post-HCT Period Research Articles

Pulmonary function as a continuum of risk: critical care utilization and survival after allogeneic hematopoietic stem cell transplantation - a multicenter cohort study.

Abnormal pre-transplant pulmonary function tests (PFTs) are associated with reduced survival after allogeneic HCT. Existing scoring systems consider risk dichotomously, attributing risk only to those with abnormal lung function. In a multicenter cohort of 1717 allo-HCT recipients, we examined the association between pre-transplant PFT measures and need for ICU admission (120d), frequency of mechanical ventilation (120d) and overall survival (5 y). Predictive models were developed and validated using Cox proportional hazards, incorporating age, FEV1 (forced expiratory volume in 1-second) and diffusing capacity (DLCO). In univariate analysis, hazard ratios for each outcome (95% CI) were: mechanical ventilation (FEV1: 0.60 [0.52-0.69], DLCO: 0.69 [0.61-0.77], p < 0.001), ICU admission (FEV1: 0.74 [0.67-0.82], DLCO: 0.79 [0.72-0.86], p < 0.001) and overall survival (FEV1: HR 0.87 [0.81-0.94], DLCO: 0.83 [0.77-0.89], p < 0.001). A multivariable Cox model was developed and compared to the HCT-CI Pulmonary score in a validation cohort. This model was better at predicting need for ICU admission and mechanical ventilation, while both models predicted overall survival (p < 0.001). In conclusion, the risk conferred by pre-transplant pulmonary function should be considered in a continuous rather than dichotomous manner. A more granular prognostication system can better inform risk of critical care utilization in the early post-HCT period.

Randomized controlled trial of pre-transplant zoledronate versus observation for prevention of bone loss in allogeneic hematopoietic cell transplantation.

Approximately half of allogeneic hematopoietic cell transplantation (HCT) recipients experience significant bone loss in the early post-HCT period. Only recently have international guidelines started recommending early screening. However, the guidance for intervention remains conservative. In this study, we sought to evaluate the efficacy of pre-transplant prophylactic zoledronate in preventing early bone loss in allogeneic HCT recipients. This was an open-label, investigator-initiated, phase 2 randomized controlled trial (RCT) of prophylactic zoledronate versus observation to prevent bone loss in allogeneic HCT recipients. Recipients aged ≥ 18 years of age were included after informed consent and randomized to prophylactic zoledronate 4 mg pre-HCT or observation in a 1:1 ratio. The primary outcome of the study was bone mineral density (BMD) loss at the femoral neck (FN), total hip (TH), and lumbar spine (LS), as assessed using dual-energy X-ray absorptiometry (DXA) on day+100 post-HCT. The secondary outcomes included BMD loss on day+365 and Z scores on day+100 and day+365 at the FN, TH, and LS sites. The trial was terminated because the interim analysis showed a significant benefit in the intervention arm, with 50% planned recruitment. A total of 40 patients were randomized to the zoledronate and control arms. Both arms were matched for age, sex, diagnosis, pre-HCT steroid exposure, body mass index, human leukocyte antigen (HLA) match, and conditioning intensity. The grade 2-4 acute graft versus host disease (GVHD) incidences were comparable. The primary endpoint of BMD loss at FN and TH at day+100 was significant (5.62% vs. -6.78%, p = 0.009, -1.59 vs. -3.98, p = 0.016, respectively). There was no difference in the secondary endpoint of BMD loss on day+365 compared to that on day+100 or baseline at any BMD site. There was no difference in the Z-scores at any site on day+100 or day+365. Prophylactic zoledronate prevented early bone loss on day+100. The indicated preemptive zoledronate beyond day+100 in recipients prevented further bone loss. Patients receiving prophylactic zoledronate may benefit from a supplementary dose of the indicated preemptive zoledronate.

Effect of cytomegalovirus infection on post-transplant hospitalization days among children undergoing allogeneic hematopoietic cell transplantation: A marginal structural model approach.

Cytomegalovirus (CMV) commonly reactivates after allogeneic hematopoietic cell transplant (HCT), potentially leading to CMV disease and significant morbidity and mortality. To reduce morbidity and mortality, many centers conduct weekly CMV blood polymerase chain reaction (PCR) surveillance testing with subsequent initiation of antiviral therapy upon CMV DNAemia detection. However, the impact of CMV DNAemia on subsequent hospitalization risk has not been assessed using models accounting for the time-varying nature of the exposure, outcome, and confounders. All allogeneic HCTs at the Children's Hospital of Philadelphia from January 2004-April 2017 were considered for inclusion. Patients were monitored with CMV surveillance via PCR testing for up to 105 days after HCT receipt. We estimated the association between CMV DNAemia and rate of hospitalization using marginal structural models (MSM). There were 343 allogeneic HCT episodes in 330 with CMV surveillance; median age was 9.0 (range: 0.1-26.2) and 46.5% were female. And 24.1% of HCT patients had at least one positive CMV blood PCR during the follow-up period. Median time to CMV DNAemia detection was 19 days (range: 4-97). The MSM estimated the incidence rate ratios for an association of CMV DNAemia with hospitalization to be 1.24, (95% confidence interval: 1.04-1.47). CMV DNAemia was associated with an increased hospitalization in the post-HCT period. The MSM accounted for time-varying nature of the outcome, exposure and confounders. The findings support prevention of CMV DNAemia in this population. We recommend further investigation into the effectiveness and safety of prophylaxis versus pre-emptive CMV prevention approaches.

Economic Burden of Hematopoietic Cell Transplantation (HCT) Among Commercially Insured Patients with Hematological Malignancies in the United States (US)

