Robert Chow

Effect of HLA-Matching Recipients to Donor Noninherited Maternal Antigens on Outcomes after Mismatched Umbilical Cord Blood Transplantation for Hematologic Malignancy

Transplantation-related mortality (TRM) is high after HLA-mismatched umbilical cord blood (UCB) transplantation (UCBT). In utero, exposure to noninherited maternal antigen (NIMA) is recognized by the fetus, which induces T regulator cells to that haplotype. It is plausible that UCBTs in which recipients are matched to donor NIMAs may alleviate some of the excess mortality associated with this treatment. To explore this concept, we used marginal matched-pair Cox regression analysis to compare outcomes in 48 NIMA-matched UCBTs (ie, the NIMA of the donor UCB unit matched to the patient) and in 116 non-NIMA-matched UCBTs. All patients had a hematologic malignancy and received a single UCB unit. Cases and controls were matched on age, disease, disease status, transplantation-conditioning regimen, HLA match, and infused cell dose. TRM was lower after NIMA-matched UCBTs compared with NIMA-mismatched UCBTs (relative risk, 0.48; P = .05; 18% versus 32% at 5 years posttransplantation). Consequently, overall survival was higher after NIMA-matched UCBT. The 5-year probability of overall survival was 55% after NIMA-matched UCBTs versus 38% after NIMA-mismatched UCBTs (P = .04). When faced with the choice of multiple HLA-mismatched UCB units containing adequate cell doses, selecting an NIMA-matched UCB unit may improve survival after mismatched UCBT.

Selection of unrelated cord blood grafts

To the editor: We are concerned about statements in the article by Barker et al,[1][1] who describe a factor of 0.75 × TNC (total nucleated cell) to “correct” the TNC content of RBC-replete cord blood units. No data are provided to justify such an opinion, and the authors cite only “personal

Guidelines for the development and validation of new potency assays for the evaluation of umbilical cord blood.

The following commentary was developed by the National Marrow Donor Program Cord Blood Advisory Group and is intended to provide an overview of umbilical cord blood (UCB) processing, summarize the current state of potency assays used to characterize UCB, and define limitations of the assays and future needs of the cord blood banking and transplant community. The UCB banking industry is eager to participate in the development of standardized assays to uniformly characterize cellular therapy products that are manufactured in a variety of ways. This paper describes the desired qualities of these assays and how the industry proposes to co-operate with developers to bring relevant assays to market. To that end, the National Marrow Donor Program (NMDP) Cord Blood Bank Network is available to serve as a resource for UCB testing material, research and development consulting, and product/assay testing in an accredited UCB manufacturing environment.

Late Effects in Hematopoietic Cell Transplant Recipients with Acquired Severe Aplastic Anemia: A Report from the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research

With improvements in hematopoietic cell transplant (HCT) outcomes for severe aplastic anemia (SAA), there is a growing population of SAA survivors after HCT. However, there is a paucity of information regarding late effects that occur after HCT in SAA survivors. This study describes the malignant and nonmalignant late effects in survivors with SAA after HCT. A descriptive analysis was conducted of 1718 patients post-HCT for acquired SAA between 1995 and 2006 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). The prevalence and cumulative incidence estimates of late effects are reported for 1-year HCT survivors with SAA. Of the HCT recipients, 1176 (68.5%) and 542 (31.5%) patients underwent a matched sibling donor (MSD) or unrelated donor (URD) HCT, respectively. The median age at the time of HCT was 20 years. The median interval from diagnosis to transplantation was 3 months for MSD HCT and 14 months for URD HCT. The median follow-up was 70 months and 67 months for MSD and URD HCT survivors, respectively. Overall survival at 1 year, 2 years, and 5 years for the entire cohort was 76% (95% confidence interval [CI]: 74-78), 73% (95% CI: 71-75), and 70% (95% CI: 68-72). Among 1-year survivors of MSD HCT, 6% had 1 late effect and 1% had multiple late effects. For 1-year survivors of URD HCT, 13% had 1 late effect and 2% had multiple late effects. Among survivors of MSD HCT, the cumulative incidence estimates of developing late effects were all <3% and did not increase over time. In contrast, for recipients of URD HCT, the cumulative incidence of developing several late effects exceeded 3% by 5 years: gonadal dysfunction 10.5% (95% CI: 7.3-14.3), growth disturbance 7.2% (95% CI: 4.4-10.7), avascular necrosis 6.3% (95% CI: 3.6-9.7), hypothyroidism 5.5% (95% CI: 2.8-9.0), and cataracts 5.1% (95% CI: 2.9-8.0). Our results indicated that all patients undergoing HCT for SAA remain at risk for late effects, must be counseled about, and should be monitored for late effects for the remainder of their lives.

