Clonal hematopoiesis-derived therapy-related myeloid neoplasms after autologous hematopoietic stem cell transplant for lymphoid and non-lymphoid disorders.

Therapy-related myeloid neoplasms (tMN) are complications of cytotoxic therapies. Risk of tMN is high in recipients of autologous hematopoietic stem cell transplantation (aHSCT). Acquisition of genomic mutations represents a key pathogenic driver but the origins, timing and dynamics, particularly in the context of preexisting or emergent clonal hematopoiesis (CH), have not been sufficiently clarified. We studied a cohort of 1507 patients undergoing aHSCT and a cohort of 263 patients who developed tMN without aHSCT to determine clinico-molecular features unique to post-aHSCT tMN. We show that tMN occurs in up to 2.3% of patients at median of 2.6 years post-AHSCT. Age ≥ 60 years, male sex, radiotherapy, high treatment burden ( ≥ 3 lines of chemotherapy), and graft cellularity increased the risk of tMN. Time to evolution and overall survival were shorter in post-aHSCT tMN vs. other tMN, and the earlier group's mutational pattern was enriched in PPM1D and TP53 lesions. Preexisting CH increased the risk of adverse outcomes including post-aHSCT tMN. Particularly, antecedent lesions affecting PPM1D and TP53 predicted tMN evolution post-transplant. Notably, CH-derived tMN had worse outcomes than non CH-derived tMN. As such, screening for CH before aHSCT may inform individual patients' prognostic outcomes and influence their prospective treatment plans. Presented in part as an oral abstract at the 2022 American Society of Hematology Annual Meeting, New Orleans, LA, 2022.

Authentic leadership at the Cleveland Clinic: psychological safety in the midst of crisis.

OBJECTIVES: The goal of this research was to examine the leadership experiences of senior leaders at the Cleveland Clinic during the recent COVID-19 pandemic crisis. A secondary goal was to examine lessons that could inform other healthcare organisations as they move into subsequent crisis situations. DESIGN: The authors examined publicly available podcast transcripts where interviewees shared their leadership experiences on the Cleveland Clinic Beyond Leadership Podcast. SETTING/PARTICIPANTS: Twenty-one publicly available qualitative transcripts were examined inductively and deductively to assess how authentic leadership principles were applied to the experiences noted. PRINCIPAL FINDINGS: Deductively, the four leadership behaviours of authentic leadership (ie, relational transparency, internalised moral perspectives, balanced processing of information and self-awareness) were noted in the transcripts. Inductively, the participants also identified the importance of developing an organisational culture rooted in psychological safety which allowed individuals from all levels of the organisation to voice their ideas, concerns and thoughts. As part of a psychologically safe culture, it was also important to understand the influence of hierarchy in healthcare, ways to encourage employee voice and the uniqueness of leadership during crisis. PRACTICAL APPLICATIONS: We first offer insights about the importance of psychological safety, particularly during a crisis. Second, we offer a number of ways that other healthcare organisations might strive to build on their own approach to authentic leadership and develop an organisational culture built on psychological safety.

Influence of Killer Immunoglobulin-Like Receptors and Somatic Mutations on Transplant Outcomes in Acute Myeloid Leukemia.

Natural killer (NK) cells are regulated by killer immunoglobulin-like receptor (KIR) interactions with human leukocyte antigen class I ligands. Various models of NK cell alloreactivity have been associated with outcomes after allogeneic hematopoietic cell transplant (alloHCT), but results have varied widely. We hypothesized that somatic mutations in acute myeloid leukemia (AML) in the context of KIR profiles may further refine their association with transplant outcomes. In this single-center, retrospective, observational study, 81 AML patients who underwent matched-related donor alloHCT were included. Post-HCT outcomes were assessed based on mutational status and KIR profiles with the Kaplan-Meier method and log-rank test. On multivariable analysis those with any somatic mutations and C1/C2 heterozygosity had less acute graft-versus-host disease (GvHD) (hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.14-0.75; P = .009), more relapse (HR, 3.02; 95% CI, 1.30-7.01; P = .010), inferior relapse-free survival (RFS; HR, 2.22; 95% CI, 1.17-4.20; P = .014), and overall survival (OS; HR, 2.21; 95% CI, 1.17-4.20; P = .015), whereas those with a missing KIR ligand had superior RFS (HR, 0.53; 95% CI, 0.30-0.94; P = .031). The presence of a somatic mutation and donor haplotype A was also associated with less acute GvHD (HR, 0.38; 95% CI, 0.16-0.92; P = .032), more relapse (HR, 2.72; 95% CI, 1.13-6.52; P = .025), inferior RFS (HR, 2.11; 95% CI, 1.07-4.14; P = .030), and OS (HR, 2.20; 95% CI, 1.11-4.38; P = .024). Enhanced NK cell alloreactivity from more KIR activating signals (donor B haplotype) and fewer inhibitory signals (recipient missing KIR ligand or C1 or C2 homozygosity) may help mitigate the adverse prognosis associated with some AML somatic mutations. These results may have implications for improving patient risk stratification prior to transplant and optimizing donor selection.

