Shortly after the unmanipulated marrow harvested was infused in superior-posterior iliac crest mono- or bilaterally, depending on the volume, during deep sedation and analgesya. In pt 1 Mononucleated cell (MNC) dose was 0.9 × 10^8/Kg for a volume of 166 ml. In pt 2 MNC dose was 0.4 × 10^8/Kg for a volume of 88 ml. In pt 3 MNC dose was 0.3 × 10^8/Kg for a volume of 140 ml. RESULTS AND CONCLUSION: In this cases the BBB technique proved feasible and safe for both the donor and the patient. Patient 1 received a second PBSC boost, without conditioning, 3 months after the BBB, and he's now alive, in CR, 13 months after the first transplant. Patient 2 died 3 months after the first transplant for pneumonia and sepsis. Patient 3 is alive, in CR, 4 months after the first HSCT. This practice can give the chance of HSC boost to patients with GF without the need of a GCSF mobilization for donors, with a minimal invasive operation. This can give the option to overcome and resolve infectious and hemorrhagic complications, bridging patients to further therapies and procedures. The intra-bone SCT may be a facilitating tool for microenvironment reconstitution, seeding and subsequent differentiation and may as well have a tolerogenic effect, through the mesenchymal stromal cells infused with the harvest. Further studies are necessary to assess the efficacy of this procedure. Disclosures: No relevant conflicts of interest to declare.