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Donor factors, in addition to HLA matching status, have been associated with recipient survival in unrelated donor (URD) hematopoietic cell transplantation (HCT); however, there is no hierarchical algorithm that weights the characteristics of individual donors against each other in a quantitative manner to facilitate donor selection. The goal of this study was to develop and validate a donor selection score that prioritizes donor characteristics associated with better survival in 8/8 HLA-matched URDs. Two separate patient/donor cohorts, the first receiving HCT between 1999 and 2011 (n = 5952, c1), and the second between 2012 and 2014 (n = 4510, c2) were included in the analysis. Both cohorts were randomly spilt, 2:1, into training and testing sets. Despite studying over 10,000 URD transplants, we were unable to validate a donor selection score. The only donor characteristic associated with better survival was younger age, with 2-year survival being 3% better when a donor 10 years younger is selected. These results support previous studies suggesting prioritization of a younger 8/8 HLA-matched donor. This large dataset also shows that none of the other donor clinical factors tested were reproducibly associated with survival, and hence flexibility in selecting URDs based on other characteristics is justified. These data support a simplified URD selection process and have significant implications for URD registries.

Background: The development of reduced intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RD) of PBSC. The effects of age on donation efficacy, toxicity, and long-term recovery in RD are poorly understood. Methods: We analyzed hematologic variables, pain, donation-related symptoms and recovery in 1211 related PBSC donors aged 18-79 enrolled in the Related Donor Safety Study (RDSafe). Results: RD >60 had a lower median CD34 level pre-apheresis compared to younger RD (age >60, 59x106/L; age 41-60, 81x106/L; age 18-40, 121x106/L; p 24L, p 60 with post-collection thrombocytopenia

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 ( Conclusions Use of unlicensed UCB units is safe and 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

Individualized treatment rules can improve health outcomes by recognizing that patients may respond differently to treatment and assigning therapy with the most desirable predicted outcome for each individual. Flexible and efficient prediction models are desired as a basis for such individualized treatment rules to handle potentially complex interactions between patient factors and treatment. Modern Bayesian semiparametric and nonparametric regression models provide an attractive avenue in this regard as these allow natural posterior uncertainty quantification of patient specific treatment decisions as well as the population wide value of the prediction-based individualized treatment rule. In addition, via the use of such models, inference is also available for the value of the optimal individualized treatment rules. We propose such an approach and implement it using Bayesian Additive Regression Trees as this model has been shown to perform well in fitting nonparametric regression functions to continuous and binary responses, even with many covariates. It is also computationally efficient for use in practice. With Bayesian Additive Regression Trees, we investigate a treatment strategy which utilizes individualized predictions of patient outcomes from Bayesian Additive Regression Trees models. Posterior distributions of patient outcomes under each treatment are used to assign the treatment that maximizes the expected posterior utility. We also describe how to approximate such a treatment policy with a clinically interpretable individualized treatment rule, and quantify its expected outcome. The proposed method performs very well in extensive simulation studies in comparison with several existing methods. We illustrate the usage of the proposed method to identify an individualized choice of conditioning regimen for patients undergoing hematopoietic cell transplantation and quantify the value of this method of choice in relation to the optimal individualized treatment rule as well as non-individualized treatment strategies.

Previous studies have shown that risks of collection-related pain and symptoms are associated with sex, body mass index, and age in unrelated donors undergoing collection at National Marrow Donor Program centers. We hypothesized that other important factors (race, socioeconomic status [SES], and number of procedures at the collection center) might affect symptoms in donors. We assessed outcomes in 2726 bone marrow (BM) and 6768 peripheral blood stem cell (PBSC) donors collected between 2004 and 2009. Pain/symptoms are reported as maximum levels over mobilization and collection (PBSC) or within 2 days of collection (BM) and at 1 week after collection. For PBSC donors, race and center volumes were not associated with differences in pain/symptoms at any time. PBSC donors with high SES levels reported higher maximum symptom levels 1 week after donation (P = .017). For BM donors, black males reported significantly higher levels of pain (OR, 1.90; CI, 1.14 to 3.19; P = .015). No differences were noted by SES group. BM donors from low-volume centers reported more toxicity (OR, 2.09; CI, 1.26 to 3.46; P = .006). In conclusion, race and SES have a minimal effect on donation-associated symptoms. However, donors from centers performing ≤ 1 BM collection every 2 months have more symptoms after BM donation. Approaches should be developed by registries and low-volume centers to address this issue.

Prospective validation of the hematopoietic cell transplantation–comorbidity index (HCT-CI) using contemporary patients treated with hematopoietic cell transplantation (HCT) across the Unites States is necessary to confirm its widespread applicability. We performed a prospective observational study including all patients (8115 recipients of allogeneic and 11,652 recipients of autologous HCT) who underwent a first HCT that was reported to the Center for International Blood and Marrow Transplant Research between 2007 and 2009. In proportional hazards models, increased HCT-CI scores were independently associated with increases in hazard ratios for nonrelapse mortality (NRM) (P < .0001) and overall mortality (P < .0001) among recipients of allogeneic HCT. HCT-CI scores of ≥3 were uniformly associated with higher risks for outcomes in both allogeneic and autologous HCT and in all subgroups, regardless of diagnoses, age, and conditioning intensity. Recipients of allogeneic HCT with scores of 1 and 2 who were ages < 18 years or were treated with lower intensity conditioning regimens had similar outcomes compared with those with a score of 0. Higher risks for overall mortality, but not for NRM, were observed among recipients of autologous HCT with scores of 1 and 2 versus 0. Our results confirm the validity the HCT-CI in both allogeneic and autologous HCT. The index should be used as a valid standard-of-care health measure in counseling patients for HCT, in clinical trial design, and in adjusting outcome analyses.

Hematopoietic cell transplantation (HCT) is a complex procedure that requires availability of adequate infrastructure, personnel, and resources at transplantation centers. We conducted a national survey of transplantation centers in the United States to obtain data on their personnel, infrastructure, and care delivery models. A 42-item web-based survey was administered to medical directors of transplantation centers in the United States that reported any allogeneic HCT to the Center for International Blood and Marrow Transplant Research in 2011. The response rate for the survey was 79% for adult programs (85 of 108 centers) and 82% for pediatric programs (54 of 66 centers). For describing results, we categorized centers into groups with similar volumes based on 2010 total HCT activity (adult centers, 9 categories; pediatric centers, 6 categories). We observed considerable variation in available resources, infrastructure, personnel, and care delivery models among adult and pediatric transplantation centers. Characteristics varied substantially among centers with comparable transplantation volumes. Transplantation centers may find these data helpful in assessing their present capacity and use them to evaluate potential resource needs for personnel, infrastructure, and care delivery and in planning for growth.