Health-Related Quality-of-Life Comparison of Adult Related and Unrelated HSC Donors: An RDSafe Study.

Multiple investigations have documented the health-related quality-of-life (HRQoL) and donation-related experiences of unrelated donors (URDs), but similar investigations of the related donor (RD) experience have been less common. The central goal of this study was to longitudinally examine and compare HRQoL of RD and URD hematopoietic stem cell (HSC) donors from predonation through 1 year postdonation. This prospective investigation included adult HSC donors ages 18 to 60 years who donated bone marrow or peripheral blood stem cells at one of 48 geographically diverse US transplant/donor centers and completed HRQoL interviews at predonation and 4 weeks and 1 year postdonation. At predonation, related donors were less ambivalent about donation (t = -3.30; P = .001), more satisfied with their decision to donate (t = 2.65; P = .009), and more likely to define themselves as donors (t = 2.94; P = .004) than were URDs. However, related donors were more concerned about the use of needles (odds ratio [OR] = 2.19; P = .012), about who would pay for the procedure (OR = 2.80; P = .011), and the possibility that they would feel responsible if the transplant failed (t = 2.31; P = .022). Shortly postdonation, related donors were more likely to report donation-related pain (t = 2.50; P = .013) and lightheadedness (OR = 3.63; P = .028). At 1 year postdonation, related donors were less likely to be fully recovered from donation (OR = 0.10; P = .010) and more likely to report a longer recovery period following donation (t = 2.57; P = .011), although this latter finding was primarily due to the percentage of related versus unrelated donors not fully recovered at 1 year postdonation (10% versus 1%). Taken together, these findings suggest that current related donor management practices may be sufficient in preparing related donors for the psychological aspects of donation but that there may be more to do in terms of calibrating the description of donation-related experiences and recovery time to the related donor group (i.e., descriptions of donation experiences based on unrelated donation may not provide best estimates of experience for this group).

Genetic Counseling and Germline Testing in the Era of Tumor Sequencing: A Cohort Study.

BACKGROUND: The clinical impact of addressing potential germline alterations from tumor-only next-generation sequencing (NGS) is not well characterized. Current guidelines for cancer genetic testing may miss clinically actionable germline changes, which may have important implications for cancer screening, treatment, and prevention. We examined whether increasing involvement of the clinical genetics service during somatic tumor-only NGS review at Molecular Tumor Board (MTB) increases the detection of germline findings. METHODS: In a retrospective evaluation of patients who underwent tumor-only NGS and were reviewed at MTB, we quantified genetic counseling (GC) referrals as well as germline testing uptake and results across three cohorts: before (C1) and after (C2) the addition of tumor-only NGS review and after (C3) instituting a formal process to coordinate NGS-based genetics referrals to preexisting oncology appointments. All statistical tests were two-sided. RESULTS: From 2013 to 2017, 907 tumor-only NGS reports were reviewed at MTB (nC1 = 281, nC2 = 493, nC3 = 133); gastrointestinal (22.5%), lung (19.7%), genitourinary (14.8%), and breast (14.1%) were the most common index cancers. GC visits due to MTB increased with each successive cohort (C1 = 1.1%, C2 = 6.9%, C3 = 13.5%; P for trend [P trend] < .001), as did germline testing (C1 = 0.7%, C2 = 3.2%, C3 = 11.3%; P trend < .001). Diagnosis of germline pathogenic variants increased with each successive cohort (C1 = 1.4%, C2 = 2.0%, C3 = 7.5%; P trend = .003) and with germline pathogenic variants found by MTB review (C1 = 0.4%, C2 = 0.4%, C3 = 2.3%; P trend = .12). CONCLUSIONS: Both review of tumor-only NGS by genetics and the institution of a process coordinating GC with oncology appointments increased the discovery of germline pathogenic variants from tumor-only NGS testing. Furthermore, this process identified germline pathogenic variant carriers who would not have otherwise met standard criteria for germline testing.