INTRODUCTION: HCT is a potentially curative treatment option for high-risk hematologic malignancies. Approximately 20,000 HCTs are performed in the US annually. A wide range of costs for both autologous HCT (auto-HCT) and allogeneic HCT (allo-HCT) are reported. For commercially insured patients with hematologic malignancies, the economic burden of an auto-HCT was estimated at $390,159 and allo-HCT at $745,341 in 2011-2014 over a 6-month pre- and 12-month post-HCT period (Bonafede 2017), indirect and caregiver costs may further increase burden (Applebaum 2017; Denzen 2017). We characterize all-cause healthcare resource utilization (HRU) and costs among commercially insured patients with hematologic malignancies who received an auto- or allo-HCT in a more contemporary era. METHODS: Adults with hematologic malignancies and ≥1 inpatient admission for an auto- or allo-HCT (Jan 2015-Mar 2020) were identified from the MarketScan Commercial and Medicare Supplemental Databases. Patients were indexed on the date of first HCT inpatient admission. Included patients had 12 months of continuous enrollment before and after the index date and ≥2 medical claims with a diagnosis code for an eligible hematologic malignancy (acute myeloid leukemia, myelodysplastic syndrome, myelofibrosis, myeloproliferative disease, acute lymphoblastic leukemia, chronic myeloid leukemia, multiple myeloma, Hodgkin disease, or lymphoma) with ≥1 claim occurring on or before the index date. Patients with an HCT prior to the index date were excluded. Controls were selected from patients meeting study criteria with the exception of an HCT claim requirement. The index date for patients in the control group was randomly assigned based on the time between diagnosis and HCT for the HCT cohorts. Controls and HCT recipients were matched 3:1 based on age, sex, insurance type, Deyo-Charlson Comorbidity Index categories, and hematologic malignancy. Total all-cause HRU and inpatient, outpatient (ie, ED [emergency department], physician office, other visits), and pharmacy costs were compared between the HCT cohorts and controls over the 6-month pre- and 12-month post-index periods. Healthcare costs (2021 US$) were based on paid amounts of adjudicated claims, including insurer/health plan payments and patient cost-sharing (copayment, deductible, and coinsurance). RESULTS: A total of 1653 auto-HCT recipients were matched to 4959 controls and 411 allo-HCT recipients matched to 1233 controls. After matching, HCT cohorts and controls were similar in age, sex, insurance type (Table 1), Deyo-Charlson Comorbidity Index categories, and hematologic malignancy. Pre-index comorbidities differed among the HCT and control cohorts, with psychiatric disturbances, infections, and heart valve disease significantly more common in both the auto- and allo-HCT recipients vs matched controls (P<0.001 for all). Multiple myeloma was the most common eligible indication for auto-HCT whereas acute myeloid leukemia/myelodysplastic syndrome/myelofibrosis/myeloproliferative disease were the most common indications for allo-HCT. Over the 18-month observation period, total all-cause costs were significantly higher for auto-HCT recipients vs matched controls ($540,194 vs $182,846; P<0.001; Figure 1), with auto-HCT recipients having significantly higher costs than controls for all categories evaluated except ED visits during the post-index period ($817 vs $879; P<0.4). Auto-HCT costs were driven by inpatient and outpatient costs. For allo-HCT recipients vs matched controls, total all-cause costs were significantly higher ($929,799 vs $190,776; P<0.001) during the 18-month observation period, with allo-HCT recipients having significantly higher costs than controls for all categories evaluated except ED visits during the pre- and post-index periods ($568 vs $533; P=0.11, $824 vs $862; P>0.9). Inpatient costs were the primary cost driver for allo-HCT recipients. CONCLUSIONS: The use of HCT, a potentially curative treatment for some patients with hematologic malignancies, is associated with considerable HRU and economic burden. This analysis did not include indirect costs, caregiver burden, or donor costs, and therefore likely underestimates the true burden of HCT for patients with hematologic malignancies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prospective Evaluation of the Fungitell® (1→3) Beta-D-Glucan Assay as a Diagnostic Tool for Invasive Fungal Disease in Pediatric Allogeneic Hematopoietic Cell Transplantation: AReport from the Children's Oncology Group.

Invasive fungal disease (IFD) is a major source of morbidity and mortality for hematopoietic cell transplant (HCT) recipients. Non-invasive biomarkers, such as the beta-D-glucan assay, may improve the diagnosis of IFD. The objective was to define the utility of surveillance testing using Fungitell® beta-D-glucan (BDG) assay in children receiving antifungal prophylaxis in the immediate post-HCT period. Weekly surveillance blood testing with the Fungitell® BDG assay was performed during the early post-HCT period in the context of a randomized trial of children, adolescents, and young adults undergoing allogeneic HCT allocated to triazole or caspofungin prophylaxis. Positivity was defined at the manufacturer cutoff of 80 pg/ml. IFD was adjudicated using blinded central reviewers. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the Fungitell® BDG assay for the outcome of proven or probable IFD. A total of 51 patients (out of 290 patients in the parent trial) contributed blood specimens. In total, 278 specimens were evaluated. Specificity was 80.8% (95% confidence interval [CI]: 75.6%-85.3%), and NPV was over 99% (95% CI: 86.8%-99.9%). However, there were no true positive results, resulting in sensitivity of 0% (95% CI: 0.0%-84.2%) and PPV of 0% (95% CI: 0.0%-6.7%). Fungitell® BDG screening is of limited utility in diagnosing IFD in the post-HCT period, mainly due to high false-positive rates. Fungitell® BDG surveillance testing should not be performed in children during the early post-HCT period while receiving antifungal prophylaxis as the pretest probability for IFD is low.

Patient-Reported Sleep Quality at Baseline Correlates with 1-Year Survival after Allogeneic Hematopoietic Cell Transplantation in Adults

Background: While allogeneic hematopoietic cell transplantation (alloHCT) offers a potential cure to many patients with serious blood disorders, the process remains physically and psychologically arduous. Sleep dysfunction is nearly universal in the early post-HCT period and can lead to impaired quality of life, depression, fatigue and inflammation. Sleep dysfunction may adversely impact alloHCT outcomes through increased pro-inflammatory pathways as shown to be associated in other populations, and lead to adverse post-alloHCT outcomes. We hypothesized that patient-reported sleep dysfunction at baseline would correlate with post-alloHCT outcomes.Material and Methods: From 2011 to 2013, the Center for International Blood and Marrow Transplant Research prospectively enrolled 390 patients from 7 transplant centers to assess the feasibility of collecting patient-reported outcomes. Patients completed the SF-36 and FACT-BMT surveys at pre-HCT, day 100, 6 months and 1 year. Sociodemographic information, disease- and transplant-specific data were routinely collected. In this study, we focus on responses to the sleep-specific question from FACT-BMT in a subset of adult patients (n=198) who underwent alloHCT for acute leukemia, myelodysplastic syndrome and myeloproliferative neoplasms. Descriptive statistics were used to summarize the patient sample and survival analysis was conducted using the Kaplan-Meier estimator. A significance level of 0.05 was used, and all tests are two-sided. The sleep question in FACT-BMT is a single validated question “I am sleeping well” with 5 answers (0- not at all, 1- a little bit, 2- somewhat, 3- quite a bit, 4- very much). We analyzed 0/1/2 as “poor sleep” and 3/4 as “good sleep” groups.Results: Table 1 shows the baseline characteristics of the cohort. Patients aged <55 years, Karnofsky Performance Score (KPS) <90, and annual household income < $60,000 were more likely to have baseline poor sleep. Median follow-up of survivors was similar between the two groups and all survivors (N=131) had at least 12 months of follow up. The 1-year overall survival was 66 (59-73)%. Baseline “good sleep” in patients <55 years correlated with superior survival at 100 days, 6 months and 1 year compared to “poor sleep” <55 years (p<0.001) (Table 2). Baseline sleep did not correlate with survival in the ≥55 age group in unadjusted analysis (Figure).Conclusions: Nearly 46% of adults undergoing alloHCT have self-reported poor sleep at pre-transplant baseline. Baseline sleep correlated with 1-year survival in patients under 55 years but not in those over 55 years of age. These intriguing results suggest further research to study potential etiologies of pre-transplant sleep dysfunction, especially in relation to pro-inflammatory pathways. Given the prevalence of sleep dysfunction, interventions to improve sleep should also be tested. [Display omitted] DisclosuresD'Souza:Merck: Research Funding; Prothena: Research Funding; Celgene: Consultancy. Lee:Bristol-Myers-Squibb: Other: One-time advisory board member; Amgen: Other: One-time advisory board member; Mallinckrodt: Honoraria; Kadmon: Other: One-time advisory board member.