Variations in cord blood manufacturing and administration are common, and the optimal practice is not known. We compared processing and banking practices at 16 public cord blood banks (CBB) in the United States and assessed transplantation outcomes on 530 single umbilical cord blood (UCB) myeloablative transplantations for hematologic malignancies facilitated by these banks. UCB banking practices were separated into 3 mutually exclusive groups based on whether processing was automated or manual, units were plasma and red blood cell reduced, or buffy coat production method or plasma reduced. Compared with the automated processing system for units, the day 28 neutrophil recovery was significantly lower after transplantation of units that were manually processed and plasma reduced (red cell replete) (odds ratio, .19; P = .001) or plasma and red cell reduced (odds ratio, .54; P = .05). Day 100 survival did not differ by CBB. However, day 100 survival was better with units that were thawed with the dextran-albumin wash method compared with the "no wash" or "dilution only" techniques (odds ratio, 1.82; P = .04). In conclusion, CBB processing has no significant effect on early (day 100) survival despite differences in kinetics of neutrophil recovery.

Clinical outcomes after primary graft failure (PGF) remain poor. Here we present a large retrospective analysis (n=23,272) which investigates means to prevent PGF and early detection of patients at high risk. In patients with hematologic malignancies, who underwent their first myeloablative allogeneic hematopoietic cell transplantation, PGF was reported in 1278 (5.5%), and there was a marked difference in PGFs using peripheral blood stem cell compared with bone marrow grafts (2.5 vs 7.3%; P

Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic cell transplantation (alloHCT) remains a major therapeutic challenge. We studied outcomes of 1788 AML patients relapsing after alloHCT (1990 to 2010) during first or second complete remission (CR) to identify factors associated with longer postrelapse survival. Median time to post-HCT relapse was 7 months (range, 1 to 177). At relapse, 1231 patients (69%) received intensive therapy, including chemotherapy alone (n = 660), donor lymphocyte infusion (DLI) ± chemotherapy (n = 202), or second alloHCT ± chemotherapy ± DLI (n = 369), with subsequent CR rates of 29%. Median follow-up after relapse was 39 months (range, 40 years (relative risk, 1.42; 95% CI, 1.24 to 1.64; P < .0001), active graft-versus-host disease at relapse (relative risk, 1.25; 95% CI, 1.13 to 1.39; P < .0001), adverse cytogenetics (relative risk, 1.37; 95% CI, 1.09 to 1.71; P = .0062), mismatched unrelated donor (relative risk, 1.61; 95% CI, 1.22 to 2.13; P = .0008), and use of cord blood for first HCT (relative risk, 1.23; 95% CI, 1.06 to 1.42; P = .0078). AML relapse after alloHCT predicted poor survival; however, patients who relapsed ≥6 months after their initial alloHCT had better survival and may benefit from intensive therapy, such as second alloHCT ± DLI.

We sought to determine whether differences in chronic graft-versus-host disease (GVHD) rates would lead to survival differences by comparing 2463 peripheral blood (PB) and 1713 bone marrow (BM) hematopoietic cell transplant recipients. Patients had acute leukemia, chronic myeloid leukemia (CML), or myelodysplastic syndrome, and they received myeloablative conditioning regimens and calcineurin-inhibitor GVHD prophylaxis. There were no significant differences in long-term survival after transplantation of PB and BM, except for patients in first chronic phase CML. For these patients, the 5-year rate of survival was lower after transplantation of PB compared with transplantation of BM (35% versus 56%, P = .001). Although mortality risks were higher in patients with chronic GVHD after both PB (hazard ratio [HR], 1.58; P < .001) and BM (HR 1.73; P < .001) transplantations, its effect on mortality did not differ by graft type (P = .42). BM is the preferred graft for first chronic phase CML, whereas as either graft is suitable for other leukemias.

Little information exists on the effect of race and ethnicity on collection of peripheral blood stem cells (PBSC) for allogeneic transplantation. We studied 10,776 donors from the National Marrow Donor Program who underwent PBSC collection from 2006 to 2012. Self-reported donor race/ethnic information included Caucasian, Hispanic, Black/African American (AA), Asian/Pacific Islander (API), and Native American (NA). All donors were mobilized with subcutaneous filgrastim at an approximate dose of 10 μg/kg/day for 5 days. Overall, AA donors had the highest median yields of mononuclear cells per liter and CD34(+) cells per liter of blood processed (3.1 × 10(9) and 44 × 10(6), respectively), whereas Caucasians had the lowest median yields at 2.8 × 10(9) and 33.7 × 10(6), respectively. Multivariate analysis of CD34(+) per liter mobilization yields using Caucasians as the comparator and controlling for age, gender, body mass index, and year of apheresis revealed increased yields in overweight and obese AA and API donors. In Hispanic donors, only male obese donors had higher CD34(+) per liter mobilization yields compared with Caucasian donors. No differences in CD34(+) per liter yields were seen between Caucasian and NA donors. Characterization of these differences may allow optimization of mobilization regimens to allow enhancement of mobilization yields without compromising donor safety.

Hematopoietic cell transplantation (HCT) with non-myeloablative conditioning (NMA) for lymphoproliferative diseases (LD) includes fludarabine with and without low-dose total body irradiation (TBI). Transplant outcomes were compared among patients ≥40 years with LD who received a HCT with TBI (N=382) and no-TBI (N=515) NMA from 2001 to 2011. The groups were comparable except for donor, graft, prophylaxis for graft-versus-host disease (GVHD), disease status and year of HCT. Cumulative incidences of grades II–IV GVHD at 100 days, were 29% and 20% (p=0.001), and chronic GVHD at 1 year were 54% and 44% (p=0.004) for TBI and no-TBI, respectively. Multivariate analysis of progression/relapse, treatment failure and mortality showed no outcome differences by conditioning. Full donor chimerism at day 100 was observed in 82% vs. 64% in the TBI and no-TBI groups, respectively (p=0.006). Subset of four most common conditioning/ GVHD prophylaxis combinations demonstrated higher rates of grades II–IV acute (p

Background Repurposing existing medications for antineoplastic purposes can provide a safe, cost-effective, and efficacious means to further augment available cancer care. Clinical and preclinical studies suggest a role for the ß-adrenergic antagonist (ß-blocker) propranolol in reducing rates of tumor progression in both solid and hematologic malignancies. In patients undergoing hematopoietic cell transplantation (HCT), the peri-transplant period is a time of increased activity of the ß-adrenergically-mediated stress response. Methods We conducted a proof-of-concept randomized controlled pilot study assessing the feasibility of propranolol administration to patients between ages 18–75 who received an autologous HCT for multiple myeloma. Feasibility was assessed by enrollment rate, tolerability, adherence, and retention. Results One hundred fifty-four patients underwent screening; 31 (20%) enrolled in other oncology trials that precluded dual trial enrollment and 9 (6%) declined to enroll in the current trial. Eighty-nine (58%) did not meet eligibility requirements and 25 (16%) were eligible; of the remaining eligible patients, all were successfully enrolled and randomized. The most common reasons for ineligibility were current ß-blocker use, age, logistics, and medical contraindications. 92% of treatment arm patients tolerated and remained on propranolol for the study duration; 1 patient discontinued due to hypotension. Adherence rate in assessable patients (n = 10) was 94%. Study retention was 100%. Conclusions Findings show that it is feasible to recruit and treat multiple myeloma patients with propranolol during HCT, with the greatest obstacle being other competing oncology trials. These data support further studies examining propranolol and other potentially repurposed drugs in oncology populations. Trial registration This randomized controlled trial was registered at clinicaltrials.gov with the identifier NCT02420223 on April 17, 2015.