Cell recovery comparison between plasma depletion/reduction- and red cell reduction-processing of umbilical cord blood

BACKGROUND AIMS Limited cell dose has hampered the use of cord blood transplantation (CBT) in adults. One method of minimizing nucleated cell loss in cord blood (CB) processing is to deplete or reduce plasma but not red blood cells - plasma depletion/reduction (PDR). METHODS The nucleated cell loss of PDR was studied, and determined to be less than 0.1% in the discarded supernatant plasma fraction in validation experiments. After testing and archival sampling, the median nucleated cell recovery for PDR processing was 90%, and median CD34(+) cell recovery 88%. In a CB bank inventory of 12 339 products with both pre- and post-processing total nucleated cells (TNC), PDR processing resulted in median post-processing TNC recoveries of 90.0% after testing and archival samples removal. Using the same 10 CB units divided into two halves, we compared directly the recovery of PDR against hydroxyethyl starch red cell reduction (RCR) for TNC, CD34(+) cells and colony-forming units (CFU-GM, CFU-E, CFU-GEMM and total CFU) after parallel processing. We also compared the loss of very small embryonic-like stem cells (VSEL). RESULTS We demonstrated significantly higher recoveries using PDR for TNC (124%), CD34(+) cells (121%), CFU-GM (225%), CFU-GEMM (201%), total CFU (186%) and VSEL (187%). The proportion of high TNC products was compared between 10 912 PDR and 38 819 RCR CB products and found to be 200% higher for products that had TNC ≥150 × 10(7) (P = 0.0001) for the PDR inventory. CONCLUSIONS Our data indicate that PDR processing of CB provides a significantly more efficient usage of this valuable and scarce resource.

Analysis of 120 pediatric patients with nonmalignant disorders transplanted using unrelated plasma-depleted or -reduced cord blood.

BACKGROUND: Unrelated cord blood (CB) is an important stem cell source for unrelated hematopoietic cell transplantation (HCT) of patients with nonmalignant disorders. Processing methods to prepare red blood cell–reduced CB units incur significant nucleated cell loss. In contrast, plasma depletion or reduction (PDR) processing of CB units entails the removal of only a portion of the plasma with minimal nucleated cell loss. However, there are relatively limited data regarding outcomes of CB transplants using units processed by PDR.

Cord Blood Stem Cell Processing, Banking and Thawing

Unrelated donor cord blood (CB) is one of the three sources of hematopoietic stem cell transplantation (HSCT) that are capable of curing ~80–160 standard hematologic and certain non-hematologic indications. Despite its many advantages, the principal drawback for CB in HSCT is its limited cell dose. Our group has focused on developing minimally manipulated technologies and strategies to maximize stem, progenitor, and nucleated cell doses to overcome this limitation. The term “MaxCell” is used in this chapter to denote two proprietary CB volume reduction processing technologies that yield virtually 100% recovery of all cell lineages in the manufactured CB products, including what the authors designate as “second generation” (2nd Gen) or plasma depletion/reduction (PDR) and “third generation” (3rd Gen) MaxCB or MaxCord CB processing technologies. In our proposed nomenclature system, the traditional red cell reduction (RCR) processing techniques are designated as “first generation” methods. The properties of various popular 1st Gen techniques are compared to the MaxCell CB processing technologies. Parallel processing with the traditional hetastarch (HES) RCR technique and the patented MaxCell CB processing technology were used to compare recovery of the various stem, progenitor, nucleated, and red cell lineages. MaxCell processing technology achieved virtually 100% recovery of all stem, progenitor, and nucleated cells tested after processing, with high cell viability upon thawing. The higher cell recovery produced MaxCell inventory with higher average stem, progenitor and nucleated cell doses, allowing patients to receive CB products with higher cell doses. Clinical outcome of HSCT using MaxCell CB products was compared to the outcome of HSCT with RCR CB products published in the literature from transplant data registries or CB banks. To allow for more rigorous comparisons, two matched-pair analysis (MP) were performed using a logistic regression model to find pairs of pediatric patients with hematologic malignancies and thalassemia transplanted with RCR CB or

Optimization of Unrelated Donor Cord Blood Transplantation for Thalassemia: Implications for Other Non‐Malignant Indications such as HIV Infection or Autoimmune Diseases

Since the first cord blood transplantation (CBT), many indications have been proven for this stem cell therapy. Besides the standard hematological indications, such as leukemia, lymphomas, and aplastic anemia, CBT has also been a proven curative therapy for nonhematological indications such as Krabbe’s disease, and osteopetrosis. As transplantrelated mortality (TRM), overall survival (OS) and disease-free survival (DFS) for CBT continue to improve with larger inventories, double CBT, higher cell dose CB products, optimal conditioning, GvHD, HLA matching, and infection prophylaxis and treatment, the utility of this stem cell source will expand to certain indications which in the past, rarely used CBT. For patients and physicians to accept CBT for indications such as thalassemia, autoimmune diseases or HIV, the benefit-risk ratio has to be significantly improved so that patients will take a chance on a risky procedure in order to improve their lifespan or quality of life. We review here some of the efforts to improve clinical outcome of CBT for thalassemia through increasing cell dosage using a combination strategy – (1) Chow’s MaxCell second and third generation technologies that maximize CB cell dosage, (2) double CBT, (3) no-wash thaw direct infusion advocated by Chow et al., and (4) optimal product selection.

Cord Blood: A Massive Waste of a Life-Saving Resource, a Perspective on Its Current and Potential Uses

Although allogeneic stem cell transplantation can cure patients with hematologic malignancies and nonmalignant disorders, limiting factors such as lack of suitable donors and graft-versus-host disease (GVHD) toxicity have led to the exploration of umbilical cord blood (UCB) as an alternative source of hematopoietic stem cells. The unique immunologic properties of UCB likely contribute to a decreased risk of GVHD. Thus, UCB represents a highly convenient hematopoietic stem cell (HSC) source that may significantly expand the HSC donor pool. Cord blood stem cells appear to confer significant advantages over adult stem cells, including ease of procurement, less of a requirement for human leukocyte antigen (HLA) matching, and fever side effects after use in transplant. Because of these characteristics, UCB is now the fastest growing source of stem cells for hematopoietic cell transplantation.