How we can mitigate the side effects associated with systemic glucocorticoid after allogeneic hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for patients with a hematologic disease. Although the clinical outcomes after allo-HCT have significantly improved during the last few decades, graft-versus-host disease (GVHD) is still a major cause of post-HCT morbidity and mortality. Systemic glucocorticoids (GC) remain an integral part of treatment in patients with GVHD including both acute and chronic GVHD. Although it is well-known that usage of systemic GC is associated with various side effects, the short- and long-term effects of GCs in the HCT setting are not well-characterized due to limited published data. In order to clarify this issue, we summarize the information on side effects associated with GCs, focusing specifically on the sequelae of these agents in the early post-HCT period. In instances where limited data are available, we included data from other fields such as autoimmune diseases, given the potential parallels between autoimmune conditions and GVHD.

1077. Infectious complications after second allogeneic hematopoietic cell transplant (allo-HCT) in adult patients with hematological malignancies

BackgroundA 2nd allo-HCT is received by some adults after relapse of their underlying malignancy, development of a second malignancy, or graft failure. Few studies have reported on infectious complications in adults given a 2nd HCTMethodsThis is a retrospective review of infectious complications and overall mortality of 60 adult patients who received a 2nd HCT from Jan. 2010 - Dec. 2015. Data were collected for 2 years post-HCT for each patient. Infections were separated into < 30 days (d) post-HCT, 30-100d post-HCT, and >100d post-HCT.ResultsMean age at 2nd HCT was 49+13; 60% were men. The most common reason for the 1st HCT was acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (73%,n= 44) The 2nd HCT was for relapse of original malignancy (62%,n=37), graft failure (27%,n=16), and new malignancy (10%,n=6). The 2nd HCT was received a median of 344d (range 29-8248) after 1st HCT. Neutrophil engraftment occurred by 13+4d in 50/60 patients.Fifty-eight patients (97%) had at least one infection during the study period. A total of 183 infections were reported: 75 (41%) were < 30d, 56 (31%) 30-100d, and 52 (28%) >100d post-HCT. Bacterial infections, primarily C. difficile, vancomycin-resistant Enterococcus, and coagulase (-) Staphylococcus caused 90 (49%) infections and were seen throughout the post-HCT period. Viral infections, predominantly CMV and BK virus, caused 60 (33%) of infections, peaking at 30-100d post-HCT. Only 19 (10%) infections were fungal, most of which were mold infections and occurred >30d post-HCT.Thirty-nine (65%) patients died by 2 years post-HCT, 27 within the first year. Cause of death was infection in 16 (41%), graft failure, relapse, or GVHD in 16 (41%), other in 7 (18%). At < 30d post-HCT, 5 deaths (71%) were from infection 4 of which were bacterial. At 30-100d post-HCT, 6/9 (69%) deaths were from relapse/graft failure/GVHD. All 6 deaths from fungal infections were >100d post-HCT. Bacterial Infections and engraftment failure within 100d post-HCT were associated with increased mortality (p .05 and < .001, respectively).ConclusionAll but 2 patients receiving a 2nd allo-HCT developed an infection. Most deaths at < 30d post-HCT were from infection. Overall 2-year mortality was 65% and 41% of deaths were related to infection.DisclosuresMarisa H. Miceli, MD, FIDSA, SCYNEXIS, Inc. (Advisor or Review Panel member)

Immune Reconstitution Following TCRαβ/CD19-Depleted Hematopoietic Cell Transplantation for Hematologic Malignancy in Pediatric Patients

TCRαβ/CD19-depleted HCT has been used with excellent outcomes in pediatric patients with hematologic malignancies, and several studies have demonstrated rapid immune reconstitution in the nonmalignant setting. However, immune recovery following TCRαβ/CD19-depleted hematopoietic cell transplantation (HCT) for malignancy remains incompletely elucidated. Furthermore, the majority of studies to date have used haploidentical and matched unrelated donors. Here we report results of immune reconstitution following TCRαβ/CD19-depleted HCT for hematologic malignancy in 51 pediatric patients with hematologic malignancies, the majority of whom received grafts from unrelated donors. Grafts were from matched unrelated (n = 20), mismatched unrelated (n = 20), and haploidentical (n = 11) donors. The median CD34+ cell dose was 10.2 × 106/kg (range, 4.54 to 20 × 106/kg), and the median TCRαβ+ cell dose was 2.53 × 104/kg (range, 0 to 44.9 × 104/kg). Conditioning was myeloablative with either busulfan or total body irradiation, cyclophosphamide, and thiotepa. Thirty-three patients also received rabbit antithymocyte globulin. No prophylactic post-transplantation immune suppression was routinely given. Forty-three patients received rituximab on day +1 for recipient positive Epstein-Barr virus serology.Forty-nine patients (96%) engrafted with a median time to neutrophil recovery of 13 days (range, 8 to 30 days). Thirty-seven patients (73%) are alive at a median follow-up of 25 months (range, 6 to 50 months). Nine patients (18%) developed grade II-IV acute graft-versus-host disease (GVHD), and 5 patients (11%) developed extensive chronic GVHD. Twenty-six patients (51%) experienced viral reactivation. T cell reconstitution was rapid with significant numbers of CD3+, CD4+, and CD8+ T cells present on first assessment at 4 months post-HCT, and significant numbers of naïve CD4+ T cells were present by 8 months post-HCT. Chronic GVHD was associated with delayed T cell recovery; however, T cell reconstitution was not affected by underlying diagnosis, donor source, TCRαβ+ T cell dose, conditioning regimen, or use of antithymocyte globulin. B cell recovery mirrored T cell recovery, and i.v. Ig was discontinued at a median of 8 months (range, 4 to 22 months) post-HCT in patients alive and relapse-free at last follow-up. Immune reconstitution is rapid following TCRαβ/CD19-depleted HCT in pediatric patients with hematologic malignancies. Donor graft source, haploidentical or unrelated, did not affect immune reconstitution. Viral reactivation is common in the first 100 days post-HCT, indicating that improved T cell defense is needed in the early post-HCT period.

