Setting Of Hematopoietic Cell Transplantation Research Articles

Clinical impact of clonal hematopoiesis in hematopoietic cell transplantation: a review, metaanalysis, and call to action.

Hematopoietic cell transplantation (HCT) is the only potentially curative treatment option for many patients with hematologic malignancies. While HCT outcomes have improved drastically over the years, patients and clinicians continue to face numerous survivorship challenges, such as relapse, graft-versushost disease, and secondary malignancies. Recent literature suggests that clonal hematopoiesis (CH), the presence of a recurrent somatic mutation in hematopoietic cells, in HCT patients or donors may be associated with outcomes in autologous and allogeneic HCT. Herein, we perform a review of the literature and summarize reported associations between CH and clinical outcomes in HCT. For commonly reported outcomes, we used meta-analysis methods to provide estimates of effect sizes when combining results. A total of 32 articles with relevant and independent contributions were included, covering both autologous (n = 19) and allogeneic (n = 13) HCT. The articles report variable risk for developing outcomes according to CH characteristics, patient disease status, and method of HCT. Using meta-analysis of available results, HCT outcomes with statistically significant effects by CH status include therapy-related myeloid neoplasms (OR 3.65, 95%CI 2.18-6.10) and overall survival (HR 1.38, 95%CI 1.20-1.58) in autologous HCT and relapse (HR 0.80, 95%CI 0.68-0.94) in allogeneic HCT. However, heterogeneity, biases, and limitations in the literature provide challenges for informing the translation of CH to clinical decision-making. We conclude with a call to action and discussion of next steps to build upon the current literature and provide granularity to the true clinical impact of CH in the setting of HCT.

Donor whole blood DNA methylation is not a strong predictor of acute graft versus host disease in unrelated donor allogeneic haematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) is used to treat many blood-based disorders and malignancies, however it can also result in serious adverse events, such as the development of acute graft-versus-host disease (aGVHD). This study aimed to develop a donor-specific epigenetic classifier to reduce incidence of aGVHD by improving donor selection. Genome-wide DNA methylation was assessed in a discovery cohort of 288 HCT donors selected based on recipient aGVHD outcome; this cohort consisted of 144 cases with aGVHD grades III-IV and 144 controls with no aGVHD. We applied a machine learning algorithm to identify CpG sites predictive of aGVHD. Receiver operating characteristic (ROC) curve analysis of these sites resulted in a classifier with an encouraging area under the ROC curve (AUC) of 0.91. To test this classifier, we used an independent validation cohort (n = 288) selected using the same criteria as the discovery cohort. Attempts to validate the classifier failed with the AUC falling to 0.51. These results indicate that donor DNA methylation may not be a suitable predictor of aGVHD in an HCT setting involving unrelated donors, despite the initial promising results in the discovery cohort. Our work highlights the importance of independent validation of machine learning classifiers, particularly when developing classifiers intended for clinical use.

Sigle Agent of Posttransplant Cyclophosphamide Without Calcineurin Inhibitor Controls Severity of Experimental Chronic GVHD.

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity following allogeneic hematopoietic cell transplantation (HCT), but its pathogenesis remains unclear. Recently, haplo-identical HCT with post-transplant cyclophosphamide (Haplo-HCT with PTCY) was found to achieve a low incidence rate of acute GVHD and chronic GVHD. However, while the pathogenesis of acute GVHD following Haplo-HCT with PTCY has been well investigated, that of chronic GVHD remains to be elucidated, especially in HLA-matched HCT with PTCY. Based on its safety profile, PTCY is currently applied for the human leucocyte antigen (HLA)-matched HCT setting. Here, we investigated the mechanisms of chronic GVHD following HLA-matched HCT with PTCY using a well-defined mouse chronic GVHD model. PTCY attenuated clinical and pathological chronic GVHD by suppressing effector T-cells and preserving regulatory T-cells compared with a control group. Additionally, we demonstrated that cyclosporine A (CsA) did not show any additional positive effects on attenuation of GVHD in PTCY-treated recipients. These results suggest that monotherapy with PTCY without CsA could be a promising strategy for the prevention of chronic GVHD following HLA-matched HCT.