Influence of major histocompatibility complex class I chain-related gene A polymorphisms on cytomegalovirus disease after allogeneic hematopoietic cell transplantation.

OBJECTIVE/BACKGROUND: Cytomegalovirus (CMV) infection and disease are common infectious complications after allogeneic hematopoietic cell transplantation (alloHCT). Major histocompatibility complex (MHC) class I chain-related gene A (MICA) is a ligand of the natural killer (NKG2D) receptor on immune effector cells that helps mediate NK cell alloreactivity. We hypothesized that MICA polymorphisms may influence CMV infection and disease incidence after alloHCT. METHODS: We conducted a retrospective analysis of 423 adults at the Cleveland Clinic with hematologic malignancies treated with a matched related or unrelated donor alloHCT. CMV cases analyzed included a compositive of instances of viral copy replication above detection limits as well as any biopsy-proven tissue invasive disease episodes. Genotypes at the MICA-129 position have been categorized as weak (valine/valine; V/V), intermediate (methionine/valine; M/V), or strong (methionine/methionine; M/M) receptor affinity. RESULTS: In multivariable analysis, V/V donor MICA-129 genotype was associated with CMV infection and disease (hazard ratio [HR] = 1.40; 95% confidence interval [CI], 1.00-1.96; p = .05), but not MICA mismatch (HR = 1.38; 95% CI, 0.83-2.29; p = .22). There was no association of acute or chronic GVHD with MICA donor-recipient mismatch (HR = 1.05; 95% 95% CI, 0.66-1.68; p = .83 and HR = 0.94; 95% CI, 0.51-1.76; p = .85, respectively) or V/V donor MICA-129 genotypes (HR = 1.02; 95% CI, 0.79-1.31; p = .89 and HR = 0.89; 95% CI, 0.65-1.22; p = .47, respectively). CONCLUSION: These findings suggest that the donor MICA-129 V/V genotype with weak NKG2D receptor binding affinity is associated with an increased risk of CMV infection and disease after alloHCT.

Therapeutic Dose Monitoring of Busulfan Is Associated with Reduced Risk of Relapse in Non-Hodgkin Lymphoma Patients Undergoing Autologous Stem Cell Transplantation.

Optimal administration of busulfan (Bu) is hampered by variable and unpredictable drug metabolism in individual patients. At our institution, Bu was previously administered with fixed weight-based dosing (WBD) in combination with cyclophosphamide (Cy) and etoposide (E) for patients with non-Hodgkin lymphoma (NHL) undergoing autologous stem cell transplantation (ASCT). In 2014, we adopted real-time pharmacokinetic (PK)-guided therapeutic drug monitoring (TDM) of Bu for all NHL patients undergoing Bu-containing ASCT. Here we compare outcomes of NHL patients who underwent ASCT with Bu/Cy/E using WBD and those who did so using TDM of Bu. We studied 336 consecutive adult NHL patients who underwent ASCT with Bu/Cy/E using WBD from January 2007 to December 2013 (n = 258) or TDM from May 2014 to December 2017 (n = 78), excluding patients with mantle cell lymphoma. Clinical outcomes, including relapse, nonrelapse mortality (NRM), progression-free survival (PFS), and overall survival (OS), hepatotoxicity and pulmonary toxicity were compared in the 2 groups. To adjust for differences in baseline characteristics between the groups, propensity-matched cohorts of WBD and TDM patients were also studied. After the first dose of Bu, the dose was increased in 36% of the patients and decreased in 41%. Changes in pulmonary and liver function from baseline to transplantation were not different between the 2 groups, although these changes showed significantly less variability with TDM than with WBD. Relapse was significantly lower and PFS was improved with TDM; 2-year estimates were 19% for TDM and 38% for WBD for relapse (P = .004) and 69% and 55%, respectively, for PFS (P = .038). No significant between-group differences in NRM or OS were seen. In multivariable analysis, TDM remained prognostic for lower risk of relapse (hazard ratio [HR], .52; 95% confidence interval [CI], .30 to .89; P = .018), but did not remain prognostic for PFS (HR, .74; 95% CI, .48 to 1.16; P = .19). Propensity-matched cohorts displayed similar patterns of outcomes. In subset analysis based on disease status at ASCT, TDM was associated with less relapse and better PFS than WBD for patients who underwent transplantation in less than complete remission (CR) compared with those who underwent transplantation in CR. Compared with WBD, PK-directed TDM of Bu reduces the incidence of relapse when used in combination with Cy and E for patients with NHL undergoing ASCT, particularly for patients in less than CR. These data support the continued use of personalized PK-guided dosing for all NHL patients undergoing ASCT with Bu-containing preparative regimens.