Evaluating Gvhd Outcomes Using Post-Transplant Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil As Gvhd Prophylaxis Compared with Methotrexate/Tacrolimus in Matched-Related and Matched-Unrelated Hematopoietic Stem Cell Transplant in Relation to the Haplo-Identical Setting: A Single Center Experience

Background: The use of post-transplant cyclophosphamide (PTCy)/tacrolimus/mycophenolate mofetil (MMF) for GVHD prophylaxis has improved outcomes in haploidentical hematopoietic cell transplantation (haplo-HCT). PTCy is now being evaluated in matched-related (MRD) and matched-unrelated (MUD) allo-HCT. Previous studies demonstrated improved GVHD-free/relapse-free survival (GRFS) when PTCy was combined with two immunosuppressive agents and PTCy has also been associated with better relapse-free survival (RFS) as demonstrated in De Jong et al 2019, though only one immunosuppressive agent was used. Currently, there is limited published data comparing outcomes using PTCy/tacrolimus/MMF to standard MRD/MUD GVHD prophylaxis of methotrexate (MTX)/tacrolimus. The importance of studying this comparison may help to improve GVHD outcomes in MRD and MUD allo-HCT. Methods: We retrospectively analyzed adult patients at USC Norris Cancer Hospital (age ≥ 19) who received allo-HCT from 2018 to 2020. The primary end-points assessed were incidence and severity of 1-year aGVHD and cGVHD. Secondary end-points included day+100 mortality, 1-year overall survival (OS), 1-year RFS, 1-year transplant-related mortality (TRM), and 1-year GRFS, defined as grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death in the 1-year post-HCT period. Results: A total of 65 adult MRD and MUD allo-HCT recipients and 53 haplo-HCT patients were reviewed. Of the MRD/MUD patients evaluated, approximately 51% (n = 33) were female and 49% (n = 32) were male. The age range was 20-69 years old (median = 46), and the most common diseases included ALL (46%), AML (31%), MDS (11%), and others (i.e. lymphoma, aplastic anemia (AA), myelofibrosis) (12%). 34% (n = 22) of patients received PTCy on D+3 and D+4 with tacrolimus/MMF/ on D+5 as GVHD prophylaxis and 66% (n = 43) of patients received MTX/tacrolimus on D+1, +3, +6, and +11 as GVHD prophylaxis. All haplo-HCT patients received standard PTCy/tacrolimus/MMF. Stem cell source was primarily PBSC except in HLH and AA patients. The PTCy group had more MUD allo-HCT (64%), degree of antigen mismatch (56%), and median age of 50.5 years compared with the MTX group at 44%, 47%, and 44 years respectively. 70% in the MTX group received MAC compared with 45% in the PTCy group. The haplo group had similar demographics to the MTX group. The mean CD34 cell doses in the PTCy, MTX, and haplo groups were 4.87, 5.36, and 7.24x106 cells/kg respectively. Incidences of total GVHD, aGVHD, and aGVHD grade 3 or 4 in the PTCy group were 55%, 50%, and 4.5% respectively compared with 65%, 35%, and 7% in the MTX group, though not significant. The haplo group had 68%, 55%, and 1.9% respectively. Incidence of total cGVHD and cGVHD requiring systemic therapy in the PTCy group was 4.5% and 0% respectively compared with 30% (p = .02) and 23% (p =.01). The haplo group had 13% and 1.9% respectively. Day+100 mortality, 1-year OS, 1-year RFS, 1-year TRM, and 1-year GRFS in the PTCy group were 0%, 80%, 60%, 0%, and 64% respectively compared with 7%, 88%, 90%, 7.3%, and 59%. The haplo group had 3.8%, 86%, 89%, 14%, and 66%. In a univariate analysis, factors significantly associated with GVHD were disease status (p = .0.12) and CD34 dose (p = 0.015) and antigen mismatch (p = 0.04) was associated with increased mortality. Discussion: Our results demonstrate improved overall and extensive cGVHD outcomes in the PTCy group and thus an improvement in 1-year GRFS. Furthermore, incidence and severity of 1-year cGVHD in this group are improved when compared with previously reported outcomes. 1-year GRFS reported in De Jong et al 2019 was 45% and 1-year GRFS reported for all groups in our study is higher at 66%, 64%, and 59% for the haplo, PTCy, and MTX groups respectively. Although this was not significant, it may be clinically meaningful given the significant improvement in extensive GVHD and improvement in all other secondary end-points except 1-year OS and RFS. Furthermore, the PTCy group had a higher percentage of mismatched antigens yet demonstrated superior outcomes. 1-year OS and RFS were superior in the MTX group however this is likely due to sample size differences. The improved extensive cGVHD and GRFS outcomes observed using PTCy/tacrolimus/MMF in the MRD/MUD setting should continue to be evaluated and currently there is an ongoing prospective, randomized study to further investigate. Disclosures Yaghmour: Jazz: Consultancy, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Cost and Healthcare Utilization in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Real-World Analysis of Medicare Beneficiaries Receiving Chimeric Antigen Receptor T-Cell Vs. Autologous and Allogeneic Hematopoietic Cell Transplants

Introduction: Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) can be treated with 3 resource intense options: autologous hematopoietic cell transplant (Auto-HCT), allogeneic HCT (Allo-HCT), or autologous anti-CD19 chimeric antigen receptor T-Cell (CAR T) therapy after two or more lines of systemic therapy, depending on the clinical scenario. Our aim was a comparative analysis of healthcare resource utilization (HCRU) and associated costs for matched samples of Medicare patients for treatment planners, payers, and policy-makers. Methods: This study utilized a retrospective, observational cohort design. Data were derived from the Center for Medicare and Medicaid Services (CMS) 100% Medicare Fee-for-Service (FFS) Part A and B claims data. Part D data for the study period were not yet available, so pharmacy claims for oral medications were not evaluated. Patients with DLBCL were included if they received CAR T or Auto-HCT between 10/1/2017 and 3/31/2019 or Allo-HCT between 7/1/2012 and 3/31/2019. Patients with more than 1 CAR T or HCT were excluded. The index date was the date of initiation of the procedure. To allow for evaluation of patient characteristics and treatments pre- and post-procedure, patients must have been continuously enrolled in Medicare FFS for 6 months prior to (PRE) and after (POST) the index date. Patients who died during the POST period were included. The 3 cohorts CAR T, Auto-HCT, and Allo-HCT were matched on baseline clinical characteristics using 1:1 propensity score matching with a caliper of 0.05, with Auto-HCT and Allo-HCT patients assumed to be clinically distinct populations offered at different lines of therapy and so were matched to CAR T patients separately. Due to limitations of the data, we were not able to match patients by line of therapy. Baseline characteristics were age, gender, race, census region, dual eligibility status (i.e. Medicare plus Medicaid), ECOG-PS (derived from claims using a validated, published method), Charlson-Deyo Comorbidity Index (CCI) and recent history of DVT/PE or cytopenias. Measures of HCRU were all-cause hospitalizations, outpatient, and emergency department (ED) visits. Costs were total paid amounts. HCRU and cost data were calculated for the 6 months PRE and POST, but do not include the utilization and costs associated with the index procedure itself. Results: The CAR T/Auto-HCT analysis included 175 patients each, while the CAR T/Allo-HCT analysis included 142 patients each. All cohorts had a median age of 69-70, with slightly more females, mostly ECOG 0-1, and were predominantly white. Only 10-15% were dual eligible. Although all groups had a median CCI of 4, the CAR T/Auto-HCT patients yielded slighter higher mean comorbidity scores (5.2-5.4) than CAR T/Allo-HCT (4.8). For the CAR T/Auto-HCT comparison (Table 1a), Auto-HCT utilization was higher than CAR T on all acute care hospitalization measures and mean total medical costs were 35% higher ($85,382 vs. $63,081, respectively) during PRE. During POST, all measures were lower than PRE for both groups including total medical costs ($25,277 and $33,876, respectively). The reductions were greater for Auto-HCT than for CAR T, resulting in Auto-HCT having lower POST utilization and costs than CAR T for all measures except % of patients with outpatient encounters. Allo-HCT utilization was higher than CAR T on all PRE measures including cost ($92,119 and $70,105, respectively, Table 1b) except ED visits. For POST vs. PRE, CAR T HCRU and costs declined ($34,477) similarly to that in the Auto-HCT comparison. But for Allo-HCT, acute care length of stay increased at POST compared to PRE, and total medical costs were relatively unchanged ($82,847) POST. POST HCRU and cost differences between these groups are not attributable to different survival rates, as no differences were seen. Conclusions: In this observational descriptive analysis, HCRU and costs for Auto-HCT patients were higher during the 6 months pre-HCT compared to a matched group of CAR T patients but were lower during the 6 months post-HCT. For a matched group of Allo-HCT patients, however, the post-HCT period showed HCRU and costs that were equal to or higher than pre-HCT and were higher than CAR T during the same period. Understanding the relative HCRU and costs associated with these 3 procedures common to relapsed/refractory DLBCL will allow for better HCR planning. Disclosures Mohammadi: Kite, A Gilead Company: Research Funding. Purdum:Kite, A Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Wong:Kite, A Gilead Company: Research Funding. Schroeder:Kite, A Gilead Company: Research Funding. Kilgore:Kite, A Gilead Company: Research Funding. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding.