Family-Focused Facilitated Fitness: Feasibility and Acceptability of a Couple-Based Physical Activity Intervention for Hematopoietic Cell Transplant Recipients and Their Caregiving Partners

Reductions in physical activity (PA) are common among patients following hematopoietic cell transplantation, and a risk factor for poor physical functioning. PA among spouses/cohabiting partners, who frequently serve as the patient's primary caregiver, may also be reduced due to caregiving demands and limited bandwidth for self-care. In addition, the patient-caregiver relationship can be compromised, and communication patterns disrupted. All PA interventions in the hematopoietic cell transplantation setting have focused entirely on patients, ignoring an opportunity to synergistically engage and benefit the caregiver as well. We sought to test feasibility and acceptability of a couple-based intervention entitled Family-Focused Facilitated Fitness (FFFF), designed to improve PA as assessed by daily step counts among both patients undergoing hematopoietic cell transplantation and their caregivers. Guided by interdependence and communal coping perspectives, FFFF is an 8-week, remotely-delivered intervention that provides training in communication skills and joint problem-solving to help patients and caregivers support one another in PA. Participants are also given a Fitbit to track their steps and weekly individualized step prescription based on the 75th percentile ranked value of their last 7 recorded daily step counts. A priori benchmarks for feasibility and acceptability in this single-arm pilot were as follows: 50% of eligible couples would agree to participate, 70% of couples would attend all 8 sessions, 80% of participants would provide valid Fitbit wear data 4/7 days/ week, and among sessions reviewed for treatment fidelity, 85% of treatment protocol elements would be covered. Couples were recruited prior to transplant. Among 26 couples approached and deemed eligible, 17 enrolled (65% agreement) and completed baseline assessment. Three couples later withdrew after transplantation but prior to receiving the intervention, resulting in 14 couples commencing the intervention, on average 21 days post-transplant. Four couples subsequently discontinued due to medical complications (n = 3) or caregiver schedule (n = 1). Among the 10 couples who completed the intervention, the percentage of participants meeting our benchmark of valid Fitbit wear at least 4 days per week was 85% in week 1, 90% in weeks 2 to 7, and 80% in week 8. Treatment fidelity was 95% on average across 24 sessions reviewed (3 cases). Treatment satisfaction scores were uniformly high across multiple dimensions, with all means above 4 on the 1 to 5 scale. Daily step counts among those attending all 8 intervention sessions increased from 2249 ± 302 steps/day in week 1 to 4975 ± 1377 steps/day in week 8 among patients, and from 8676 ± 3760 steps/day in week 1 to 9838 ± 3723 steps/day in week 8 among caregivers. Qualitative feedback indicated perceived mental and physical health benefits of the program. Participants also offered suggestions for adaptations to accommodate medical setbacks and constraints. All a priori feasibility benchmarks were met or exceeded. Results offer promise for utility of the program to engage and leverage patient-caregiver dyads to increase PA following transplant. An investigation using a randomized controlled design will be necessary to adequately examine change over time relative to control and its possible impact on clinical and patient-reported outcomes.

Systematic Literature Review of Incidence and Management of Non-HCT-Related Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS)