Comparative effectiveness of busulfan/cyclophosphamide versus busulfan/fludarabine myeloablative conditioning for allogeneic hematopoietic cell transplantation in acute myeloid leukemia and myelodysplastic syndrome.

OBJECTIVE/BACKGROUND: Busulfan/cyclophosphamide (Bu/Cy) and busulfan/fludarabine (Bu/Flu) are both standard myeloablative conditioning (MAC) regimens for allogeneic hematopoietic cell transplantation (alloHCT). We compared the effectiveness of these regimens with a focus on quality of life (QOL). METHODS: This was a single center, retrospective analysis of adult acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients who underwent a first T-cell replete HLA-8/8 matched related or unrelated donor alloHCT. Patients received a myeloablative regimen of either parenteral Bu/Cy or Bu/Flu. Outcomes assessed included infections, graft-versus-host-disease (GVHD), relapse, relapse mortality (RM), relapse-free survival (RFS), nonrelapse mortality (NRM), overall survival (OS), and QOL. RESULTS: From 2008 to 2017, 126 AML and 84 MDS adult patients age ≥18 years were identified meeting inclusion criteria. In terms of QOL, there were no significant differences between Bu/Cy and Bu/Flu cohorts in the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT) scores or mucositis severity for either AML or MDS patients. Amongst AML patients, those receiving Bu/Flu had more rapid neutrophil and platelet recovery and a shorter length of hospital stay (LOS); there were no differences in the other posttransplant outcomes. Similarly, amongst MDS patients, those receiving Bu/Flu had more rapid platelet recovery and a shorter LOS as well as more CMV infections, but less NRM and no differences in other outcomes. CONCLUSION: We confirmed that myeloablative Bu/Flu conditioning has comparable clinical and QOL outcomes to Bu/Cy.

Conditional Long-Term Survival after Autologous Hematopoietic Cell Transplantation for Diffuse Large B Cell Lymphoma.

Autologous hematopoietic cell transplantation (AHCT) is standard therapy for patients with chemosensitive, relapsed, diffuse large B cell lymphoma (DLBCL). We performed a retrospective cohort study to delineate subsequent (conditional) and relative survival in 371 adult patients with DLBCL who underwent AHCT between 2000 and 2014 and had survived for 1, 2, 3, or 5 years after transplant. The probability of overall survival at 10 years after AHCT was 62%, 71%, 77%, and 86%, respectively, for the 4 cohorts, whereas that of progression-free survival (PFS) was 55%, 65%, 72%, and 81%, respectively. The respective cumulative incidence of nonrelapse mortality (NRM) at 10 years after transplantation was 13%, 12%, 11%, and 8%, respectively. In multivariable analysis, older age was associated with greater mortality risk among all but 5-year survivors; relapse within the landmark time was associated with greater mortality risk in all groups. Older age and relapse within the landmark time were associated with worse PFS in all groups. Standardized mortality ratio (SMR) was significantly higher than an age-, gender-, and race-matched general population, with the magnitude of SMR decreasing as the landmark time increased (4.0 for 1-year, 3.0 for 2-year, 2.4 for 3-year, and 1.8 for 5-year survivors). Our study provides information on long-term survival and prognosis that will assist in counseling patients with DLBCL who have received AHCT. Survival improves with longer time in remission post-transplant, although patients continue to remain at risk for NRM, underscoring the need for continued vigilance and prevention of late complications.

Correction: Time to initial cancer treatment in the United States and association with survival over time: An observational study.