Early post-transplantation factors predict survival outcomes in patients undergoing allogeneic hematopoietic cell transplantation for myelofibrosis

Factors predicting allogeneic hematopoietic cell transplantation (HCT) outcomes in myelofibrosis in the early post-HCT period have not been defined thus far. We attempt to study such factors that can help identify patients at a higher risk of relapse or death. This retrospective study included 79 patients who underwent first HCT for myelofibrosis at three centers between 2005 and 2016. Univariate analysis showed that red blood cell (RBC) transfusion dependence (HR 9.02, 95% CI 4.0–20.35), platelet transfusion dependence (HR 8.17, 95%CI 3.83–17.37), 100% donor chimerism in CD33 + cells (HR 0.21, 95%CI 0.07–0.62), unfavorable molecular status (HR 4.41, 95%CI 1.87–10.39), normal spleen size (HR 0.42, 95%CI 0.19–0.94), grade ≥ 2 bone marrow fibrosis (vs. grade ≤ 1; HR 2.7, 95%CI 1.1–6.93) and poor graft function (HR 2.6, 95%CI 1.22–5.53) at day +100 were statistically significantly associated with relapse-free survival (RFS). RBC transfusion dependence and unfavorable molecular status were also statistically significant in the multivariate analysis. Patients in whom both of these factors were present had a significantly worse RFS when compared to those with one or none. While limited by a small sample size, we demonstrate the significance of transfusion dependence and molecular status at day +100 in predicting outcomes.

CYP2C19 Metabolizer Status Does Not Influence the Safety or Efficacy of Pentamidine

<h3>Background</h3> <i>Pneumocystis jirovecii</i> (PJP) infections are a significant cause of morbidity and mortality in recipients of hematopoietic cell transplantations (HCT), and PJP prophylaxis is a standard of care. The gold standard for PJP prophylaxis is sulfamethoxazole and trimethoprim (SMX/TMP), however, SMX/TMP is known to cause neutropenia so it is often avoided in the pre- and early post-HCT period. Alternatively, pentamidine can be administered in the early post HCT period without concern of marrow suppression. Pentamidine is a substrate of the CYP2C19, a CYP450 enzyme with known polymorphisms affecting metabolizer activity. A previous adult study demonstrated that patients with at least one ‘no function' allele were at an increased risk of serious adverse effects including death. We sought to determine the influence of CYP2C19 metabolizer status on the safety and efficacy of pentamidine in pediatric HCT population. <h3>Methods</h3> A retrospective chart review was conducted on all patients undergoing HCT at Cincinnati Children's Hospital between June 2013 and September 2018. Analysis of single nucleotide polymorphisms of CYP2C19 (*2, *3, *4, *5, *6, *7, *8, *17) were performed on a Taqman™ Low Density Array as part of routine clinical care. Incidence of breakthrough PJP infections, pentamidine discontinuation due to adverse effects as well as patient and transplant demographic information were collected. <h3>Results</h3> A total of 319 patients received pentamidine and had CYP2C19 genotyping perfomed during the study period.There were 8 poor metabolizers (two no function alleles), 101 intermediate metabolizers (one no function allele and one normal or increased function allele), 128 normal metabolizers (two normal function alleles) and 82 ultrarapid metabolizers (two increased function alleles or one normal allele and one increased function allele). There was no difference in the number of patients who discontinued therapy due to adverse events among metabolizer status groups, nor was there a difference in the number of breakthrough PJP infections (Table 1). <h3>Conclusions</h3> Our study demonstrates that, in contrast to the adult study, it is safe and efficacious to administer pentamidine in pediatric HCT patients regardless of CYP2C19 metabolizer status.

Pre-Transplant Fecal Microbial Diversity Independently Predicts Critical Illness after Hematopoietic Cell Transplantation