Graft-versus-host disease (GVHD) is a common complication after hematopoietic cell transplantation (HCT) and associated with significant morbidity and mortality. Preventing GVHD without chronic therapy or increasing relapse is a desired goal. Here we report a benchmark analysis to evaluate the performance of 6 GVHD prevention strategies tested at single institutions compared with a large multicenter outcomes database as a control. Each intervention was compared with the control for the incidence of acute and chronic GVHD and overall survival and against novel composite endpoints: acute and chronic GVHD, relapse-free survival (GRFS), and chronic GVHD, relapse-free survival (CRFS). Modeling GRFS and CRFS using the benchmark analysis further informed the design of 2 clinical trials testing GVHD prophylaxis interventions. This study demonstrates the potential benefit of using an outcomes database to select promising interventions for multicenter clinical trials and proposes novel composite endpoints for use in GVHD prevention trials.

Cancers treated by transplantation are often curative, but immunosuppressive drugs are required to prevent and (if needed) to treat graft-versus-host disease. Estimation of an optimal adaptive treatment strategy when treatment at either one of two stages of treatment may lead to a cure has not yet been considered. Using a sample of 9,563 patients treated for blood and bone cancers by allogeneic hematopoietic cell transplantation drawn from the Center for Blood and Marrow Transplant Research database, we provide a case study of a novel approach to Q-learning for survival data in the presence of a potentially curative treatment, and demonstrate the results differ substantially from an implementation of Q-learning that fails to account for the cure-rate.

This paper presents the first deep reinforcement learning (DRL) framework to estimate the optimal Dynamic Treatment Regimes from observational medical data. This framework is more flexible and adaptive for high dimensional action and state spaces than existing reinforcement learning methods to model real-life complexity in heterogeneous disease progression and treatment choices, with the goal of providing doctor and patients the data-driven personalized decision recommendations. The proposed DRL framework comprises (i) a supervised learning step to predict the most possible expert actions, and (ii) a deep reinforcement learning step to estimate the long-term value function of Dynamic Treatment Regimes. Both steps depend on deep neural networks. As a key motivational example, we have implemented the proposed framework on a data set from the Center for International Bone Marrow Transplant Research (CIBMTR) registry database, focusing on the sequence of prevention and treatments for acute and chronic graft versus host disease after transplantation. In the experimental results, we have demonstrated promising accuracy in predicting human experts' decisions, as well as the high expected reward function in the DRL-based dynamic treatment regimes.

The Primary Immune Deficiency Treatment Consortium (PIDTC) is enrolling children with severe combined immunodeficiency (SCID) to a prospective natural history study. We analyzed patients treated with allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2014, including 68 patients with typical SCID and 32 with leaky SCID, Omenn syndrome, or reticular dysgenesis. Most (59%) patients were diagnosed by newborn screening or family history. The 2-year overall survival was 90%, but was 95% for those who were infection-free at HCT vs 81% for those with active infection (P = .009). Other factors, including the diagnosis of typical vs leaky SCID/Omenn syndrome, diagnosis via family history or newborn screening, use of preparative chemotherapy, or the type of donor used, did not impact survival. Although 1-year post-HCT median CD4 counts and freedom from IV immunoglobulin were improved after the use of preparative chemotherapy, other immunologic reconstitution parameters were not affected, and the potential for late sequelae in extremely young infants requires additional evaluation. After a T-cell-replete graft, landmark analysis at day +100 post-HCT revealed that CD3 < 300 cells/μL, CD8 < 50 cells/μL, CD45RA < 10%, or a restricted Vβ T-cell receptor repertoire (

Corticosteroids are the accepted primary therapy for acute graft-versus-host disease (GVHD), but durable responses are seen in only about half of the patients. Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0802, a phase 3 multicenter randomized double-blinded trial, was designed to test whether mycophenolate mofetil (MMF) plus corticosteroids was superior to corticosteroids alone as initial therapy for acute GVHD. Patients with newly diagnosed acute GVHD were eligible if they required systemic therapy. Patients were randomized to receive prednisone with either MMF or placebo. The primary end point was acute or chronic GVHD-free survival at day 56 after initiation of therapy. A futility rule for GVHD-free survival at day 56 was met at a planned interim analysis after 235 patients (of 372) were enrolled: 116 MMF, 119 placebo. Baseline characteristics were well balanced between treatment groups including grade and organ distribution of GVHD. GVHD-free survival at day 56, cumulative incidence of chronic GVHD at 12 months, overall survival, Epstein-Barr virus reactivation, severe, life-threatening infections, relapse at 12 months, and quality of life were similar. The addition of MMF to corticosteroids as initial therapy for acute GVHD does not improve GVHD-free survival compared with corticosteroids alone. This trial was registered at www.clinicaltrials.gov as #NCT01002742.

Summary Double-unit cord blood (CB) grafts may improve engraftment and relapse risk in adults with haematological malignancies. We performed a prospective high-dose myeloablative double-unit CB transplantation (CBT) trial in adults with high-risk acute leukaemia or myelodysplasia (MDS) between 2007 and 2011. The primary aim was to establish the 1-year overall survival in a multi-centre setting. Fifty-six patients (31 acute myeloid leukaemia, 19 acute lymphoblastic leukaemia, 4 other acute leukaemias, 2 myelodysplastic syndrome [MDS]) were transplanted at 10 centres. The median infused total nucleated cell doses were 2·62 (larger unit) and 2·02 (smaller unit) x 107/kg. The cumulative incidence of day 100 neutrophil engraftment was 89% (95% confidence interval [CI]: 80–96). Day 180 grade II-IV acute graft-versus-host disease (GVHD) incidence was 64% (95%CI: 51–76) and 36% (95%CI: 24–49) of patients had chronic GVHD by 3-years. At 3-years post-transplant, the transplant-related mortality (TRM) was 39% (95%CI: 26–52), and the 3-year relapse incidence was 11% (95%CI: 4–21). With a median 37-month (range 23–71) follow-up of survivors, the 3-year disease-free survival was 50% (95%CI: 37–63). Double-unit CBT is a viable alternative therapy for high-risk acute leukaemia/ MDS in patients lacking a matched unrelated donor. This is especially important for minority patients. The relapse incidence was low but strategies to ameliorate TRM are needed.

The introduction of reduced-intensity conditioning (RIC) regimens made it possible to offer allogeneic hematopoietic cell transplantation (alloHCT) to older patients with myelodysplastic syndromes (MDS). However, the relative risks and benefits of alloHCT compared with novel nontransplant therapies continue to be the source of considerable uncertainty. We will perform a prospective biologic assignment trial to compare RIC alloHCT with nontransplant therapies based on donor availability. Primary outcome is 3-year overall survival. Secondary outcomes include leukemia-free survival, quality of life, and cost-effectiveness. Four hundred patients will be enrolled over roughly 3 years. Planned subgroup analyses will evaluate key biologic questions, such as the impact of age and response to hypomethylating agents on treatment effects. Findings from this study potentially may set a new standard of care for older MDS patients who are considered candidates for alloHCT.