[This corrects the article DOI: 10.1371/journal.pone.0213209.].

Clinical Factors Associated With Cost in Head and Neck Cancer: Implications for a Bundled Payment Model.

PURPOSE: To determine which factors influence cost in head and neck cancer (HNC) to inform the development of a bundled payment model (BPM). METHODS: Patients with stages 0 to IVB (by American Joint Commission on Cancer, 7th edition) HNC of various sites and histology treated definitively at a single tertiary care center during 2013 were included. Clinical variables and direct cost data were obtained, and their associations were investigated using χ2, t, Wilcoxon rank sum, and analysis of variance testing. Results were used to develop a BPM. RESULTS: One hundred fifty patients were included; 87% were white, 74% were men, 48% had oropharyngeal cancer, and 58% had stage IVA disease. Treatment consisted of surgery alone (17%), radiation alone (11%), surgery plus radiation (14%), chemoradiation (45%), and surgery plus chemoradiation (13%). On multivariable analysis, both increasing group stage and number of treatment modalities used were significantly associated with higher cost. Given that stage often dictates treatment, we developed three cost tiers that were based on overall treatment modality. Tier A, the least costly, consisted of single-modality therapy with either surgery alone or radiation alone (median cost divided by the median overall cost of treatment, 0.54; 25th to 75th percentile range, 0.29 to 1.02), followed by tier B, which consisted of bimodality therapy with either chemoradiation or surgery plus radiation (1.03; range, 0.81 to 1.35), followed by tier C, which consisted of trimodality therapy with surgery plus chemoradiation (1.43; range, 1.10 to 1.96). CONCLUSION: The number of treatment modalities required is the primary driver of cost in HNC. These data can simplify development of a comprehensive HNC BPM.

Time to initial cancer treatment in the United States and association with survival over time: An observational study.

BACKGROUND: Delays in time to treatment initiation (TTI) for new cancer diagnoses cause patient distress and may adversely affect outcomes. We investigated trends in TTI for common solid tumors treated with curative intent, determinants of increased TTI and association with overall survival. METHODS AND FINDINGS: We utilized prospective data from the National Cancer Database for newly diagnosed United States patients with early-stage breast, prostate, lung, colorectal, renal and pancreas cancers from 2004-13. TTI was defined as days from diagnosis to first treatment (surgery, systemic or radiation therapy). Negative binomial regression and Cox proportional hazard models were used for analysis. The study population of 3,672,561 patients included breast (N = 1,368,024), prostate (N = 944,246), colorectal (N = 662,094), non-small cell lung (N = 363,863), renal (N = 262,915) and pancreas (N = 71,419) cancers. Median TTI increased from 21 to 29 days (P<0.001). Aside from year of diagnosis, determinants of increased TTI included care at academic center, race, education, prior history of cancer, transfer of facility, comorbidities and age. Increased TTI was associated with worsened survival for stages I and II breast, lung, renal and pancreas cancers, and stage I colorectal cancers, with hazard ratios ranging from 1.005 (95% confidence intervals [CI] 1.002-1.008) to 1.030 (95% CI 1.025-1.035) per week of increased TTI. CONCLUSIONS: TTI has lengthened significantly and is associated with absolute increased risk of mortality ranging from 1.2-3.2% per week in curative settings such as early-stage breast, lung, renal and pancreas cancers. Studies of interventions to ease navigation and reduce barriers are warranted to diminish potential harm to patients.

BEAM or BUCYVP16-conditioning regimen for autologous stem-cell transplantation in non-Hodgkin's lymphomas.

High-dose chemotherapy followed by autologous hematopoietic cell transplantation (AHCT) is an effective salvage therapy for patients with relapsed chemosensitive non-Hodgkin's lymphoma (NHL). However, the optimal conditioning regimen is unclear. Different conditioning regimens prior to AHCT have been used with the two most common being BEAM (carmustine, etoposide, cytarabine, and melphalan) and BUCYVP16 (busulfan, cyclophosphamide, and etoposide). We sought to compare the two regimens for patients with relapsed NHL undergoing AHCT. We retrospectively compared the outcomes of patients treated with BEAM (N = 269) at The Ohio State University and BUCYVP16 (N = 409) at the Cleveland Clinic followed by AHCT between 2006 and 2014. The primary endpoints were progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR). Patient characteristics between the two groups were similar. After a median follow-up of 3.9 years for BEAM and 4.3 years for BUCYVP16 from AHCT, the rate of relapse (p = 0.69), PFS (p = 0.52), and OS (p = 0.11) were similar between the two conditioning regimens. No differences in survival outcomes were seen in disease subtypes. Multivariable analysis showed significant association toward improved OS with BEAM (HR: 1.56, 95% CI 1.16-2.10) (p < 0.01). Even though the study is limited by its retrospective nature and some differences in cohort, the findings indicate that BEAM could serve as an alternative conditioning regimen prior to AHCT for NHL.