Background: VOD/SOS is a potentially life-threatening complication caused by damage to sinusoidal endothelial cells. It has historically been associated with toxicity from conditioning regimens preceding hematopoietic cell transplantation (HCT), but its epidemiology and characteristics outside the HCT setting are not well understood. We conducted a systematic review to examine the incidence, mortality, diagnosis, and the burden of illness of non-HCT VOD/SOS. Methods: We searchedMEDLINE and Embase (2002-2023), as well as recent congress proceedings (2019-2023) for studies reporting the following in the non-HCT VOD/SOS setting: incidence, diagnosis, relevant medical history, disease management, clinical burden, health-related quality of life, costs, and patients' (pts) unmet needs. All study designs were eligible except case series with <5 participants. Studies of pulmonary VOD or VOD/SOS resulting from ingestion of pyrrolizidine alkaloids were excluded. Two independent reviewers screened titles/abstracts and full-text articles and assessed the methodological quality of studies. Results: Of 3874 records screened, 92 studies were included; 57% were retrospective cohort studies and 70% were conducted in the United States or Europe. VOD/SOS was reported in 17 acute myeloid leukemia (AML) studies and 13 acute lymphoblastic leukemia (ALL) studies. The highest incidences of non-HCT VOD/SOS occurred in pts with colorectal liver metastases (CLM; median 35%) and Wilms tumor (median 14%; Table 1). The occurrences of severe non-HCT VOD/SOS and mortality are provided in Table 2. Clinical criteria (eg, McDonald, Seattle, or Baltimore) were widely used to diagnose both hematological (i.e., AML and ALL) and nonhematological disease (i.e., Wilms tumor), while Rubbia-Brandt histological criteria were used to diagnose VOD/SOS in pts with CLM. While most studies did not report how non-HCT VOD/SOS was managed, 26 studies reported defibrotide use: 80/112 pts (71%) with hematologic cancer and 223/309 pts (72%) in other disease settings. In 7/26 studies, all pts who received defibrotide recovered. Two of 26 studies reported high rates of recovery from VOD/SOS at 70 days following defibrotide initiation: one with 71% of patients alive at day 70 following the start of defibrotide (58/82 pts) and one with 83% of patients alive at day 70 (5/6 pts). Nine studies did not report any outcomes related to defibrotide and another did not distinguish between outcomes in pts treated with defibrotide compared with other treatments. No defibrotide use was reported in studies evaluating pts with CLM. Among non-defibrotide treatments, the most reported VOD/SOS treatment was supportive therapy (14%; 13/92 studies), followed by switching or pausing chemotherapy (11%; 10/92 studies). One study reported outcomes for 206 children who received supportive care for VOD/SOS during 6-thioguanine therapy for ALL; only three pts had acute hepatic failure and all pts recovered from VOD/SOS. Of the studies reporting switching or pausing chemotherapy to manage VOD/SOS, four studies reported 100% recovery from VOD/SOS, and five studies did not report treatment outcomes. The severity of VOD/SOS in these pts was unknown. Four studies reported any adverse events (AEs) in pts treated for VOD/SOS: two reported zero AEs (in four children with ALL treated with defibrotide and two children with Wilms tumor treated with N-acetylcsteine); one reported AEs in 27% (of 82 defibrotide-treated pts, mostly with hematologic cancers); and one reported ≥1 treatment-emergent serious AE of interest in 15% (of 46 pts with hematologic or nonhematologic cancers treated with defibrotide), including infection (9%) and hemorrhage (9%). Conclusions: Non-HCT VOD/SOS occurs in diverse disease areas, including hematologic and solid tumor cancers. A lack of consensus regarding VOD/SOS diagnosis in the non-HCT setting may lead to underdiagnosis; therefore, clinicians should be vigilant for VOD/SOS even in non-HCT pts. Though defibrotide is approved for post-HCT VOD/SOS, there is no approved therapy for non-HCT VOD/SOS; future trials should focus on diagnosis and treatment outside the HCT setting, which represents a significant unmet need. Limitations include a lack of population-based studies to estimate true incidence and that the evidence is based on studies whose main objective was not to investigate non-HCT VOD/SOS.

IPSS-M for Transplant Decision Making of Patients with Myelodysplastic Syndromes: A Retrospective Single-Center Study

Background. The only curative treatment of Myelodysplastic syndromes (MDS) is represented by allogeneic hematopoietic cell transplantation (HCT). The risk scoring system conventionally used in clinical practice for transplant decision-making is IPSS-R (Greenberg PL et al, 2012), which has been shown to predict the HCT outcome(Della Porta MG et al, 2014). The recent broader application of next generation sequencing (NGS) in clinical practice provides an abundance of molecular data and poses the challenge of better prognostic stratification in MDS patients. Recently, Bernard et al(Elsa Bernard et al, 2022) developed a molecular prognostic score called IPSS-Molecular (IPSS-M) which defines six risk categories based on the patient's molecular profile combined with clinical and cytogenetic data. In the original study, only 9% of patients underwent HSCT, therefore the utility of this score in the transplant decision making needs to be explored. Aim.The aim of this study is to evaluate the impact of IPSS-M on the outcome of HCT in patients with MDS. Methods and Results. This is a single center study including 60 consecutive MDS patients who received allogeneic HCT from 2004 to 2023 at Papa Giovanni XXIII Hospital, Bergamo. The median age at transplantation was 57 years and 70% were males. HCT related parameters are listed in Table 1. Of note, 53 out of 60 patients (88%) received an upfront HCT. According to IPSS-RA (age-adjusted IPSS-R), patients clustered in Very Low (4/60), Low (11/60), Intermediate (24/60), High (16/60) and Very High (5/60) risk groups. We retrospectively performed a NGS study before HCT by using a panel of 30 genes for all patients who had available DNA and calculated IPSS-M score for each patient. According to IPSS-M, patients clustered in Very Low (2/60), Low (12/60), Moderate Low (15/60), Moderate High (9/60), High (12/60) and Very High (10/60). Re-stratification occurred in 59% of patients (35/60), of which 22% (13/60) were down-staged and 37% (22/60) were upstaged. With a median follow-up time of 7 years after HSCT, the 5-year overall (OS) and relapse-free survival (RFS) was 67% and 64% respectively. In order to evaluate the utility of IPSS-M in estimating OS and RFS in HCT setting compared to IPSS-R, a concordance test was performed. In terms of OS and RFS, IPSS-M resulted respectively in a C-index of 0.772 and 0.729 compared to 0.567 and 0.607 of IPSS-R (table 2). Conclusions. Despite the limitations due to the small sample and the retrospective design of the study, we conclude that IPSS-M performed better compared to the conventional score in predicting RFS and OS of our MDS patients undergoing HSCT, providing data supporting the integration of clinical and molecular information in this setting. Further improvements may be achieved by integrating the molecular data with clinical information regarding HSCT-related parameters such as performance status, donor and conditioning regimen.

