Umbilical Cord Blood Transplantation: Connecting Its Origin to Its Future

Transplantation of umbilical cord blood (UCB) is an attractive alternative source of hematopoietic stem cells (HSCs). The unique properties of cord blood and its distinct immune tolerance and engraftment kinetics compared to bone marrow (BM) and peripheral blood progenitor cells, permit a wider disparity in human leukocyte antigen levels between a cord blood donor and recipient after an unrelated umbilical cord blood transplant (UCBT). In addition, it is readily available and has a lowered risk of graft-versus-host disease (GvHD), with similar long-term clinical outcomes, compared to BM transplants. However, the relatively low number of cells administered by UCB units, as well as the associated delayed engraftment and immune reconstitution, pose limitations to the wide application of UCBT. Research into several aspects of UCBT has been evaluated, including the ex vivo expansion of cord blood HSCs and the process of fucosylation to enhance engraftment. Additionally, UCB has also been used in the treatment of several neurodegenerative and cardiovascular disorders with varying degrees of success. In this article, we will discuss the biology, clinical indications, and benefits of UCBT in pediatric and adult populations. We will also discuss future directions for the use of cord blood

Toward a Rapid Production of Multivirus-Specific T Cells Targeting BKV, Adenovirus, CMV, and EBV from Umbilical Cord Blood

Umbilical cord blood (CB) has emerged as an effective alternative donor source for hematopoietic stem cell transplantation. Despite this success, the prolonged duration of immune suppression following CB transplantation and the naiveté of CB T cells leave patients susceptible to viral infections. Adoptive transfer of ex vivo-expanded virus-specific T cells from CB is both feasible and safe. However, the manufacturing process of these cells is complicated, lengthy, and labor-intensive. We have now developed a simplified method to manufacture a single culture of polyclonal multivirus-specific cytotoxic T cells in less than 30 days. It eliminates the need for a live virus or transduction with a viral vector, thus making this approach widely available and GMP-applicable to target multiple viruses. The use of overlapping PepMixes as a source of antigen stimulation enable expansion of the repertoire of the T cell product to any virus of interest and make it available as a third party “off the shelf” treatment for viral infections following transplantation

Progress toward curing HIV infection with hematopoietic cell transplantation.

HIV-1 infection afflicts more than 35 million people worldwide, according to 2014 estimates from the World Health Organization. For those individuals who have access to antiretroviral therapy, these drugs can effectively suppress, but not cure, HIV-1 infection. Indeed, the only documented case for an HIV/AIDS cure was a patient with HIV-1 and acute myeloid leukemia who received allogeneic hematopoietic cell transplantation (HCT) from a graft that carried the HIV-resistant CCR5-∆32/∆32 mutation. Other attempts to establish a cure for HIV/AIDS using HCT in patients with HIV-1 and malignancy have yielded mixed results, as encouraging evidence for virus eradication in a few cases has been offset by poor clinical outcomes due to the underlying cancer or other complications. Such clinical strategies have relied on HIV-resistant hematopoietic stem and progenitor cells that harbor the natural CCR5-∆32/∆32 mutation or that have been genetically modified for HIV-resistance. Nevertheless, HCT with HIV-resistant cord blood remains a promising option, particularly with inventories of CCR5-∆32/∆32 units or with genetically modified, human leukocyte antigen-matched cord blood

Steroid-Refractory Acute GVHD: Predictors and Outcomes

Patients with steroid-resistant acute graft versus host disease (aGVHD) have a dismal prognosis, with mortality rates in excess of 90%. We sought to identify a subgroup of patients less likely to benefit from initial therapy with corticosteroids as well as the impact of response on day 14 on outcome. Retrospective evaluation was performed of patients with biopsy-proven aGVHD treated with corticosteroids after allogeneic HSCT at M.D. Anderson Cancer Center from 1998 through 2002 (N = 287). Overall response to first-line therapy on day 14 was 56%. Grade III-IV aGVHD and hyperacute GVHD were the most significant factors predicting failure. Patients who fail to respond to steroids by day 14 should be considered for clinical trials. Severity of aGVHD, hyperacute GVHD, and sex mismatch could be integrated into prognostic scoring systems which may allow for pretreatment identification of patients unlikely to benefit from standard therapy with corticosteroids

Impact of the timing of hepatitis B virus identification and antiâ hepatitis B virus therapy initiation on the risk of adverse liver outcomes for patients receiving cancer therapy

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138209/1/cncr30729_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138209/2/cncr30729.pd

Clofarabine ± Fludarabine with Once Daily i.v. Busulfan as Pretransplant Conditioning Therapy for Advanced Myeloid Leukemia and MDS