Allogeneic hematopoietic cell transplantation (alloHCT) with reduced-intensity conditioning is an appealing option for patients with high-risk multiple myeloma (MM). However, progression after alloHCT remains a challenge. Maintenance therapy after alloHCT may offer additional disease control and allow time for a graft-versus-myeloma effect. The primary objective of this clinical trial was to determine the tolerability and safety profile of maintenance lenalidomide (LEN) given on days 1 to 21 of 28 days cycles, with intrapatient dose escalation during 12 months/cycles after alloHCT. Thirty alloHCT recipients (median age, 54 years) with high-risk MM were enrolled at 8 centers between 2009 and 2012. The median time from alloHCT to LEN initiation was 96 days (range, 66 to 171 days). Eleven patients (37%) completed maintenance and 10 mg daily was the most commonly delivered dose (44%). Most common reasons for discontinuation were acute graft-versus-host disease (GVHD) (37%) and disease progression (37%). Cumulative incidence of grades III to IV acute GVHD from time of initiation of LEN was 17%. Outcomes at 18 months after initiation of maintenance were MM progression, 28%; transplantation-related mortality, 11%; and progression-free and overall survival, 63% and 78%, respectively. The use of LEN after alloHCT is feasible at lower doses, although it is associated with a 38% incidence of acute GVHD. Survival outcomes observed in this high-risk MM population warrant further study of this approach.

Sometimes in clinical trials, the hazard rates are anticipated to be nonproportional, resulting in potentially crossing survival curves. In these cases, researchers are usually interested in which treatment has better long-term survival. The log-rank test and the weighted log-rank test may not be appropriate or efficient to use here, because they are sensitive to differences in survival at any time and don’t just focus on long-term outcomes. Also in a prospective clinical trial, patients are entered sequentially over calendar time, so that group sequential designs may be considered for ethical, administrative and economic concerns. Here we develop group sequential methods for testing the null hypothesis that the survival curves are identical after a prespecified time point. Several classes of tests are considered, including an integrated difference in survival probabilities after this time point, and linear or quadratic combinations of two component test statistics (pointwise comparisons of survival at the time point and comparisons of hazard rates after the time point). We examine the type I errors, stopping probabilities, and powers of these tests through simulation studies under the null and different alternatives, and we apply them to a real bone marrow transplant clinical trial.

We compared serious early and late events experienced by 2726 bone marrow (BM) and 6768 peripheral blood stem cell (PBSC) donors who underwent collection of PBSC or BM between 2004 and 2009 as part of a prospective study through the National Marrow Donor Program. Standardized FDA definitions for serious adverse events (SAEs) were used, and all events were reviewed by an independent physician panel. BM donors had an increased risk for SAEs (2.38% for BM vs 0.56% for PBSC; odds ratio [OR], 4.13; P < .001), and women were twice as likely to experience an SAE (OR for men, 0.50; P = .005). Restricting the analysis to life-threatening, unexpected, or chronic/disabling events, BM donors maintained an increased risk for SAEs (0.99% for BM vs 0.31% for PBSC; OR, 3.20; P < .001). Notably, the incidence of cancer, autoimmune illness, and thrombosis after donation was similar in BM vs PBSC donors. In addition, cancer incidence in PBSC donors was less than that reported in the general population (Surveillance, Epidemiology, and End Results Program database). In conclusion, SAEs after donation are rare but more often occurred in BM donors and women. In addition, there was no evidence of increased risk for cancer, autoimmune illness, and stroke in donors receiving granulocyte colony-stimulating factor during this period of observation.

Because the outcome of allogeneic hematopoietic cell transplantation (HCT) is predominantly influenced by disease type and status, it is essential to be able to stratify patients undergoing HCT by disease risk. The Disease Risk Index (DRI) was developed for this purpose. In this study, we analyzed 13,131 patients reported to the Center for International Blood and Marrow Transplant Research who underwent HCT between 2008 and 2010. The DRI stratified patients into 4 groups with 2-year overall survival (OS) ranging from 64% to 24% and was the strongest prognostic factor, regardless of age, conditioning intensity, graft source, or donor type. A randomly selected training subgroup of 9849 patients was used to refine the DRI, using a multivariable regression model for OS. This refined DRI had improved prediction ability for the remaining 3282 patients compared with the original DRI or other existing schemes. This validated and refined DRI can be used as a 4- or 3-group index, depending on the size of the cohort under study, for prognostication; to facilitate the interpretation of single-center, multicenter, or registry studies; to adjust center outcome data; and to stratify patients entering clinical trials that enroll patients across disease categories.

Idiopathic pneumonia syndrome (IPS) is a diffuse, noninfectious lung injury that occurs acutely after allogeneic hematopoietic cell transplantation (HCT). IPS-related mortality has been historically high (>50%) despite treatment with systemic corticosteroids and supportive care measures. We have now examined the role of tumor necrosis factor inhibition in a randomized, double-blind, placebo-controlled trial of corticosteroids with etanercept or placebo. Thirty-four subjects (≥18 years) with IPS after HCT were randomized to receive methylprednisolone (2 mg/kg/day) plus etanercept (0.4 mg/kg twice weekly × 4 weeks; n = 16) or placebo (n = 18). No active infections and a pathogen-negative bronchoscopy were required at study entry. Response (alive, with complete discontinuation of supplemental oxygen support) and overall survival were examined. This study, originally planned to accrue 120 patients, was terminated prematurely due to slow accrual. In the limited number of patients examined, there were no differences in response rates at day 28 of study. Ten of 16 patients (62.5% [95% confidence interval {CI}, 35.4% to 84.8%]) receiving etanercept and 12 of 18 patients (66.7% [95% CI, 41.0% to 86.7%]) receiving placebo met the day 28 response definition (P = 1.00). The median survival was 170 days (95% CI, 11 to 362) with etanercept versus 64 days (95% CI, 26 to 209) with placebo (P = .51). Among responders, the median time to discontinuation of supplemental oxygen was 9 days (etanercept) versus 7 days (placebo). Therapy was well tolerated, with 1 toxicity-related death from infectious pneumonia in the placebo arm. The treatment of IPS with corticosteroids in adult HCT recipients was associated with high early response rates (>60%) compared with historical reports, with poor overall survival. The addition of etanercept did not lead to further increases in response, although the sample size of this truncated trial preclude a definitive conclusion.