BEAM versus BUCYVP16 Conditioning before Autologous Hematopoietic Stem Cell Transplant in Patients with Hodgkin Lymphoma.

High-dose chemotherapy followed by autologous hematopoietic stem cell transplant (AHSCT) is a standard of care for patients with relapsed Hodgkin lymphoma. Different conditioning regimens before AHSCT have been used, with the 2 most common being BEAM (carmustine, etoposide, cytarabine, and melphalan) and BUCYVP16 (busulfan, cyclophosphamide, and etoposide). We retrospectively compared the outcomes of patients treated with BEAM (n = 128) or BUCYVP16 (n = 105) followed by AHSCT. After a median follow-up of 4.2 years for BEAM and 3.8 for BUCYVP16 from AHSCT, the 5-year cumulative incidence of relapse was 29% with BEAM compared with 56% with BUCYVP16 (P < .001). Median progression free survival (PFS) and overall survival (OS) were not reached with BEAM and were 2.0 and 7.8 years with BUCYVP16, respectively. Improved PFS (P < .001) and OS (P = .001) were observed with BEAM for patients who needed transplant within 24 months from diagnosis and for patients not in complete remission (non-CR; P = .001 and P < .001, respectively) at AHSCT. In this large retrospective comparison the use of BEAM conditioning before AHSCT resulted in a statistically significant improved PFS and OS and lower relapse compared with BUCYVP16. This supports the use of BEAM as a frontline conditioning regimen before AHSCT for early relapsed and non-CR Hodgkin lymphoma.

Higher Risks of Toxicity and Incomplete Recovery in 13- to 17-Year-Old Females after Marrow Donation: RDSafe Peds Results.

Although donation of bone marrow (BM) or peripheral blood stem cells (PBSCs) from children to family members undergoing allogeneic transplantation are well-established procedures, studies detailing levels of pain, symptoms, and long-term recovery are lacking. To address this lack, we prospectively enrolled 294 donors age <18 years at 25 pediatric transplantation centers in North America, assessing them predonation, peridonation, and at 1 month, 6 months, and 1 year postdonation. We noted that 71% of children reported pain and 59% reported other symptoms peridonation, with resolution to 14% and 12% at 1 month postdonation. Both older age (age 13 to 17 years versus younger) and female sex were associated with higher levels of pain peridonation, with the highest rates in older females (57% with grade 2-4 pain and 17% with grade 3-4 pain). Multivariate analyses showed a 4-fold increase in risk for older females compared with males age <13 years (P <.001). At 1 year, 11% of 13- to 17-year-old females reported grade 2-4 pain, compared with 3% of males age 13 to 17 years, 0% of females age <13 years, and 1% of males age <13 years (P = .01). Males and females age 13 to 17 years failed to return to predonation pain levels at 1 year 22% and 23% of the time, respectively, compared with 3% and 10% in males and females age <13 years (P = .002). Our data show that females age 13 to 17 years are at increased risk of grade 2-4 pain at 1 year and >20% of females and males age 13 to 17 years do not return to baseline pain levels by 1 year after BM donation. Studies aimed at decreasing symptoms and improving recovery in older children are warranted.

Related peripheral blood stem cell donors experience more severe symptoms and less complete recovery at one year compared to unrelated donors.