Background Fecal microbiota composition is associated with important outcomes after allo-HCT including survival, relapse, GVHD, and infections. We previously demonstrated in a multicenter observational study that HCT patients present with fecal microbiota configurations that have lower diversity and are distinct from those of healthy individuals, and that pre-HCT microbiota injury predicts poor overall survival. Here, we hypothesized that pre-HCT fecal microbiota features predict development of critical illness post-HCT. Methods We analyzed 828 adults who received a first allo-HCT from 2009 to 2017 at a single institution who had an evaluable fecal sample in our biobank collected within the 10 days prior to cell infusion. The patients were heterogeneous with respect to transplant indication, conditioning intensity, graft source (cord blood, peripheral blood, marrow) and graft manipulation (CD34-selection). The V4-V5 regions of 16S rRNA genes of DNA extracted from fecal samples were amplified and annotated taxonomically. The outcome of interest was time to ICU admission, which was assessed using survival-analysis methods. The reason for admission to the ICU was evaluated for each subject. Results Seventy-five (9%) patients were admitted to the intensive care unit (ICU) between the day of cell infusion and day +50; the peak incidence of ICU admission occurred on day +10. The most common indications for ICU admission were respiratory failure (65%) and infection (27%). Patients were stratified based on fecal microbiota diversity, as assessed by 16S sequencing of stool samples collected prior to transplantation, into high (inverse Simpson index ≥4) and low (&lt;4) diversity groups following a previously-published cutoff. Patients with low diversity pre-HCT had a strikingly higher risk of ICU admission than those with high diversity (HR 2.38 [95% CI 1.5-3.7], p &lt;0.001, see the Figure). This association remained significant in a multivariate Cox proportional hazard model that accounted for conditioning intensity, graft source, graft manipulation, and the HCT-CI comorbidity index (multivariate p = 0.003). HCT-CI score was also an independent predictor of ICU admission. The association between pre-HCT fecal diversity and ICU admission was also significant when the outcome definition was limited to ICU transfers for reason of respiratory failure or sepsis (to the exclusion of such indications as hemorrhage, anaphylaxis, or isolated dysfunctions of the cardiac, renal, or neurological systems). Conclusion Pre-transplant fecal microbial diversity is an independent predictor of intensive-care-requiring critical illness in the post-HCT period. These observations highlight the pre-HCT period as a window of opportunity to (a) assess microbiota injury in conjunction with comorbidity evaluation, (b) inform selection of antibiotic prophylaxis, gut-decontamination, GVHD-prophylaxis, or conditioning regimens, and (c) intervene with microbiota injury-remediation or prevention strategies. Figure Disclosures Brereton: Seres Therapeutics: Other: Salary Support. Clurman:Seres Therapeutics: Research Funding. Slingerland:Seres Therapeutics: Other: Salary supported by Seres funding. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Scordo:McKinsey &amp; Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy. Politikos:Angiocrine Bioscience Inc: Research Funding. Gyurkocza:Actinium Pharmaceuticals: Research Funding. Barker:Angiocrine Bioscience Inc: Research Funding; Gamida Cell: Research Funding; Merck: Research Funding. Perales:Kyte/Gilead: Research Funding; Miltenyi: Research Funding; 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; 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; 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; 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. Giralt:Amgen: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Actinium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kite: Consultancy; Johnson &amp; Johnson: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Miltenyi: Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy. van den Brink:Merck &amp; Co, Inc.: Consultancy, Honoraria; Acute Leukemia Forum (ALF): Consultancy, Honoraria; Magenta and DKMS Medical Council: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Other: Licensing; Amgen: Consultancy, Honoraria; Therakos: Consultancy, Honoraria; Seres Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Flagship Ventures: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Evelo: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria. Pamer:Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Seres Therapeutics: Honoraria, Patents &amp; Royalties; MedImmune: Honoraria; Novartis: Honoraria; Ferring Pharmaceuticals: Honoraria. Peled:Seres Therapeutics: Research Funding.

Risks and Benefits of Bronchoscopy during the First 100 Days Following Allogeneic Hematopoietic Cell Transplantation

BACKGROUND Pulmonary infiltrates are common after allogeneic hematopoietic cell transplantation (HCT) and can have infectious or non-infectious etiologies. Fiberoptic Bronchoscopy (FOB) with bronchoalveolar lavage (BAL) is frequently used to evaluate these patients. However, the diagnostic yield can be highly variable according to patient populations, and the impact on management is not well defined, especially in the era of modern antimicrobial therapies. The aim of this study was to investigate the diagnostic and therapeutic yield of FOB-BAL in adult patients with pulmonary infiltrates during the first 100 days following HCT. METHODS We retrospectively reviewed the medical records of adult HCT patients who underwent FOB-BAL during the first 100 days post HCT between January 2005 and December 2015 at Mayo Clinic, Rochester, MN. The interval from HCT to FOB was stratified into early (days 1-30) vs. late (days 31-100). The finding of progressively more hemorrhagic effluent and/or ≥ 20% hemosiderin-laden macrophages in BAL were considered diagnostic for diffuse alveolar hemorrhage (DAH). Univariate and multivariate logistic regression models were fit to identify clinical and transplant characteristics that may impact the diagnostic yield of FOB-BAL. RESULTS A total of 114 patients (median age 55 years), representing 12% of all HCT patients underwent FOB-BAL. Underlying diagnoses were AML in 36%, MDS in 16%, ALL in 16%, MPN in 12% , CLL in 7%, and other in 13%. Transplants were from matched related donor in 43%, matched unrelated donor in 40%, and other donor/matching status in 17%. FOB-BAL was performed during the early period in 61% and during the late period in 39% of patients. In the early period, FOB-BAL provided a specific diagnosis in 49% of patients (30% DAH and 19% infection). In the late period, FOB-BAL had a diagnostic yield of 55% (14% DAH and 36% infection) (Figure 1). The distribution of bacterial and viral infections identified via BAL were similar during the early period (39% and 38%, respectively), whereas more bacterial than viral infections were identified in the later period (56% vs. 19%, respectively) (Figure 2). Non-invasive testing for respiratory tract infection was performed in 34% of patients. These included nasopharyngeal swab for RSV/Influenza PCR in 16% (all negative), multiplex respiratory pathogen PCR in 5% (1 positive for coronavirus), and sputum culture in 21% (positive in 8 patients). This compares with the identification of an infectious pathogen via BAL in 36% of patients; bacterial in 16%, viral in 11%, and fungal in 10%. Transbronchoscopic lung biopsy biopsies were performed in 8 patients and provided diagnostic information in 3 patients (eosinophilic pneumonia, organizing pneumonia and diffuse alveolar damage each in 1 patient). Procedural complications occurred in 3 patients; 2 after transbronchoscopic lung biopsy (1 bleeding and 1 pneumothorax) and 1 during FOB-BAL (atrial fibrillation with rapid ventricular rate). In a multivariable logistic regression model, the underlying diagnosis, presence of acute respiratory failure, and early vs. later time period after HCT were independently affecting the diagnostic yield of FOB-BAL, with higher likelihood of DAH being diagnosed in patients with AML/MDS and during the early post-HCT period, and higher likelihood of DAH being diagnosed in patients with acute respiratory failure (Table 1). In 40% of patients, FOB-BAL findings lead to treatment changes. These included addition of antimicrobials in 24% and addition of corticosteroids in 22% (17% DAH, 2% idiopathic pneumonia syndrome, and 1% organizing pneumonia) (Figure 3). FOB findings lead to more antimicrobial modifications in the early than in the later period (32% vs. 18%, respectively). Overall survival was poor in all the three groups, although significantly better in patients with non-diagnostic FOB findings (median of 2, 3, and 11 months in patients with DAH, infection, or non-diagnostic FOB finings, respectively) (p = 0.03) (Figure 4). CONCLUSION FOB-BAL provides clinically useful information in the post-transplant period. BAL findings were diagnostic in 51% of patients, and led to management changes in 40% of patients. Transbronchoscopic lung biopsy is associated with higher rates of procedural complications. Further characterization of the underlying diagnosis in patients with non-diagnostic FOB-BAL findings remains an unmet clinical goal. Disclosures Sakemura: Humanigen: Patents &amp; Royalties. Kenderian:Morphosys: Research Funding; Kite/Gilead: Research Funding; Lentigen: Research Funding; Humanigen: Other: Scientific advisory board , Patents &amp; Royalties, Research Funding; Tolero: Research Funding; Novartis: Patents &amp; Royalties, Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