This article discusses the use of biobehavioral measures as outcomes for health care intervention studies. Effect size (ES) values for salivary cortisol and observation-based measures of pain and agitation were examined. Effects pre to post treatment were assessed separately for nursing home residents with and without acute psychotic symptoms. This study revealed large positive effects on both pain and agitation measures in the group with acute psychotic symptoms and small-to-medium positive effects on these same measures in the group without acute psychotic symptoms. In both of these groups, the ES values were not consistently positive on the cortisol measures. Prior to determining whether a measure can be used to estimate minimum clinically important differences, it is essential to consider if the biomarker will be responsive to therapy in the populations and contexts being studied. [[Res Gerontol Nurs. 2014; 7(2):56–65.]

Introduction: Approximately 7% of unrelated hematopoietic stem cell (HSC) donors are asked to donate a subsequent time to the same or different recipient. In a recent large CIBMTR study of second time donors, Stroncek et al. incidentally found that second peripheral blood stem cell (PBSC) collections had lower total CD34+ cells, CD34+ cells per liter of whole blood processed, and CD34+ cells per kg donor weight. Based on smaller studies, the time between the two independent PBSC donations (inter-donation interval) as well as donor sex, race and baseline lymphocyte counts appear to influence CD34+ cell yields at subsequent donations. Our objective was to retrospectively evaluate factors contributory to CD34+ cell yields at subsequent PBSC donation amongst NMDP donors. Methods. The study population consisted of filgrastim (G-CSF) mobilized PBSC donors through the NMDP/CIBMTR between 2006 and 2017, with a subsequent donation of the same product. evaluated the impact of inter-donation interval, donor demographics (age, BMI, race, sex, G-CSF dose, year of procedure, need for central line) and changes in complete blood counts (CBC), on the CD34+ cell yields/liter (x106/L) of blood processed at second donation and pre-apheresis (Day 5) peripheral blood CD34+ cell counts/liter (x106/L) at second donation. Linear regression was used to model log cell yields as a function of donor and collection related variables, time between donations, and changes in baseline values from first to second donation. Stepwise model building, along with interactions among significant variables were assessed. The Pearson chi-square test or the Kruskal-Wallis test compared discrete variables or continuous variables, respectively. For multivariate analysis, a significance level of 0.01 was used due to the large number of variables considered. Results: Among 513 PBSC donors who subsequently donated a second PBSC product, clinically relevant decreases in values at the second donation were observed in pre-apheresis CD34+ cells (73.9 vs. 68.6; p=0.03), CD34+cells/L blood processed (32.2 vs. 30.1; p=0.06), and total final CD34+ cell count (x106) (608 vs. 556; p=0.02). Median time interval between first and second PBSC donations was 11.7 months (range: 0.3-128.1). Using the median pre-apheresis peripheral blood CD34+ cell counts from donation 1 as the cut-off for high versus low mobilizers, we found that individuals who were likely to be high or low mobilizers at first donation were also likely to be high or low mobilizers at second donation, respectively (Table 1). This was independent of the inter-donation interval. In multivariate analyses, those with an inter-donation interval of >12 months, demonstrated higher CD34+cells/L blood processed compared to donors donating within a year (mean ratio 1.15, p Pre-apheresis peripheral blood CD34+ cells on Day 5 of second donation were also affected by the inter-donation interval, with higher cell counts associated with a longer time interval (>12 months) between donations (1.23, p6.9) (1.3, p Conclusions: In this large retrospective study of second time unrelated PBSC donors, a longer inter-donation interval was confirmed to be associated with better PBSC mobilization and collection. Given hematopoietic stem cell cycling times of 9-12 months in humans, where possible, repeat donors may be chosen based on these intervals to optimize PBSC yields. Changes in BMI are also to be considered while recruiting repeat donors. Some of these parameters may be improved marginally by increasing G-CSF dose within permissible limits. In most instances, however, sub-optimal mobilizers at first donation appear to donate suboptimal numbers of HSC at their subsequent donation. Disclosures Pulsipher: CSL Behring: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding; Bellicum: Consultancy; Amgen: Other: Lecture; Jazz: Other: Education for employees; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Honoraria. Shaw:Therakos: Other: Speaker Engagement.

Background: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are a common indication for allogeneic hematopoietic stem cell transplant (HCT) in first complete remission (CR1). Despite HCT, relapses are common and cure rates are limited thereafter. The use of FLT3 inhibitors as post-HSCT maintenance therapy has not been prospectively evaluated in the phase 3 setting. Gilteritinib is a selective, potent FLT3 inhibitor with robust activity and favorable tolerability in relapsed/refractory AML. This trial will compare the safety and efficacy of 2-year maintenance therapy with gilteritinib versus placebo in patients with FLT3-ITD+ AML in CR1 after allogeneic HSCT. The broad goal of this study is to determine if there is a benefit to FLT3 inhibition as maintenance therapy post-HCT and to identify which patients, if any, benefit. We will use a novel NGS-based assay for FLT3-ITD mutations to detect minimal residual disease (MRD) in order to stratify patients pre-HSCT and correlate with relapse post-HCT. Study Design and Methods: This Phase 3, randomized, double-blind, placebo-controlled multicenter trial (NCT02997202; Blood and Marrow Transplant Clinical Trials Network Protocol 1506), is being conducted at 149 sites worldwide. The target enrollment is 532 adult subjects (aged ≥18 years) with FLT3-ITD+ AML in CR1 who are ≥30 days and ≤90 days from scheduled allogeneic HSCT. Of these 532 subjects, 346 subjects who have achieved successful engraftment without uncontrolled graft-versus-host disease (GVHD) or other serious toxicity will be randomized (1:1; stratified by conditioning regimen intensity, time from HSCT [Day 0] to randomization [30-60 days vs 61-90 days], and presence of minimal residual disease [MRD] in the pre-transplant bone marrow sample) to receive oral gilteritinib (120 mg) or matching placebo as maintenance therapy for 2 years. The primary endpoint is relapse-free survival (RFS) in the two treatment arms; RFS will be assessed from the time of randomization to the time of death or morphologic leukemia relapse (as defined by Revised IWG criteria). MRD status will continue to be monitored over the duration of the maintenance therapy, although investigators will be blinded to the MRD assay results. Overall survival is a key secondary endpoint. Other endpoints include safety/tolerability, non-relapse mortality, event-free survival, incidences of acute/chronic GVHD, and MRD. As of July 31, 2019, 341 patients have been registered and 236 have been randomized. To achieve a target number of 346 subjects for randomization (n=173 per treatment arm), we estimated that enrollment of 532 subjects would be required given an expected dropout rate of 35% between the time of registration to the time of randomization. The RFS rate in the placebo arm (control) is assumed to be 67% at 1 year, 59% at 2 years, and 55% at 3 years (according to the Center for International Blood & Marrow Transplant Research data for FLT3-ITD+ patients transplanted in CR1 who were alive and were progression free at 60 days). A total of 122 events will provide 85% power to detect a hazard ratio (HR) of 0.57 (corresponding to a 15% difference in 2-year RFS) with two-sided significance level of 0.05. With a 2-year accrual period and a 5% annual dropout rate, enrollment of 346 subjects will ensure a high probability of obtaining 122 events. The primary efficacy analysis will be performed using the intention-to-treat (ITT) population, which is defined as all subjects who are randomized. RFS will be compared across the treatment groups using the stratified Log-rank test. A stratified Cox model with treatment as covariate will be used to determine HR and confidence intervals at 1, 2, and 3 years. Kaplan-Meier estimates of RFS will be reported at 1, 2, and 3 years. No interim efficacy or futility analyses are planned. Figure Disclosures Levis: Daiichi Sankyo Inc: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding. Hamadani:Otsuka: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Medimmune: Consultancy, Research Funding; Pharmacyclics: Consultancy; Takeda: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Celgene: Consultancy; Merck: Research Funding; Janssen: Consultancy. Rosales:Astellas: Employment. Delgado:Astellas: Employment. Bahceci:Astellas: Employment, Patents & Royalties. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Horowitz:Actinium: Other: Unrestricted educational and research grant; Gamida Cell: Other: Unrestricted educational and research grant, Research Funding; Oncoimmune: Other: Unrestricted educational and research grant; Miltenyi Biotech: Other: Unrestricted educational and research grant, Research Funding; Janssen: Other: Unrestricted educational and research grant, Research Funding; Kite Pharma/Gilead: Other: Unrestricted educational and research grant, Research Funding; Magenta: Consultancy, Other: Unrestricted educational and research grant; GlaxoSmithKline: Other: Unrestricted educational and research grant; Shire: Other: Unrestricted educational and research grant; CSL Behring: Other: Unrestricted educational and research grant, Research Funding; Seattle Genetics: Other: Unrestricted educational and research grant; Mesoblast: Other: Unrestricted educational and research grant, Research Funding; Bristol-Myers Squibb: Other: Unrestricted educational and research grant, Research Funding; Daiichi Sankyo: Other: Unrestricted educational and research grant; Sanofi: Other: Unrestricted educational and research grant, Research Funding; Pharmacyclics: Other: Unrestricted educational and research grant; Amgen: Other: Unrestricted educational and research grant; Chimerix: Other: Unrestricted educational and research grant; Regeneron: Other: Unrestricted educational and research grant. Chen:Incyte: Consultancy; Kiadis: Consultancy; Magenta: Consultancy; Abbvie: Consultancy; Takeda: Consultancy.