Post-Transplant Cyclophosphamide Equalizes Clinical Outcomes of Allogeneic Hematopoietic Cell Transplantation across Racial and Ethnic Populations

Background Despite being the only curative option for many hematologic malignancies, allogeneic hematopoietic cell transplant (HCT) has been plagued by health disparities due to differences in access, donor availability, and outcomes across racial and ethnic minority populations (REM) (Gragert, NEJM, 2014). Even when a matched donor is available, HCT outcomes for REM patients are historically worse compared to non-Hispanic white (NHW) patients. (Landry, Stem Cell Investigation, 2021). The development of post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis has led to increased use of HLA haploidentical (haplo) or mismatched unrelated donors (MMUD) with comparable outcomes to HLA matched HCT (McCurdy, Advances in Hematology, 2015). While PTCy allows for almost every transplant-eligible REM patient to have a suitable donor, there is limited data evaluating whether this transplant platform results in similar outcomes for REM patients compared to NHW patients. The aim of this study was to investigate if disparities in transplant outcomes still exist between REM patients and NHW patients who received an HLA mismatched transplant with PTCy. Methods We retrospectively analyzed 302 consecutive adult patients who underwent haplo or MMUD HCT with PTCy at Moffitt Cancer Center between 2014 and 2022. All endpoints were compared between four groups: NHW, Hispanic-White, Black, and Other (Asian, biracial, or multiracial.) Results In this cohort, 59% (n=178) of patients identified as NHW, 14% (n=41) as Hispanic-White, 16% (n=48) as Black, 7% (n=21) as biracial or multiracial, and 4% (n=11) identified as Asian. Most patients were male (57%). The median age of all patents was 58. The most common indication for transplant was acute myeloid leukemia (48%), myeloablative conditioning (MAC) was utilized in 42%, and 89% received peripheral blood stem cells grafts. REM patients were more likely to be <65 years of age (60% vs 66-90%, p<0.001), female (36% vs 50-54%, p=0.04), and receive MAC conditioning (33% vs 40-71%, p<0.001). Median follow-up was 21 months. In all clinical outcomes, no significant differences were observed between NHW and REM patients. At day 100, the cumulative incidence of Grade II-IV aGVHD was 37% [95% CI 30-44%] for NHW patients, 32% [95% CI, 18-46%] for Hispanic-White patients, 27% [95% CI, 15-40%] for Black patients, and 26% [95% CI, 13-41%] for patients of Other races (p= 0.38). The cumulative incidence of moderate to severe cGVHD at 2 years was 21% [95% CI 15-28%] for NHW patients, 25% [95% CI, 13-39%] for Hispanic-White, 17% [95% CI, 7.8-29%] for Black, and 27% [95% CI, 13-42%] for patients of Other races (p = 0.80). At 2 years, the probability of relapse was 25% [95% CI 19-32%] for NHW patients, 24% [95% CI, 12-39%] for Hispanic-White patients, 27% [95% CI, 15-40%] for Black patients, and 18% [95% CI, 7.1-33%] for patients of Other races (p = 0.97). During the same time interval, non-relapse mortality (NRM) for NHW patients, Hispanic-White patients, Black patients, and patients of Other races were 19% [95% CI, 13-25%], 15% [95% CI, 5.9-27%], 19% [95% CI, 9.4-32%], and 24% [95% CI, 11-40%] (p = 0.73), respectively. At 2 years, relapse free survival (RFS) was 56% [95% CI 49-64%] for NHW patients, 61% [95% CI, 47-79%] for Hispanic-White patients, 54% [95% CI, 41-71%] for Black patients, and 58% [95% CI, 43-78%] for patients of Other races (p = 0.77). Comparably, OS at 2 years for NHW, Hispanic-White patients, Black patients, and patients of Other races was 64% [95% CI, 57-72%], 72% [95% CI, 60-88%], 53% [95% CI, 40-71%], and 63% [95% CI, 49-83%] respectively after two years (p = 0.92). In multivariate analysis, race/ethnicity had no significant impact on incidence of Grade II-IV aGVHD (p= 0.40), moderate/severe cGVHD (p = 0.80), rates of relapse (p = 0.86), NRM (p= 0.77), RFS (p = 0.69), or OS (p = 0.64) (Table). Conclusions These results show that the use of HLA mismatched donor HCT with PTCy achieves comparable clinical outcomes between REM and NHW patients. Our study suggests that PTCy effectively contributes to equitable healthcare in the setting of allogeneic HCT for REM patients.