Although a combination of i.v. busulfan (Bu) and fludarabine (Flu) is a safe, reduced-toxicity conditioning program for acute myelogenous leukemia/myelodysplastic syndromes (AML/MDS), recurrent leukemia posttransplantation remains a problem. To enhance the conditioning regimen’s antileukemic effect, we decided to supplant Flu with clofarabine (Clo), and assayed the interactions of these nucleoside analogs alone and in combination with Bu in Bu-resistant human cell lines in vitro. We found pronounced synergy between each nucleoside and the alkylator but even more enhanced cytotoxic synergy when the nucleoside analogs were combined prior to exposing the cells to Bu. We then designed a 4-arm clinical trial in patients with myeloid leukemia undergoing allogeneic stem cell transplantation (allo-SCT). Patients were adaptively randomized as follows: Arm I–Clo:Flu 10:30 mg/m2, Arm II—20:20 mg/m2, Arm III—30:10 mg/m2, and Arm IV–single-agent Clo at 40 mg/m2. The nucleoside analog(s) were/was infused over 1 hour once daily for 4 days, followed on each day by Bu, infused over 3 hours to a pharmacokinetically targeted daily area under the curve (AUC) of 6000 μMol-min ± 10%. Fifty-one patients have been enrolled with a minimum follow-up exceeding 100 days. There were 32 males and 19 females, with a median age of 45 years (range: 6-59). Nine patients had chronic myeloid leukemia (CML) (BC: 2, second AP: 3, and tyrosine-kinase inhibitor refractory first chronic phase [CP]: 4). Forty-two patients had AML: 14 were induction failures, 8 in first chemotherapy-refractory relapse, 7 in untreated relapse, 3 in second or subsequent relapse, 4 were in second complete remission (CR), and 3 in second CR without platelet recovery (CRp), 2 were in high-risk CR1. Finally, 1 patient was in first CRp. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus and mini-methorexate (MTX), and those who had an unrelated or 1 antigen-mismatched donor received low-dose rabbit-ATG (Thymoglobulin™). All patients engrafted. Forty-one patients had active leukemia at the time of transplant, and 35 achieved CR (85%). Twenty of the 42 AML patients and 5 of 9 CML patients are alive with a projected median overall survival (OS) of 23 months. Marrow and blood (T cell) chimerism studies at day +100 revealed that both in the lower-dose Clo groups (groups 1+2) and the higher-dose Clo groups (groups 3+4), the patients had a median of 100% donor (T cell)-derived DNA. There has been no secondary graft failure. In the first 100 days, 1 patient died of pneumonia, and 1 of liver GVHD. We conclude that (1) Clo ± Flu with i.v. Bu as pretransplant conditioning is safe in high-risk myeloid leukemia patients; (2) clofarabine is sufficiently immunosuppressive to support allo-SCT in myeloid leukemia; and (3) the median OS of 23 months in this high-risk patient population is encouraging. Additional studies to evaluate the antileukemic efficacy of Clo ± Flu with i.v. Bu as pretransplant conditioning therapy are warranted

Impact of Type of Induction Therapy on Outcomes in Older Adults With AML After Allogeneic Stem Cell Transplantation

Although venetoclax-based lower-intensity regimens have greatly improved outcomes for older adults with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy, the optimal induction for older patients with newly diagnosed AML who are suitable candidates for hematopoietic stem cell transplant (HSCT) is controversial. We retrospectively analyzed the post HSCT outcomes of 127 patients ≥60 years of age who received induction therapy at our institution with intensive chemotherapy (IC; n = 44), lower-intensity therapy (LIT) without venetoclax (n = 29), or LIT with venetoclax (n = 54) and who underwent allogeneic HSCT in the first remission. The 2-year relapse-free survival (RFS) was 60% with LIT with venetoclax vs 54% with IC, and 41% with LIT without venetoclax; the 2-year overall survival (OS) was 72% LIT with venetoclax vs 58% with IC, and 41% with LIT without venetoclax. The benefit of LIT with venetoclax induction was greatest in patients with adverse-risk AML (2-year OS: 74%, 46%, and 29%, respectively). Induction with LIT, with or without venetoclax, was associated with the lowest rate of nonrelapse mortality (NRM) (2-year NRM: 17% vs 27% with IC; P = .04). Using multivariate analysis, the type of induction therapy did not significantly affect any of the post HSCT outcomes evaluated; hematopoietic cell transplantation-specific comorbidity index was the only factor that independently predicted RFS and OS. LIT plus venetoclax followed by HSCT is a feasible treatment strategy in older, fit, HSCT-eligible patients with newly diagnosed AML and may be particularly beneficial for those with adverse-risk disease

2: Donor-Recipient Host-Versus-Graft Human Leukocyte Antigen Mismatches and Outcome of Cord Blood Transplants

Digitalitzat per Artypla