Graft-versus-host disease (GVHD) remains the major source of morbidity and transplant-related mortality after allogeneic hematopoietic cell transplant (alloHCT). Since the mid-1980s, the standard prophylaxis for GVHD has been a calcineurin inhibitor plus methotrexate (MTX). Subsequent clinical trials designed to intensify GVHD prophylaxis have shown an increased risk of relapse, thus negating survival benefit. The ideal GVHD prophylaxis regimen is therefore associated with a high graft-versus-host disease-free, relapse-free survival (GRFS), a composite endpoint that reflects survival without morbidity. A recent 3-arm randomized phase II study conducted through the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 1203) showed a benefit in GRFS using post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil (PTCy/Tac/MMF) with a hazard ratio of 0.72 (90% confidence interval 0.54 - 0.94, p-0.044) compared to contemporary non-randomized CIBMTR Tac/MTX controls. Based upon these results, the BMT CTN has launched 1703, a multicenter randomized phase III study of standard Tac/MTX vs PTCy/Tac/MMF in the setting of reduced intensity conditioning, matched peripheral blood stem cell transplantation (RIC PBSCT). The primary endpoint of 1703 is GRFS at 1 year, and several secondary endpoints, including patient-reported outcomes, will be analyzed. A series of recent, predominantly single-center studies have shown an association with the composition of intestinal microbiota and the development of acute GVHD, which suggests that this may be a potential modifiable biomarker of disease. The generalizability of findings from these studies is yet unknown, and no large multi-center studies on the intestinal microbiota of HCT patients has yet been carried out. Patients enrolled in 1703 will be eligible to co-enroll in BMT CTN 1801, the Mi-Immune study, detailing microbiota and immune reconstitution in this cohort. The primary endpoint of 1801 is 1-year non-relapse mortality by tertiles of stool microbial diversity at engraftment. Secondary objectives, including effect of GVHD prophylaxis on diversity, oligodomination and risk of bloodstream infection, volume of antimicrobial exposure, and T-cell receptor diversity, will be analyzed. The combined studies of BMT CTN 1703/1801 will define the standard of care for GVHD prophylaxis in the RIC PBSCT setting and vastly expand our knowledge on the impact of intestinal microbiota in critical outcomes after alloHCT. This clinical trial is registered at ClinicalTrials.gov NCT03959241. Figure Disclosures Holtan: Incyte: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; CSL Behring: Consultancy. Bhatt:ArcBio: Other: Scientific Advisory Board; January.ai: Other: Scientific Advisory Board; Caribou Bioscience: Other: Scientific Advisory Board; Kaleido Biosciences: Consultancy, Other: Paid Consultant; Janssen Human Microbiome Institute: Consultancy, Other: Paid Consultant; Illumina: Honoraria; 10x Genomics: Other: Research collaboration without funding support; Illumina: Other: Research collaboration without funding support; Agilent: Research Funding; Global Oncology, Inc: Other: Nonprofit Board. Perales:Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kean:HiFiBio: Consultancy; BlueBirdBio: Research Funding; Gilead: Research Funding; Regeneron: Research Funding; EMDSerono: Consultancy; FortySeven: Consultancy; Magenta: Research Funding; Kymab: Consultancy; Jazz: Research Funding; Bristol Meyers Squibb: Patents & Royalties, Research Funding. Hamadani:Medimmune: Consultancy, Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Merck: Research Funding; Celgene: Consultancy; Otsuka: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau. Bolaños-Meade:Incyte Corporation: Other: DSMB fees.

Introduction Renal dysfunction is a recognized risk factor for mortality after HCT, as it is included in the comorbidity index (HCT CI). Yet, further understanding on outcomes in patients with different level of renal dysfunction or undergoing hemodialysis (HD) at time of transplant remains scant. This study explores the impact of different levels renal dysfunction on major HCT outcomes in a large population using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Methods The study population included 8,102 patients age 40 years and older who received HCT for treatment of malignancies from 2008 to 2016, with available pre-transplant creatinine measurement. eGFR, calculated using CKD-EPI (CKD-epidemiology collaboration) method, was used to assigned patients in four categories: eGFR ≥ 90ml/min (eGFR≥ 90, N=4,237, reference), eGFR 60-90ml/min (eGFR 60-90, N=3,158), eGFR 45-59ml/min (eGFR 45-59, N=538) and eGFR Results Patient characteristics are shown in table 1. The groups were comparable on disease risk index, graft and donor source, but patients with eGFR>90 were younger and received myeloablative conditioning more frequently. The cohort of eGFR Conclusion These findings indicate that degree of renal dysfunction is an independent predictor of OS, TRM, probability of receiving HD and SOS when adjusted for other risk factors. The impact of eGFR on the need of HD, a complication that increases morbidity post HCT is an important finding. Additionally, the outcomes of a subset of patients on HD at time of transplants are dismal. These results can further assist the prognostic assessment of candidates for an allogeneic HCT. Disclosures Stadtmauer: Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Research Funding; Tmunity: Research Funding; Abbvie: Research Funding. Wingard:Ansun: Consultancy; Pluristem: Consultancy; Celgene: Consultancy; Merck: Consultancy; Shire: Consultancy. Ganguly:Seattle Genetics: Speakers Bureau; Daiichi Sankyo: Research Funding; Kite Pharma: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board. Pasquini:Pfizer: Other: Advisory Board; Amgen: Consultancy; Medigene: Consultancy; BMS: Research Funding; Novartis: Research Funding; Kit Pharma: Research Funding.