Toxicities Associated with Tyrosine Kinase Inhibitor Maintenance Following Allogeneic Hematopoietic Cell Transplantation in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Background Use of tyrosine kinase inhibitor (TKI) maintenance following allogeneic hematopoietic cell transplantation (HCT) in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia may help to prevent post HCT relapse but is difficult to administer due to toxicity. However, these toxicities and their impact on maintenance is not fully characterized. Herein, we report our experience at a single, large transplant center to describe toxicities encountered with post HCT TKI maintenance in Ph+ ALL. Methods Ph+ ALL patients (pts) who underwent 1st allogeneic HCT at City of Hope between 2003-2021 and received at least one dose of TKI maintenance were included in this retrospective analysis. Baseline characteristics and toxicities were summarized via descriptive analysis, and groups were compared via Fischer test. Survival analyses were calculated from the time of TKI initiation. Results Baseline characteristics are described in Table 1. Of the 186 pts studied, 50 (26.8%) received imatinib and 136 (73.2%) received a newer generation TKI (NG-TKI: 112 dasatinib, 6 nilotinib, 1 bosutinib, 17 ponatinib) at a median time of 78 days (IQR, 41-134) and 91 days (IQR, 58-129), respectively. A total of 96 patients (51.6%) began TKI maintenance within 90 days of HCT. Post HCT TKI was started prophylactically in 149 patients (80.1%) while 37 patients (19.9%) received TKI preemptively for positive MRD. The MRD status at time of HCT differed between the imatinib group and NG-TKI group. In the imatinib group MRD was negative in 33 of 50 patients (66.0%) compared with 78 of 136 patients (57.4%) in the NG-TKI group (P<0.01). There were 12 (24.0%) vs 18 (13.2%) with an unknown MRD-status at HCT in the imatinib vs NG-TKI groups, respectively ( P<0.01). The median follow-up duration for surviving patients in the entire cohort was 5.5 years (range, 1.0-17.5). The median cumulative TKI exposure was 413.5 days (range, 4-2740). The median cumulative imatinib exposure in patients initially receiving imatinib was 328 days (range, 3-2216), while the median cumulative NG-TKI exposure in patients initially receiving NG-TKI was 268.5 days (range, 3-2740), respectively. The median cumulative exposure of dasatinib, nilotinib, bosutinib and ponatinib were 249 days (range, 3-2740), 222 days (range, 114-839), 371 days, and 576 days (range, 72-921), respectively. Twenty-seven (54.0%) vs 75 (55.2%) patients completed >12 months of initial imatinib and NG-TKI maintenance (P=1.0), respectively. Of the treated patients, 78 pts (41.9%) required at least one dose reduction of their initial TKI due to toxicity; 19 of them (10.2%) required ≥2 dose reductions. When imatinib maintenance was used as the initial TKI, a dose reduction due to toxicity was required in 18 patients (36.0%), of whom 7 patients (14.0%) required ≥2 dose reductions. Initial NG-TKI maintenance required a dose reduction due to toxicity in 60 (44.1%), of whom 12 (8.8%) required ≥2 dose reductions. One hundred and thirty-nine patients (74.7%) had their maintenance TKI therapy interrupted, 122 (65.6%) due to toxicity. Sixty-seven patients (36.0%) did not complete their pre-determined maintenance period owing to toxicity; 70 pts (37.6%) discontinued one TKI, and 11 (5.9%) discontinued two TKIs, due to toxicity. The most common reasons for discontinuing the initial TKI are listed in Table 2, including 45.2% of patients due to toxicity, and 12.9% due to progressive disease. Toxicity-related discontinuations occurred within 6 months on that TKI in 63.0% of patients, and 75.3% within the first 12 months. Five-year overall survival and progression-free survival from the start of TKI were similar between the imatinib and NG-TKI group; 83.1% vs 76.9% (P=0.74) and 72.8% vs 70.5% (P=0.63), respectively (Figure 1). Conclusion Toxicities resulting in dose reductions, interruptions, and discontinuation are common in TKI maintenance post HCT. The toxicity profile (mainly GI and blood count related), frequency, and severity of TKIs in the post HCT setting appears to be different than what has been previously reported in the pre-HCT setting, making it a formidable challenge to meet the recommended cumulative TKI maintenance exposure (2 years) per the NCCN guidelines. While the choice of TKI did not appear to impact on long-term outcomes and relapse rates were not excessive in our analysis, further studies are needed to develop tolerable and personalized TKI maintenance strategies.

