One of the major limitations of unrelated umbilical cord blood transplantation (UCBT) is the lack of donor cells available for post-transplant donor leukocyte infusions (DLI) to boost immunity or induce GVL. Starting from ~5% fraction of a UCB graft we report the feasibility and biological characteristics of ex vivo expansion of frozen/thawed cord blood T cells by anti-CD3 and anti-CD28 antibody-coated Dynal beads in the presence of IL-2. We postulated that while undergoing expansion, CB T cells may mature towards a Th1/Tc1 phenotype and acquire the potential for cytotoxicity. While an almost 2 log expansion also led to the acquisition of IL-12Rα and increase in Th1 characteristics, post-expansion lymphocytes produced less IFNγ, TNFα, Granzyme B, stored almost no perforin, and lacked cytotoxicity against allogeneic targets. Collectively, these suggest relative safety from acute/hyperacute GVHD. CD8+ T cells expanded preferentially while a higher rate of apoptosis among CD4+ T cells promoted an inverted CD4/CD8 ratio. Most expanded T cells retained expression of CD27, CD28, L-selectin, however, the majority down regulated CCR-7. In sum, CB T cell proliferation sustained by CD3/CD28 costimulatory beads and IL-2 can lead to clinically relevant doses of DLI from a very small fraction of the UCB graft, although future strategies to reduce apoptosis may enhance their clinical potential.
The occurrence of primary extraosseous Ewing sarcoma (EES) of the central nervous system (CNS) has only rarely been reported in the literature. It is important to distinguish this entity from the more common central primitive neuroectodermal tumor (PNET) of brain, since the management of these tumors is different from that of EES. We present the clinical, radiologic, and pathologic features of two cases of EES occurring in the brain. The diagnosis was further confirmed by detection of a rearrangement of the FLI1 and/or EWS gene loci in tumors from both patients using fluorescent in situ hybridization (FISH). Although rare, the possibility of EES should be considered particularly when tumors that arise near the meningeal surface of the brain and have the pathologic appearance of a PNET. Demonstration of t(11;22)(q24;q12) by molecular analysis essentially confirms the diagnosis and enables the oncologist to choose appropriate therapy.
Sickle cell disease can be corrected by hematopoietic cell transplantation but success is limited by low availability of matched related/unrelated donors and comorbidities leading to the increased transplant-related morbidity/mortality. There is a need for expanded donor pools and reduced intensity regimens. We describe a case of a second unrelated cord blood transplant after a novel preparative regimen in a child with sickle cell disease related stroke and liver fibrosis. Hydroxyurea, rituximab, and alemtuzumab were followed by thiotepa and low dose total body irradiation before unrelated cord blood transplant. Rapid full donor chimerism and improved performance status was achieved and sustained over 2 years after transplant.
UCBT may be curative in patients (pts) with high-risk SCD. Unrelated cord blood units matched at >4/6 HLA are acceptable for UCBTs and available to most pts. We reviewed UCBTs in 7 children with SCD and cerebrovascular accidents performed in 4 centers (1998 to 2003): 4 pts were conditioned with conventional myeloablative regimens, and 3 pts with reduced-intensity regimens. The former received busulfan (BU), cyclophosphamide (CY) and anti-thymocyte globulin (ATG) (3 pts) or BU/CY/ATG plus fludarabine (FLU) (1 pt). Of 3 pts who received 4/6 HLA-matched UCBTs after BU/CY/ATG and GVHD prophylaxis with methylprednisone (MP) and cyclosporine (CSP) or tacrolimus (TAC), 2 have durable engraftment, 1 had autologous reconstitution (BMT2004; 34:405–11). A 5 yr old (yo) female with transfusion-induced alloimmunization received a 5/6 HLA-matched UCBT (6.2 X 10^7/kg nucleated [NC] cells) after BU/CY/ATG/FLU, followed by CSP and MP post-transplant. PMN engraftment and VNTR > 98% of donor origin were documented 24 and 37 days, respectively, after UCBT. Complications included elevated liver enzymes during conditioning, grade IV GVHD of skin, GI and liver, grade III mucositis, VOD, parainfluenza 3 infection, candidemia and adenovirus viremia. Pt died of severe acute GVHD and multi-organ failure 73 days after UCBT. Two different reduced-intensity regimens were used in the other 3 pts. An 8 yo male received a 4/6 HLA-matched UCBT (3.2 X 10^7/kg NC) after conditioning with alemtuzumab, rituximab, hydroxyurea, thiotepa and TBI (600cGy, with 300 cGy total dose to liver and kidneys) and received TAC and mycophenolate mofetil (MMF) post-transplant. This patient failed UCBT 8 months earlier (FLU/CY/ATG/TLI, 4/6 HLA). PMN engraftment and VNTR > 98% of donor origin was documented within 18 days after UCBT. Complications included grade I skin GVHD, grade 1 mucositis and parainfluenza 1 infection. This pt remains engrafted and fully active 1.6 ys after UCBT. A 4 yo female and a 16 yo male received 4/6 or 5/6 HLA-matched cord units, respectively, after BU or CY, ATG, FLU and total lymphoid irradiation (200 or 500 cGy) and received CSP and MMF post-transplant. Neither had evidence of donor engraftment, and autologous reconstitution was documented within 2 weeks after UCBT. Sustained donor engraftment occurred in 3/4 pts (75%) who underwent UCBT after myeloablative conditioning and 1/3 pts (33%) who underwent UCBT after reduced-intensity conditioning. Two of the 3 pts who engrafted after myeloablative preparative regimens developed acute grade III–IV GVHD, and 1 of these pts developed extensive chronic GVHD. The 1 pt who engrafted after a reduced-intensity preparative regimen developed grade I acute GVHD only. Significant viral infections (CMV 1 pt, adenovirus, parainfluenzavirus 2 pts each) occurred in 4 pts. In this limited experience, following various conditioning regimens, optimal GVHD and infection prevention remains a challenge. Both apparent lesser risk and documented durable engraftment may justify further development of non-myeloablative strategies for UCBT in children with high-risk SCD.
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