Pintip Chitphakdithai’s research while affiliated with National Marrow Donor Program and other places

The incidence and risk factors for severe adverse events (SAEs) in related donors (RD) of hematopoietic cell transplants is unknown. The Related Donor Safe (RDSafe) study is a prospective observational cohort of 1680 RDs, and represents an opportunity to examine characteristics of SAEs in RDs. In this cohort, we found that SAEs were reported in a total 12 (0.71%) RDs. Of these, five SAEs occurred in bone marrow donors (5/404, 1.24%), and seven (7/1276, 0.55%) were in donors of peripheral blood stem cells (PBSC). All of the SAEs were considered to be related (definite, probable, or possible) to the donation process. There were no donor fatalities. Of the 12 RDs who experienced an SAE, 10 were either overweight or obese. Five of the 12 RDs had pre-donation medical conditions that would have resulted in either possible or definite ineligibility for donation were they being assessed as unrelated donors. These SAE data will be useful in the counselling of prospective RDs prior to planned donation, and may be helpful in identifying donors who should be considered medically unsuitable for donation.

The National Marrow Donor Program (NMDP) operates the Be The Match Registry to serve patients who require an allogeneic hematopoietic cell transplant (alloHCT). The factors that result in progression of an active donor search (ie, request for tissue typing or stem cell donation) to alloHCT are poorly understood. Some factors, such as differences in access by ethnic group, are known; however, deeper understanding of other patient and search factors is needed. Our study sought to identify the likelihood of patient progression from initiation of an active search for an unrelated adult donor/umbilical cord blood to transplant and to evaluate factors associated with proceeding to transplantation within 6 months. A retrospective cohort of US donor searches (ie, transplant center's first request of donor/cord blood unit testing; N = 8816) of the Be The Match Registry from January to December 2016 was analyzed. An adult unrelated donor search prognosis score, which categorizes the prognosis of the donor search as good, fair, or poor based on the patient HLA type and race/ethnic group, was included. At 6 months, 3744 (42%) patients had received a transplant. White patients were more likely to receive a transplant (n = 2590 of 5687, 45%) compared to black/African American patients (n = 187 of 700, 27%; P < .001). In multivariate analysis, the adult unrelated donor search prognosis score was associated with proceeding to adult donor or cord blood transplant within 6 months across all patient populations. A poor search prognosis score had an odds ratio (OR) of 0.32 (95% confidence interval [CI], 0.26 to 0.39, P < .001), 0.22 (95% CI, 0.09 to 0.54, P = .001), 0.39 (95% CI, 0.23 to 0.65, P < .001), and 0.26 (95% CI, 0.14 to 0.45, P < .001) for adults with malignant disease, adults with nonmalignant disease, children with malignant disease, and children with nonmalignant disease, respectively. This study identified important factors in the likelihood of a patient proceeding to HCT and suggests areas for future intervention to reduce the barriers to transplant.

Allogeneic hematopoietic cell transplantation (alloHCT) is a highly specialized procedure. We surveyed adult transplant centers in the United States (US) and then used data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) (2008–2010) to evaluate associations of center volume, infrastructure, and care delivery models with survival post alloHCT. Based on their 2010 alloHCT volume, centers were categorized as low-volume (≤40 alloHCTs; N = 42 centers, 1900 recipients) or high-volume (>40 alloHCTs; N = 41 centers, 9637 recipients). 100-day survival was 86% (95% CI, 85–87%) in high-volume compared with 83% (95% CI, 81–85%) in low-volume centers (difference 3%; P < 0.001). One-year survival was 62% (95% CI, 61–63%) and 56% (95% CI, 54–58%), respectively (difference 6%; P < 0.001). Logistic regression analyses adjusted for patient and center characteristics; alloHCT at high-volume centers (odds ratio [OR] 1.32; P < 0.001) and presence of a survivorship program dedicated to HCT recipients (OR 1.23; P = 0.009) were associated with favorable 1-year survival compared to low-volume centers. Similar findings were observed in a CIBMTR validation cohort (2012–2014); high-volume centers had better 1-year survival (OR 1.24, P < 0.001). Among US adult transplant centers, alloHCT at high-volume centers and at centers with survivorship programs is associated with higher 1-year survival.