Improving Outcomes of Peripheral Blood Stem Cell (PBSC) HLA-Mismatched Unrelated Donor (MMUD) Hematopoietic Cell Transplantation (HCT): Effect of Graft Versus Host Disease (GVHD) Prophylaxis

Human leukocyte antigen (HLA) well matched donor (related or unrelated) has remained the preferred donor source for patients undergoing HCT for hematological disease, but the probability of finding a suitable related or unrelated donor has varied based on ethnic groups. HLA-mismatch unrelated donor (MMUD) transplantation has improved access to HCT in underrepresented minority groups and patients of mixed race. Historically, MMUD HCT has been associated with inferior survival outcomes compared to matched unrelated donor HCT when using conventional platforms of GVHD prophylaxis. (PMID: 31449184, 20538804). Efforts to improve outcomes have investigated the addition of a third agent such as anti-thymocyte globulin (ATG), mini-methotrexate (MTX) or mycophenolate mofetil (MMF). More recently, a study by the National Marrow Donor Program (NMDP) demonstrated the feasibility of post-transplant cyclophosphamide (PTCy) based GVHD prophylaxis in MMUD HCT using bone marrow (BM) grafts (PMID: 33905264). Additionally, our group demonstrated promising overall survival (OS) and GVHD-free/relapse-free-survival (GRFS) rates in peripheral blood stem cell (PBSC) MMUD HCT using PTCy based GVHD prophylaxis (PMID: 34156440). Here, we compare outcomes of PBSC MMUD HCT among patients receiving GVHD prophylaxis with either: (1) tacrolimus plus sirolimus (T/S), (2) T/S plus mini-methotrexate (T/S/MTX), or (3) PTCy, MMF, and tacrolimus or sirolimus (PTCy). Patients with various hematologic malignancies that underwent PBSC MMUD HCT (≥5/8 HLA-matched donors) at City of Hope between January 2005 and December 2021 were included in this retrospective review. Of 390 subjects included, GVHD prophylaxis included T/S (n=114), T/S/MTX (n=160), and PTCy (n=116). The median age was 51 (range:15-79), 53.3% of patients belonged to a racial/ethnic minority, and 34.8% (n=136) patients had disease risk index high or very high. Degree of HLA mismatch was 7/8 (91.3%), 6/8 (8.5%), and 5/8 (0.3%). Hematologic diseases included AML (40.3%), ALL (20.3%), MDS/MPN (15.9%), Lymphoma (16.9%), and CML/CMMol (6.7%). Most common conditioning regimens were fTBI-based (34.4%) and melphalan-based (57.2%). HCT comorbidity index was ≥ 3 in 30.8% (n=120), which was most common in PTCy compared to T/S and T/S/MTX: 48.3% vs. 23.7% vs. 23.1%, P<.001. The rate of neutrophil engraftment (15 days vs. 15 days vs 16 days, P=0.002) and platelet engraftment (15 days vs. 16 days vs 27 days, P=0.004) were shorter in T/S compared to T/S/MTX and PTCy, respectively. With median follow-up of 5.4 years (range: 1.0-16.7) the 5-year OS was superior in PTCy (P=0.045) compared to T/S and T/S/MTX: 58.0% (95% CI: 46.6-67.8) vs. 41.1% (95% CI: 31.9-50.1) and 39.6% (95% CI: 32-47.2). The 5-year disease-free survival (DFS) was superior in PTCy (P=0.042) compared to T/S and T/S/MTX: 54.2% (95% CI: 43.3-63.9) vs. 37.1% (95% CI: 28.2-46.0) vs. 37.2% (95% CI: 29.7-44.6), respectively. There was no significant difference in 5-year cumulative incidence of relapse (CIR) in T/S vs. T/S/MTX vs. T/S vs. PTCy: 29.1% (95% CI: 21.0-37.6) vs. 29.5% (95% CI: 22.6-36.7) vs. 22.1% (95% CI: 14.3-31.0), respectively. Additionally, there was no significant difference in 2-year NRM between the cohorts (P=0.459): 24.6% (95% CI: 17.1-32.9) vs. 23.1% (95% CI: 16.9-29.9) vs. 20.4% (95% CI: 13.5-28.4), respectively. The rate of 100-day Grade III-IV acute GVHD were similar between in the cohorts (P=0.321): 19.3% (95% CI: 12.6-27.0) vs. 18.1% (95% CI: 12.6 -24.5) vs. 12.9% (95% CI: 7.6-19.7). When comparing T/S vs. T/S/MTX and PTCy, the incidence of chronic GVHD was less in the PTCy cohort at both 1-year and 2-years (P<.001) with 1-year incidence of 55.0% (95% CI: 45.1-63.7) vs. 61.9% (95% CI: 53.8-68.9) vs. 38.9% (95% CI: 30-47.8), respectively, and 2-year incidence of 58.9% (95% CI: 49.0-67.6) vs. 66.2% (95% CI: 58.3-73.1) vs. 42.7% (95% CI: 33.4-51.6), respectively. To our knowledge, this is the largest reported single center outcome of PBSC MMUD HCT. In this study, we demonstrate the superiority of PTCy based GVHD prophylaxis compared to T/S and T/S/MTX in outcomes of 5-year OS (P=0.045), 5-year DFS (P=0.042), and incidence of chronic GVHD (P<.001). Our experience further supports the superiority of PTCy as the preferred GVHD prophylaxis in the PBSC MMUD HCT setting achieved by lowering chronic GVHD and associated complications.