Immunophenotyping and Function of Peripheral Blood Mononuclear Cells in Patients Undergoing Unrelated Allogeneic Transplantation with Post-Transplantation Cyclophosphamide in Combination with ATG Anti-Graft Versus Host Disease Prophylaxis

Post-transplant cyclophosphamide (PTCy) effectively prevents alloreactive responses from unmanipulated grafts, but its effect on subsequent immune reconstitution remains largely undetermined. A total of 32 patients (pts) (ages &gt; 18) who underwent allogeneic hematopoietic stem cell transplantation (HCT) mainly for acute leukemia and myelodysplastic syndrome were evaluated. Blood samples were collected at 15, 30, 60, 90, 180 and 270 days post-HCT. Cell phenotype was assessed on peripheral blood mononuclear cells (PBMC) using multiparametric flow cytometry. The proliferative and activation T cell capacity in response to mitogenic stimulation was determined. Pts who received graft versus host disease (GVHD) prophylaxis with PTCy/ATG combination (n=8) were compared with pts who received ATG (Grafalon®, Neovii) alone (n=13), and pts undergoing HCT with no ATG (n=11). Five healthy controls served for the functional assays. First, CD4+ and CD8+ T cell differentiation was evaluated assessing CD62L, CD45RA, and CCR7 expression. A smaller percentage of effector cells was detected in the PTCy/ATG group at days 30, 60 and 90 after HCT, compared to the no-ATG and ATG cohorts. Accordingly, the percentage of central memory and effector memory cells was significantly increased in PTCy/ATG pts at the same time points. Next, immuno-modulatory cell populations were assessed. A transient increase in the percentage of CD4+CD25+CD127- Treg cells was detected in both ATG and PTCy/ATG cohorts in the early post-HCT period, reaching maximal frequency of 21% Treg out of the CD4+ subset (range 14-42%) in the ATG group and 19% (range 12-30%) in the PTCy/ATG group on day 21, suggesting that Treg cells are relatively spared by Cy. However, a distinct expression pattern of checkpoint molecules was revealed in pts receiving PTCy/ATG. The percentage of PD1-positive CD4+ and CD8+ cells was comparable in the no-ATG and ATG cohorts (44% vs 45% and 35% vs 41%, respectively). Yet, PD1 expression was significantly increased on both CD4+ (61%, p&lt;0.05) and CD8+ cells (60%, p&lt;0.02) from pts receiving PTCy/ATG. Similarly, an increased frequency of LAG-3+ CD8+ cells was observed in the PTCy /ATG pts, in comparison to the no-ATG and ATG groups. Concomitantly, HLA-DR expression on CD56+ NK subset was decreased in PTCy/ATG pts versus the ATG and non-ATG groups (47% vs 61% vs 67%, respectively, p&lt;0.05), indicating reduced activation of NK cells. Furthermore, a significant increase in the percentage of CD28-CD127- cells out of CD8+ cells was detected in PTCy/ATG pts compared to the ATG and no-ATG groups on day 60 post-HCT (82% vs 56% vs 38%, respectively, p&lt;0.02). CD57 up-regulation combined with CD28 down-regulation on T cells reflected an exhausted/senescent phenotype; therefore, we further analyzed the frequency of CD28-CD57+ T cells. Significantly elevated expression of CD57 on CD8+CD28- cells was detected in the PTCy/ATG cohort, in comparison to the ATG and no-ATG groups (65% vs 43% vs 21%, respectively, p&lt;0.01). Exhausted/senescent T cells showed functional impairment, which manifested as reduced potential for cytokine production and poor proliferative capacity. Notably, both CD4+ and CD8+ cells from ATG and PTCy/ATG cohorts demonstrated diminished proliferation in response to ex-vivo αCD3/αCD28 stimulation, when compared to the no-ATG cohort and healthy controls (p&lt;0.01). Moreover, significantly reduced production of IFNγ in response to stimulation was detected in PTCy/ATG and ATG pts (p&lt;0.01). PBMC from the no-ATG cohort displayed inducible IFNγ production levels comparable with healthy controls. Finally, PTCy/ATG-treated patients demonstrated altered phenotypic and functional recovery of the CD8+ cells. While CD4+ cells gradually downregulated PD1 expression and up-regulated co-stimulatory molecules CD28 and CD127 on days 180 and 270, notably CD8+ cells retained exhausted/tolerogenic phenotype as late as 270 days post-HCT. Our results demonstrate that the acquisition of senescent/exhausted phenotype by cytotoxic CD8+ cells is a distinctive feature of HCT with ATG conditioning. PTCy further compromises recovery of CD8+ cells and impairs NK activation, resulting in a sustained immunosuppression. Hopefully, these results will not only lead to a better understanding of the tolerance mechanisms behind PTCy/ATG anti GVHD prophylaxis but will also assist in the development of novel clinical treatments. Disclosures No relevant conflicts of interest to declare.

High Post-Transplant Ferritin Level Associates with Adverse Survival and Higher Mortality Rate following Allogeneic Hematopoietic Stem Cell Transplant, whereas Pre-Transplant Ferritin Level Does Not