There are limited data on the effect of donor body mass index (BMI) on peripheral blood stem cell (PBSC) mobilization response to granulocyte colony-stimulating factor (G-CSF), especially in unrelated donors. Obesity has been associated with persistent leukocytosis, elevated circulating progenitor cells, and enhanced stem cell mobilization. Therefore, we hypothesized that adequate collection of CD34+ cells may be achieved with lower doses (per kilogram of body weight) of G-CSF in donors with higher BMI compared with donors with lower BMI. Using the Center for International Blood and Marrow Transplant Research database, we evaluated the impact of donor BMI on G-CSF–mobilized PBSC yield in healthy unrelated donors. We examined 20 884 PBSC donations collected at National Marrow Donor Program centers between 2006 and 2016. We found significantly higher collection yields in obese and severely obese donors compared with normal and overweight donors. An increase in average daily G-CSF dose was associated with an increase in stem cell yield in donors with normal or overweight BMI. In contrast, an increase in average daily G-CSF dose beyond 780 μg per day in obese and 900 μg per day in severely obese donors did not increase cell yield. Pain and toxicities were assessed at baseline, during G-CSF administration, and postcollection. Obesity was associated with higher levels of self-reported donation-related pain and toxicities in the pericollection and early postdonation recovery periods. This study suggests a maximum effective G-CSF dose for PBSC mobilization in obese and severely obese donors, beyond which higher doses of G-CSF add no increased yield.

Umbilical Cord Blood (UCB) transplant (UCBT) is a curative procedure for patients with hematologic malignancies and genetic disorders and expands access for non-Caucasian patients unable to find a fully matched unrelated donor. In 2011, the Food and Drug Administration (FDA) required that unrelated UCBT use either licensed UCB or unlicensed UCB via an Investigational New Drug (IND). The National Marrow Donor Program® (NMDP) manages an IND under which 2456 patients (1499 adults and 957 children (564 malignant disease and 393 non-malignant disease) received single or double UCBT between October 2011 and December, 2016. Median age was 31 years (<1 to 81); 50% of children and 36% of adults were non-Caucasian. Median days to neutrophil engraftment (absolute neutrophil count ≥ 500/mm3) were 22, 20 and 19 days and the incidence of engraftment at 42 days was 89%, 88%, and 90% for adult, pediatric malignant, and pediatric non-malignant, respectively. Acute GVHD Grades II-IV was 35%, 32%, and 24%, chronic GVHD was 24%, 26%, and 24% and one year overall survival (OS) was 57%, 71%, and 79% for adults, pediatric malignant, and pediatric non-malignant.. In multivariate analysis, younger age, lower HCT-CI, early stage chemotherapy sensitive disease, and higher performance score predicted improved OS for adults. In a subset analysis of children with malignancies receiving single UCBT, use of either licensed (n=48) or unlicensed UCB (n=382) was associated with similar engraftment and survival. Use of unlicensed UCB units is safe, effective and provides an important graft source for a diverse population.