JAK2V617F mutation and associated chromosomal alterations in primary and secondary myelofibrosis and post-HCT outcomes

AbstractJAK2V617F is the most common driver mutation in primary or secondary myelofibrosis for which allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment. Knowledge of the prognostic utility of JAK2 alterations in the HCT setting is limited. We identified all patients with MF who received HCT between 2000 and 2016 and had a pre-HCT blood sample (N = 973) available at the Center of International Blood and Marrow Transplant Research biorepository. PacBio sequencing and single nucleotide polymorphism–array genotyping were used to identify JAK2V617F mutation and associated mosaic chromosomal alterations (mCAs), respectively. Cox proportional hazard models were used for HCT outcome analyses. Genomic testing was complete for 924 patients with MF (634 primary MF [PMF], 135 postpolycythemia vera [PPV-MF], and 155 postessential thrombocytopenia [PET-MF]). JAK2V617F affected 562 patients (57.6% of PMF, 97% of PPV-MF, and 42.6% of PET-MF). Almost all patients with mCAs involving the JAK2 region (97.9%) were JAK2V617-positive. In PMF, JAK2V617F mutation status, allele burden, or identified mCAs were not associated with disease progression/relapse, nonrelapse mortality (NRM), or overall survival. Almost all PPV-MF were JAK2V617F-positive (97%), with no association between HCT outcomes and mutation allele burden or mCAs. In PET-MF, JAK2V617F high mutation allele burden (≥60%) was associated with excess risk of NRM, restricted to transplants received in the era of JAK inhibitors (2013-2016; hazard ratio = 7.65; 95% confidence interval = 2.10-27.82; P = .002). However, allele burden was not associated with post-HCT disease progression/relapse or survival. Our findings support the concept that HCT can mitigate the known negative effect of JAK2V617F in patients with MF, particularly for PMF and PPV-MF.

Family Caregiver Experiences in the Inpatient and Outpatient Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation Settings: A Qualitative Study