Beta-adrenergic signaling regulates multiple molecular pathways that contribute to cancer progression; beta-adrenergic antagonists efficiently block many of these effects in animals. We previously demonstrated that hematopoietic cell transplant (HCT) patients exposed to socioeconomic stress show activation of a conserved transcriptional response to adversity (CTRA) transcriptome profile, which in turn is associated with increased relapse and decreased disease-free survival. We conducted a randomized controlled trial to evaluate whether the beta-antagonist propranolol is effective in decreasing gene expression of CTRA-related genes of 25 individuals receiving an autologous HCT for multiple myeloma. Propranolol was administered for one week prior to transplant and 4 weeks following transplant. Blood was collected at baseline, Day −2, and Day +28. Intention-to-treat analyses assessed effects on the 53-gene CTRA indicator profile and measures of CTRA-related cellular processes. Twelve participants were randomized to the intervention group and 13 to the control arm. Relative to the control group, propranolol-treated patients showed greater decreases from baseline to Day −2 and Day +28 for both CTRA gene expression (p = .017) and bioinformatic measures of CD16- classical monocyte activation (p = .005). Propranolol-treated patients also showed up-regulation of CD34+ hematopoietic progenitor cells (p = .011). Peri-transplant administration of propranolol can down-regulate CTRA gene expression, inhibit myeloid-based cellular dynamics, and up-regulate the CD34+ cells. Ongoing follow-up and future replication studies will be required to assess impacts on clinical outcomes.

The survival of patients with relapsed acute myelogenous leukemia (AML) after autologous hematopoietic stem cell transplantation (auto-HCT) is very poor. We studied the outcomes of 302 patients who underwent secondary allogeneic hematopoietic cell transplantation (allo-HCT) from an unrelated donor (URD) using either myeloablative (n = 242) or reduced-intensity conditioning (RIC; n = 60) regimens reported to the Center for International Blood and Marrow Transplantation Research. After a median follow-up of 58 months (range, 2 to 160 months), the probability of treatment-related mortality was 44% (95% confidence interval [CI], 38%-50%) at 1-year. The 5-year incidence of relapse was 32% (95% CI, 27%-38%), and that of overall survival was 22% (95% CI, 18%-27%). Multivariate analysis revealed a significantly better overal survival with RIC regimens (hazard ratio [HR], 0.51; 95% CI, 0.35-0.75; P < .001), with Karnofsky Performance Status score >= 90% (HR, 0.62; 95% CI, 0.47-0.82: P = .001) and in cytomegalovirus-negative recipients (HR, 0.64; 95% CI, 0.44-0.94; P = .022). A longer interval (>18 months) from auto-HCT to URD allo-HCT was associated with significantly lower riak of relapse (HR, 0.19; 95% CI, 0.09-0:38; P < .001) and improved leukemia-free survival (HR, 0.53; 95% CI, 0.34-0.84; P = .006). URD allo-HCT after auto-HCT relapse resulted in 20% long-term leukemia-free survival, with the best results seen in patients with a longer interval to secondary URD transplantation, with a Karnofsky Performance Status score >90%, in complete remission, and using an RIC regimen. Further efforts to reduce treatment-related mortaility and relapse are still needed. (C) 2013 American Society for Blood and Marrow Transplantation.

While in last four decades significant strides have been made in understanding the biology of graft-versus-host disease (GvHD) and its prevention, little is known about the different populations of lymphocytes and the changes in response to treatment for this condition. BMT-CTN 0302 was a randomized phase II clinical trial in the Blood and Marrow Transplant Clinical Trials Network that assessed the efficacy of combination therapy with steroids plus 1 of 4 other agents: pentostatin, mycophenolate mofetil, etanercept, or denileukin diftitox, in patients with acute GvHD. Patients enrolled in the study had their blood analyzed by flow cytometry on days 0, 14, and 28 of therapy to enumerate the number of total lymphocytes, T cells, B cells and lymphocytes expressing activation markers. Baseline lymphocyte total counts and the subpopulations were similar in the four treatment arms. Responding patients at day 28 had a smaller decrease in their total CD45+ cells (p=0.005) compared to non-responding patients. In univariate analysis those who developed chronic GvHD had significantly more CD8+ cells at day 14 compared to those without it (p =0.005). There was no significant association between baseline lymphocyte counts and survival. In univariate analysis, among patients with higher lymphocyte counts at days 14 and 28, there was a trend towards better survival at day 180 although this did not reach the pre-determined threshold for significance. Among the four different treatment arms, we found no significant differences in lymphocyte total or subpopulation counts and no notable influence on outcomes.

Although peripheral blood stem cells (PBSCs) have replaced bone marrow (BM) as the most common unrelated donor progenitor cell product collected, a direct comparison of concurrent PBSC versus BM donation experiences has not been performed. We report a prospective study of 2726 BM and 6768 PBSC donors who underwent collection from 2004 to 2009. Pain and toxicities were assessed at baseline, during G-CSF administration, on the day of collection, within 48 hours of donation, and weekly until full recovery. Peak levels of pain and toxicities did not differ between the 2 donation processes for most donors. Among obese donors, PBSC donors were at increased risk of grade 2 to 4 pain as well as grade 2 to 4 toxicities during the pericollection period. In contrast, BM donors were more likely to experience grade 2 to 4 toxicities at 1 week and pain at 1 week and 1 month after the procedure. BM donors experienced slower recovery, with 3% still not fully recovered at 24 weeks, whereas 100% of PBSC donors had recovered. Other factors associated with toxicity included obesity, increasing age, and female sex. In summary, this study provides extensive detail regarding individualized risk patterns of PBSC versus BM donation toxicity, suggesting donor profiles that can be targeted with interventions to minimize toxicity.

To assess the impact of spleen status on engraftment and early morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT), we analyzed 9,683 myeloablative allograft recipients from 1990 to 2006; 472 had prior splenectomy (SP), 300 splenic irradiation (SI), 1,471 with splenomegaly (SM), and 7,440 with normal spleen (NS). Median times to neutrophil and platelet engraftment were 15 vs. 18 days and 22 vs. 24 days for the SP and NS groups, respectively (p5.7x106/kg improved platelet engraftment at day+28. After adjusting variables by Cox regression, the incidence of graft-versus-host disease (GVHD) and overall survival were not different among groups. Splenomegaly is associated with delayed engraftment while splenectomy prior to HCT facilitates early engraftment without impact on survival.