Background Autologous (Auto) blood collection from healthy adult bone marrow (BM) donors is commonly performed before BM harvest to meet potential peri-operative transfusion needs and avoid necessity of allogeneic (Allo) blood exposure. Although Auto blood transfusion has been associated with advantages, it is not without risk. Bacterial contamination of blood product, misidentification of the blood unit and transfusion associated circulatory overload have been seen as commonly with Auto blood as with Allo blood transfusion. In addition, many collected units remain unused and discarded leading to wastage of resources. This study examines donor and collection variables associated with Auto blood transfusion with an aim to evaluate the impact of Auto blood transfusion on donor health after BM harvest. Method The primary outcome was incidence of highest toxicity level across selected body symptoms associated with BM harvest. The secondary outcomes were incidence of skeletal pain at 2 days, 1 and 6 months after harvest. The population studied was domestic unrelated BM donors reported to the NMDP/CIBMTR between 2006 and 2017. The NMDP donor form does not capture whether the donor had storage of Auto blood. It only asks whether the donor received blood transfusion. Thus, analysis was focused on whether the donor received Auto blood transfusion. Donors who received Allo blood were excluded (n=25). Logistic regression was used to compare pain and toxicities of those receiving and not receiving Auto units, after adjusting for donor characteristics. Stepwise variable selection with significance level of 0.01 was used. Results Examination of 7024 BM donors revealed 60% (n=4211) received at least 1 unit of Auto blood. The donors who had Auto blood tended to be male, younger, overweight, had lower hemoglobin pre-harvest, received longer duration of anesthesia and underwent higher volume BM harvest (Table 1). Before 2016, donor centers were advised by NMDP to collect 1 or more Auto blood units based on expected BM volume collection. In 2016 Auto blood collection was made discretionary as a center choice resulting in a significant decline in Auto blood transfusion in more recent years. Based on the multivariate analysis, there was no significant difference in grade 2 to 4 highest toxicity level 2 days after harvest between cohorts with or without Auto blood transfusion. Donors who received Auto blood were more likely to experience grade 2 to 4 skeletal pain 2 days post BM donation. However, grade 2 to 4 skeletal pain at 1 and 6 months after BM harvest were comparable between the two cohorts (Table 2). Time to recovery of symptoms was significantly longer in transfusion cohort (Figure 1). Conclusion Based on our data there is no evidence of clinical benefit in donors receiving Auto blood transfusion compared to those who do not. Thus, Auto blood transfusion may not be justified as a routine practice in healthy BM donors.

Peripheral blood stem cells (PBSC) have been increasingly used for allogeneic hematopoietic cell transplantation compared to bone marrow stem cells. Currently, the National Marrow Donor Program (NMDP) policy recommends 5 days of daily filgrastim followed by either 1 day of large volume apheresis or 2 days of smaller volume apheresis for unrelated donors, according to collection center choice. To date, there are no studies to compare the difference between one and two days of apheresis. We examined 22,348 adult unrelated donor collections in 184 centers from 2006-2016. 20,004 (89.5%) donors were collected in 1 day vs. 2,344 (9.5%) in 2 days. There were both patient and collection center differences between the two groups (Table 1). In general, patients who underwent apheresis over 2 days were more likely to be women, older and had a lower body-mass index (BMI)/ weight. Centers performing 2-day collections performed fewer annual collections on average (162 vs 265). Donors undergoing 2-day collections were more likely to experience citrate toxicity (52% vs 36%) and more likely to be hospitalized (6% vs 1%). Successful collection of the requested CD34 count was achieved on the first day in 82% of one day collection (vs 16% of 2-day collections). Despite not administering filgrastim the evening after the first day of collection, in patients who underwent 2 days of apheresis, the median concentration of CD34⁺cells/L in the product on the second day of apheresis was higher than the first day (23.8 × 10⁶ CD34⁺/L 1st day vs. 28.7 × 10⁶ CD34⁺/L 2nd day, p<0.001. Either procedure was generally well tolerated in both groups. Toxicity was defined as fever in the absence of signs of infection, fatigue, skin rash, local-site reaction, nausea, vomiting, anorexia, insomnia, dizziness, and syncope. The incidence and time course of toxicity experienced by donors between 1-day vs. 2-day collections at various times after collection is shown in Figure 1 and generally no substantial differences were noted. When considering factors identified by previous studies to be associated with toxicity, greater toxicity was noted in women, older donors, donors collected via central lines, and donors with greater BMI whereas less toxicity was noted in those with higher CD34 counts and more blood processed on the first day of collection. We conclude that there did not seem to be any advantage to two days of collection, and one day collections afford advantages of more donor convenience, lower cost, and more efficient use of apheresis facility capacity.