Unlike unrelated donor registries, transplant centers lack uniform approaches to related donor assessment and deferral. To test whether related donors are at increased risk for donation-related toxicities, we conducted a prospective observational trial of 11,942 related and unrelated donors aged 18-60 years. Bone marrow (BM) was collected at 37 transplant and 78 National Marrow Donor Program centers, and peripheral blood stem cells (PBSC) were collected at 42 transplant and 87 unrelated donor centers in North America. Possible presence of medical comorbidities was verified prior to donation, and standardized pain and toxicity measures were assessed pre-donation, peri-donation, and one year following. Multivariate analyses showed similar experiences for BM collection in related and unrelated donors; however, related stem cell donors had increased risk of moderate [odds ratios (ORs) 1.42; P<0.001] and severe (OR 8.91; P<0.001) pain and toxicities (OR 1.84; P<0.001) with collection. Related stem cell donors were at increased risk of persistent toxicities (OR 1.56; P=0.021) and non-recovery from pain (OR 1.42; P=0.001) at one year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43; P<0.001) and non-recovery from toxicities (OR 3.71; P<0.001) at one year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43; P<0.001) and non-recovery from toxicities (OR 3.71; P<0.001) at one year. Related donors reporting grade ≥2 pain had significant decreases in Health-Related Quality of Life (HR-QoL) scores at one month and one year post donation (P=0.004). In conclusion, related PBSC donors with comorbidities are at increased risk for pain, toxicity, and non-recovery at one year after donation. Risk profiles described in this study should be used for donor education, planning studies to improve the related donor experience, and decisions regarding donor deferral. Registered at clinicaltrials.gov identifier:00948636.

Effect of Aging and Predonation Comorbidities on the Related Peripheral Blood Stem Cell Donor Experience: Report from the Related Donor Safety Study.

The development of reduced-intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RDs) of peripheral blood stem cells (PBSCs). The effects of age on donation efficacy, toxicity, and long-term recovery in RDs are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms, and recovery in 1211 PBSC RDs aged 18 to 79 enrolled in the Related Donor Safety Study. RDs aged > 60 had a lower median CD34+ level before apheresis compared with younger RDs (age > 60, 59 × 106/L; age 41 to 60, 81 × 106/L; age 18 to 40, 121 × 106/L; P < .001). This resulted in older donors undergoing more apheresis procedures (49% versus 30% ≥ 2 collections, P < .001) and higher collection volumes (52% versus 32% > 24 L, P < .001), leading to high percentages of donors aged > 60 with postcollection thrombocytopenia <50 × 109/L (26% and 57% after 2 and 3days of collection, respectively). RDs aged 18 to 40 had a higher risk of grades 2 to 4 pain and symptoms pericollection, but donors over age 40 had more persistent pain at 1, 6, and 12 months (odds ratio [OR], 1.7; P = 0.02) and a higher rate of nonrecovery to predonation levels (OR, 1.7; P = .01). Donors reporting comorbidities increased significantly with age, and those with comorbidities that would have led to deferral by National Marrow Donor Program unrelated donor standards had an increased risk for persistent grades 2 to 4 pain (OR, 2.41; P < .001) and failure to recover to predonation baseline for other symptoms (OR, 2.34; P = .004). This information should be used in counseling RDs regarding risk and can assist in developing practice approaches aimed at improving the RD experience for high-risk individuals.

Effect of bone marrow CD34+cells and T-cell subsets on clinical outcomes after myeloablative allogeneic hematopoietic cell transplantation.

Donor-derived T-cells mediate graft-versus-leukemia effect, immune reconstitution, and graft-versus-host-disease (GvHD) after allogeneic hematopoietic cell transplantation (HCT). We examined the association of donor cell subsets with outcomes in recipients of myeloablative allogeneic HCT using bone marrow (BM, N = 359) grafts from 2002 to 2014 with related or unrelated donors. Analysis considered pre-infusion graft total nucleated cell (TNC), CD34+ CD3+, CD4+, CD8+ doses. Most patients received busulfan-cyclophosphamide or etoposide-total body irradiation conditioning for acute leukemia or myelodysplastic syndrome. Calcineurin inhibitor-mycophenolate mofetil (CNI-MMF) (49%) or calcineurin inhibitor-methotrexate (CNI-MTX) (47%) were used for GvHD prophylaxis. In multivariable analysis, higher CD34+ dose was associated with platelet engraftment (P < 0.001) and lymphocyte recovery (P = 0.006). There was no association of donor cell subsets with donor chimerism or overall survival. In conclusion, BM graft composition is associated with myeloablative allogeneic HCT outcomes and future studies to evaluate optimal graft composition are needed.