In the setting of myeloablative conditioning and conventional post-grafting immunoprophylaxis for GvHD with a calcineurin inhibitor and methotrexate, randomized studies of bone marrow (BM) vs peripheral blood (PB) as the allograft source in transplantation from HLA-matched related donors1 or unrelated donors2 showed comparable outcomes with the exception of an absolute increase of 6–15% in the incidence of chronic GvHD after transplantation of PB. However, in the setting of non-ablative conditioning, a recent retrospective study from the Center for International Blood and Marrow Transplant Research (CIBMTR) showed that rates of acute GvHD, chronic GvHD and overall survival were similar after transplantation of BM compared with PB.3 To test whether outcomes were similar after haplo-BM and haplo-PB transplants using non-ablative conditioning with the Hopkins regimen,4 we compared data from a multi-center phase II trial of haplo-BM conducted in the US (Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 06035, 6) with published and unpublished data from phase II trials of haplo-PB transplants in the US, Europe and Australia7, 8, 9 by means of a matched-pair analysis. Patients 70 years of age or younger who met the eligibility criteria for BMT CTN 0603 were matched for age±10 years and for low-intermediate-high disease risk index (DRI). DRI is a composite of disease, disease status and cytogenetic risk (acute leukemia and myelodysplastic syndrome) that has been shown to independently risk stratify survival in heterogeneous adult patient cohorts with hematologic malignancy regardless of conditioning intensity or graft source.10

Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocol 0902 evaluated whether exercise and stress management training before hematopoietic cell transplantation (HCT) improved physical and mental functioning after HCT. Neither overall survival nor other patient-reported transplantation outcomes were improved by the training intervention. In some animal studies of HCT, moderate-intensity exercise for 8 weeks before HCT has been associated with positive effects on hematopoietic progenitors, resulting in improved donor engraftment and improved survival. Accordingly, we performed a secondary analysis of data from BMT CTN 0902 to determine whether exercise engagement before HCT was associated with engraftment and survival. We found no significant associations between self-reported pre-HCT exercise levels and engraftment or survival. There was also no effect of pretransplantation exercise on either neutrophil or platelet engraftment. These findings do not support the observations in animal models but are limited by several shortcomings that do not refute the hypothesis that exercise before HCT may be beneficial.

Allogeneic (allo) hematopoietic cell transplantation (HCT) can induce long-term remissions in chemosensitive relapsed follicular lymphoma (FL). The Blood and Marrow Transplant Clinical Trials Network conducted a multicenter phase 2 trial to examine the efficacy of alloHCT using reduced-intensity conditioning with rituximab (RTX) in multiply relapsed, chemosensitive FL. The primary endpoint was 2-year progression-free survival (PFS). The conditioning regimen consisted of fludarabine, cyclophosphamide, and high-dose RTX (FCR), in which 3 of the 4 doses of RTX were administered at a dose of 1 gm/m2. Graft-versus-host disease (GVHD) prophylaxis was with tacrolimus and methotrexate. Sixty-five patients were enrolled and 62 were evaluable. Median age was 55 years (range, 29 to 74). This group was heavily pretreated: 77% had received ≥ 3 prior regimens, 32% had received ≥ 5 prior regimens, and 11% had received prior autologous HCT. Donors were HLA-matched siblings (n = 33) or HLA-matched unrelated adults (n = 29). No graft failures occurred. The overall response rate after HCT was 94% with 90% in complete remission (CR), including 24 patients not in CR before alloHCT. With a median follow-up of 47 months (range, 30 to 73), 3-year PFS and overall survival rates were 71% (95% confidence interval, 58% to 81%) and 82% (95% confidence interval, 70% to 90%), respectively. Three-year cumulative incidences of relapse/progression and nonrelapse mortality were 13% and 16%, respectively. Two-year cumulative incidences of grades 2 to 4 and grades 3 or 4 acute GVHD were 27% and 10%, respectively, and extensive chronic GVHD incidence was 55%. Serum RTX concentrations peaked at day +28 and remained detectable as late as 1 year in 59% of patients with available data. In conclusion, alloHCT with FCR conditioning confers high CR rates, a low incidence of relapse/progression, and excellent survival probabilities in heavily pretreated FL patients.

We sought to confirm the prognostic importance of simple clinically available biomarkers of C-reactive protein, serum albumin, and ferritin prior to allogeneic hematopoietic cell transplantation. The study population consisted of 784 adults with acute myeloid leukemia in remission or myelodysplastic syndromes undergoing unrelated donor transplant reported to the Center for International Blood and Marrow Transplant Research. C-reactive protein and ferritin were centrally quantified by ELISA from cryopreserved plasma whereas each center provided pre-transplant albumin. In multivariate analysis, transplant-related mortality was associated with the pre-specified thresholds of C-reactive protein more than 10 mg/L (P= 0.008) and albumin less than 3.5 g/dL (P= 0.01) but not ferritin more than 2500 ng/mL. Only low albumin independently influenced overall mortality. Optimal thresholds affecting transplant-related mortality were defined as: C-reactive protein more than 3.67 mg/L, log(ferritin), and albumin less than 3.4 g/dL. A 3-level biomarker risk group based on these values separated risks of transplant-related mortality: low risk (reference), intermediate (HR= 1.66, P= 0.015), and high risk (HR= 2.7, P< 0.001). One-year survival was 74%, 67% and 56% for low-, intermediate-and high-risk groups. Routinely available pre-transplant biomarkers independently risk-stratify for transplant-related mortality and survival.

The Serial Trial Intervention (STI) is a decision support tool to address the problem of underassessment and undertreatment of pain and other unmet needs of people with dementia. This study compared the effectiveness of the 5-step and 9-step versions of the STI using a two-group repeated measures quasi-experimental design with randomization of 12 matched nursing homes. The sample consisted of 125 residents with moderate to severe dementia. Both the 5- and 9-step STIs significantly decreased discomfort and agitation from pre- to posttest (effect sizes = 0.45 to 0.90). The 9-step version was more effective for comorbid burden and increased cortisol slope (effect sizes = 0.50 and 0.49). Process variables were all statistically significantly improved using the 9-step STI. Nurse time was not different between the two groups. The clinical decision support rules embedded in the STI, particularly the 9-step version, helped nurses change practice and improved resident outcomes.

This descriptively designed study examined the sensitivity and specificity of staff nurses’ identification of behavior change in nursing home residents with dementia. Behavior changes and whether further physical assessment was indicated were described and compared with judgments made by one expert advanced practice nurse. The convenience sample included 155 residents and 38 staff nurses from 11 nursing homes. Verbal symptoms and body part cues were the most prevalent behaviors, regardless of the assessor. Sensitivity, or probability of identifying a real behavior change, was generally low for the staff nurses, ranging from 35% to 65% for the different types of behaviors, while specificity was high at more than 95%. Additional assessment was believed to be needed for 51% of residents by the staff nurse and for 73% of residents by the expert. This study found that staff nurses are under-identifying behavior changes and the need for additional physical assessment.