Background Umbilical Cord Blood (UCB) transplant (UCBT) is a curative procedure for patients with hematologic malignancies and genetic disorders, and expands transplant options for a racially/ethnically diverse population, who are often unable to find a fully matched unrelated donor. In 2011, the Food and Drug Administration (FDA) required that all unrelated UCBT use either licensed UCB or unlicensed UCB via an Investigational New Drug (IND). Methods To allow continued access to unlicensed UCB units, the National Marrow Donor Program® (NMDP) manages a prospective distribution protocol for unlicensed UCB units, under an IND, 10-Cord Blood Access. This is an interim report of outcomes of 2466 US patients receiving unlicensed UCB units from 2011-2016. Of note, only 6% of available UCB units were licensed by December 2016. Results 1509 adults and 957 children (564 malignant disease and 393 non-malignant disease) received single or double UCBT between October 2011 and December 2016. Median age was 31 years (<1 to 81); 50% of children (Figure 1) and 35% of adults (Figure 2) were non-Caucasian. Median days to neutrophil engraftment (absolute neutrophil count ≥ 500/mm3) were 22, 19 and 18 days and the incidence of neutrophil engraftment at 42 days was 89%, 88%, and 90% for adult, pediatric malignant and pediatric non-malignant cohorts respectively. The incidence of acute GVHD Grades II-IV was 27% (95% confidence interval [CI]: 25-29%), 26% (95% CI: 22-29%), and 16% (95% CI:12-19%) for adults, pediatric malignant and pediatric non-malignant cohorts, respectively. The incidence of chronic GVHD was 24% (95% CI: 22-27%), 27% (95% CI: 23-30%) and 25% (95% CI: 21-30%) for adult, pediatric malignant and pediatric non-malignant cohorts, respectively. One year overall survival (OS) was 57% (95% CI: 54-59%), 71% (95% CI: 67-75%), and 79% (95% CI: 75-83%) for adults, pediatric malignant and pediatric non-malignant cohorts, respectively (Figure 3). One year disease-free survival was 57% (95% CI: 54-59%) and 70% (95% CI: 66-74%) for adults and children with malignancy, respectively. OS was similar among different racial/ethnic groups. Conclusions Use of unlicensed UCB units is safe and effective, and provides an important graft source for a diverse population.

Bone marrow (BM) is an essential source of hematopoietic stem cell grafts for many allogeneic hematopoietic cell transplant (HCT) recipients, including adult patients (for specific diseases and transplantation strategies) and the majority of pediatric recipient. However, since the advent of granulocyte colony-stimulating factor-mobilized peripheral blood stem cell (PBSC) grafts, there has been a significant decrease in the use of BM in HCT, thought to be due mainly to the increased logistical challenges in harvesting BM compared with PBSCs, as well as generally no significant survival advantage of BM over PBSCs. The decreased frequency of collection has the potential to impact the quality of BM harvests. In this study, we examined >15,000 BM donations collected at National Marrow Donor Program centers between 1994 and 2016 and found a significant decline in the quality of BM products, as defined by the concentration of total nucleated cells (TNCs). The mean TNC concentration in BM donations dropped from 21.8 × 10 ⁶ cells/mL in the earliest era (1994 to 1996) to 18.7 × 10 ⁶ cells/mL in the most recent era (2012 to 2016) (means ratio,.83; P <.001). This decline in BM quality was seen despite the selection of more donors perceived to be optimal (eg, younger and male). Multivariate regression analysis showed that higher-volume centers (performing >30 collections per era) had better-quality harvests with higher concentrations of TNCs collected. In conclusion, we have identified a significant decrease in the quality of BM collections over time, and lower-volume collection centers had poorer-quality harvests. In this analysis, we could not elucidate the direct cause for this finding, suggesting the need for further studies to investigate the key factors responsible and to explore the impact on transplant recipients.