Background: Allogeneic hematopoietic stem cell transplantation (HCT) is a curative therapy for many hematologic and non-hematologic diseases; however, it is associated with significant morbidity and mortality. Many studies have shown that elevated pre-transplant ferritin levels are associated with increased risk of morbidity and mortality following HCT. Given ferritin's association with systemic inflammation, it is a plausible potential prognostic marker in the post-HCT period, including in patients with graft-versus-host disease (GVHD). The present study attempts to determine whether post-transplant serum ferritin level is an independent prognostic marker for outcomes post-HCT, especially in the subgroups of patients with acute or chronic GVHD.Methods and patients: A total of 229 patients who had serum ferritin level data available within one-year post HCT were enrolled into this retrospective study. These patients underwent HCT at Princess Margaret Cancer Centre, Toronto, Canada between 2001-2013. Patients' characteristics and transplant procedures were: median age: 51 (range:19-70); refined disease risk index: low (n=70), intermediate (n=108), high (n=51); donor type: HLA-matched related donors (n=94), HLA-matched or partially-matched unrelated donors (n=135); conditioning regimen: myeloablative (n=120), reduced intensity (n=109).Acute and chronic GVHD were respectively classified using the 1994 consensus conference and NIH consensus criteria. Primary outcomes were overall survival (OS), non-relapse mortality (NRM), and relapse. Kaplan-Meier method was used for OS; cumulative incidences were used for NRM and relapse, considering competing risks. Multivariate analysis employed Cox or Fine-Gray proportional hazard regression model. Factors evaluated included recipient age and CMV status, donor-recipient sex, comorbidity score, performance index, GVHD prophylaxis, post-transplant serum ferritin level (ferritinPost-HCT), and serum ferritin level prior to HCT (ferritinPre-HCT). Recursive partitioning was used to stratify patients into low or high risk groups based on ferritinPost-HCT (≤3,169 vs >3,169 ng/mL) and ferritinPre-HCT (≤669 vs >669 ng/mL).Results: Median follow-up duration among survivors was 46 months post-HCT (range:2.8-147.2 months). Median ferritinPost-HCT was 2,178 ng/mL (range: 45-30,647; Figure A), measured at a median of 137 days post-HCT. There was a weak correlation between ferritinPost-HCT and ferritinPre-HCT (Pearson's correlation r=0.242, p=0.002).Compared to the group with low ferritinPost-HCT, the high ferritinPost-HCT group had lower three-year OS (40.0% vs 66.7%, p<0.001; Figure B) and higher NRM (48.6% vs 17.8%, p<0.001 Figure C), but no difference in cumulative incidence of relapse (10.5% vs 19.7%, p=0.079; Figure D). A landmark analysis was performed where the day of ferritinpost-HCT measurement was considered day 0. Results of this landmark analysis showed consistent findings: high ferritinPost-HCT showed lower three-year OS (38.3% vs 65.4%; p<0.001) and higher NRM (50.6% vs 17.7%; p<0.001) compared to low ferritinPost-HCT, but no difference in relapse (10.7% vs 21.3%, p=0.077). In multivariate analysis, ferritinPost-HCT was found to be an independent prognostic factor for OS (p=0.001, HR 2.323) and NRM (p<0.001, HR 3.905). However, pre-transplant ferritin level (ferritinPre-HCT) did not stratify well for OS (57.0% vs 61.8%, p=0.636) or NRM (30.8% vs 22.7%, p=0.247).Out of 229 patients, 171 (74.6%) developed any grade of acute GVHD, and 61 (26.6%) developed chronic GVHD. Median onset of acute and chronic GVHD were, respectively, 33.5 days and 145 days. Level of ferritinPost-HCT was significantly higher in the group that developed acute GVHD than in those without acute GVHD. However, there was no difference in ferritinPost-HCT between patients with or without chronic GVHD. FerritinPost-HCT was found to be an independent prognostic marker in the subgroup with acute GVHD for OS (p=0.001, HR 2.531) and NRM (p<0.001, HR 3.584), and in the subgroup with chronic GVHD for OS (p=0.042, HR 3.226) and NRM (p=0.009, HR 14.130).Conclusions: In our cohort, high ferritinPost-HCT levels were significantly associated with decreased OS and increased NRM, independent of other prognostic factors including ferritinPre-HCT or GVHD. Further prospective study including larger number of patients is warranted. [Display omitted] DisclosuresLipton:ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kim:BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Paladin: Consultancy.

Effect of Antihuman T Lymphocyte Globulin on Immune Recovery after Myeloablative Allogeneic Stem Cell Transplantation with Matched Unrelated Donors: Analysis of Immune Reconstitution in a Double-Blind Randomized Controlled Trial

We recently conducted a randomized double-blind study in which we demonstrated that moderate/severe chronic graft-versus-host disease (cGVHD) but not cGVHD-free survival was reduced in patients receiving anti-T lymphocyte globulin (ATLG) versus placebo. In a companion study we performed immunophenotypic analysis to determine the impact of ATLG on immune reconstitution (IR) and to correlate IR with clinical outcomes. The randomized study (n = 254) included patients (aged 18 to 65 years) who underwent myeloablative transplants for acute myeloid leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia from HLA-matched unrelated donors. Ninety-one patients consented for the companion IR study (ATLG = 44, placebo = 47). Blood samples were collected on days 30, 100, 180, and 360 after hematopoietic cell transplantation (HCT), and multiparameter flow cytometry was performed in a blinded fashion. Reconstitution of CD3+ and CD4+ T cells was delayed up to 6 months post-HCT in the ATLG arm, whereas absolute regulatory T cell (Treg) (CD4+25+127-) numbers were lower only in the first 100 days. Analysis of the CD4+ Treg and conventional T cells (Tconv) (CD4+25–127+) compartments showed a profound absence of naive Tregs and Tconv in the first 100 days post-HCT, with very slow recovery for 1 year. B cell and natural killer cell recovery were similar in each arm. Higher absolute counts of CD3+, CD4+, CD8+ T, Tregs, and Tconv were associated with improved overall survival, progression-free survival, and nonrelapse mortality but not moderate/severe cGVHD. Although ATLG delays CD3+ and CD4+ T cell recovery post-transplant, it has a relative Treg sparing effect after the early post-HCT period, with possible implications for protection from cGVHD. ATLG severely compromises the generation of naive CD4+ cells (Treg and Tconv), potentially affecting the diversity of the TCR repertoire and T cell responses against malignancy and infection.

Quality of Life of Caregivers of Hematopoietic Cell Transplant Recipients

Caregivers are critical to recipient recovery after hematopoietic cell transplant (HCT); however, little is known about their long-term health and quality of life (QoL). In this study we surveyed 4446 caregiver–recipient pairs in the post-HCT period to describe their QoL and its determinants. In total, 849 caregiver–recipient pairs at a median of 6 years after autologous or allogeneic HCT responded. Among 849 responding caregivers at a median of 6 years post-HCT, 67% of caregivers were women and 68% indicated they were still providing care to the recipient. Mean and median QoL measures of caregivers were at or above general population norms; however, approximately 20% of caregivers reported poor QoL relative to general population norms. Multivariate analysis revealed that caregiver characteristics, including age, gender, and educational attainment, were important determinants of caregiver QoL. Additional determinants of caregiver QoL included recipient QoL, relapse after autologous HCT, and ongoing use of immunosuppression after allogeneic HCT. Additionally, the prevalence of depression and sleep disorders appear to be higher in caregivers than in the general population. We have identified a population of caregivers who may benefit from interventions aimed at improving QoL and health outcomes. HCT clinical practice should also consider caregiver well-being.

Challenges around Access to and Cost of Life-Saving Medications after Allogeneic Hematopoietic Cell Transplantation for Medicare Patients

Hematopoietic cell transplantation (HCT) is an expensive, medically complicated, and potentially life-threatening therapy for multiple hematologic and nonhematologic disorders with a prolonged trajectory of recovery. Similar to financial issues in other cancer treatments, adverse financial consequences of HCT are emerging as an important issue and may be associated with poor quality of life and increased distress in HCT survivors. Prescription medicine coverage for HCT for Medicare and some Medicaid beneficiaries, especially in the long-term, remains suboptimal because of inadequate payer formularies or prohibitive copays. With an increasing number of older patients undergoing HCT and improvement in the overall survival after HCT, the problem of financial burden faced by Medicare beneficiaries with fixed incomes is going to worsen. In this article, we describe the typical financial burden borne by HCT recipients based on estimated copayment amounts attached to the categories of key medications as elucidated through 2 case studies. We also suggest some possible solutions for consideration to help these patients and families get through the HCT by minimizing the financial burden from essential medications needed during the post-HCT period.