Caregivers (ie, family and friends) are essential in providing care and support for patients undergoing hematopoietic cell transplantation (HCT) and throughout their recovery. Traditionally delivered in the hospital, HCT is being increasingly provided in the outpatient setting, potentially heightening the burden on caregivers. Extensive work has examined the inpatient HCT caregiving experience, yet little is known about how caregiver experiences may differ based on whether the HCT was delivered on an inpatient or outpatient basis, particularly during the acute recovery period post-HCT. This study explored the similarities and differences in caregiver experiences in the inpatient and outpatient settings during the early recovery from reduced-intensity conditioning (RIC) allogeneic HCT. We conducted semistructured interviews (n = 15) with caregivers of adults undergoing RIC allogeneic HCT as either an inpatient (n = 7) or an outpatient (n = 8). We recruited caregivers using purposeful criterion sampling, based on the HCT setting, until thematic saturation occurred. Interview recordings were transcribed and coded through thematic analysis using Dedoose v.9.0. The study analysis was guided by the transactional model of stress and coping and the model of adaptation of family caregivers during the acute phase of BMT. Three themes emerged to describe similar experiences for HCT caregivers regardless of setting: (1) caregivers reported feeling like they were a necessary yet invisible part of the care team; (2) caregivers described learning to adapt to changing situations and varying patient needs; and (3) caregivers recounted how the uncertainty following HCT felt like existing between life and death while also maintaining a sense of gratitude and hope for the future. Caregivers also reported distinct experiences based on the transplantation setting and 4 themes emerged: (1) disrupted routines: inpatient caregivers reported disrupted routines when caring for the HCT recipient while simultaneously trying to manage non-caregiving responsibilities at home and work, and outpatient caregivers reported having to establish new routines that included frequent clinic visits with the patient while altering or pausing home and work responsibilities; (2) timing of caregiver involvement: inpatient caregivers felt more involved in care after the patient was discharged from the HCT hospitalization, whereas outpatient caregivers were already providing the majority of care earlier in the post-transplantation period; (3) fear of missing vital information: inpatient caregivers worried about missing vital information about the patient's care and progress if not physically present in the hospital, whereas outpatient caregivers feared overlooking vital information that may warrant contacting the care team as they monitored the patient at home; and (4) perceived adequacy of resources to meet psychosocial and practical needs: inpatient caregivers reported having adequate access to resources (ie, hospital-based services), whereas outpatient caregivers felt they had more limited access and needed to be resourceful in seeking out assistance. Inpatient and outpatient HCT caregivers described both similar and distinct experiences during the acute recovery period post-HCT. Specific interventions should address caregiver psychosocial needs (ie, distress, illness uncertainty, communication, and coping) and practical needs (ie, community resource referral, preparedness for home-based caregiving, and transplantation education) of HCT caregivers based on setting.

Alemtuzumab and CXCL9 levels predict likelihood of sustained engraftment after reduced-intensity conditioning HCT.

Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peritransplantation alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from the Bone Marrow Transplant Clinical Trials Network 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism <5% after initial engraftment and/or requirement of cellular intervention). Thirty-three patients with hemophagocytic lymphohistiocytosis (n= 25) and other IEIs (n= 8) who underwent HCTs with T-cell-replete grafts were included. Patients with day 0 alemtuzumab levels ≤0.32μg/mL had a markedly lower incidence of MC, 14.3%, vs 90.9% in patients with levels >0.32μg/mL (P= .008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels >0.32μg/mL (P= .08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day 14+ CXCL9 level ≤2394 pg/mL (day 14+ median) was 73.6% vs 0% in patients with a level >2394 pg/mL (P= .002). CXCL9 levels inversely correlated with alemtuzumab levels. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely affect sustained engraftment in the nonmyeloablative HCT setting. This trial was registered at www.clinicaltrials.gov as #NCT01998633.

Non-hematopoietic cell transplant-related veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in solid tumor and hematologic malignancies: A systematic review.

e24094 Background: VOD/SOS is a serious liver injury caused by toxic damage to sinusoidal endothelial cells. It has been linked to conditioning regimens preceding hematopoietic cell transplant (HCT) but little is known about its epidemiology and characteristics outside the HCT setting. We conducted a systematic review to examine the incidence, burden of illness, and management of non-HCT VOD/SOS. Methods: We searched MEDLINE, Embase (2002–2022), and relevant congress proceedings (2019–2022) for studies reporting incidence, diagnosis, clinical and patient characteristics, humanistic and economic burden, and treatments in non-HCT VOD/SOS. All study designs were eligible except case series of &lt; 5 patients. Pyrrolizidine alkaloid-induced VOD/SOS was excluded. Results: We identified 3,544 records and included 80 studies; 58% were retrospective cohort studies. Sample sizes ranged from 5 to 12,941; 38% of the studies included &gt; 100 patients. The highest incidences of non-HCT VOD/SOS were in patients with colorectal liver metastases (CLM) (median 41%) and Wilms tumor (median 14%) (table). Diagnostic criteria were heterogenous. Rubbia-Brandt histological criteria were used in CLM. In other disease settings, diagnosis varied and was based on clinical criteria (eg, McDonald, Seattle, or Baltimore). Management of VOD/SOS included defibrotide, supportive therapy (eg, fluid restriction, blood products) and switching/pausing chemotherapy. No usable data were found on humanistic/economic burden. Conclusions: Non-HCT VOD/SOS occurs in diverse disease areas, including hematologic and solid tumor cancers. Lack of consensus regarding diagnosis of non-HCT VOD/SOS may indicate underdiagnosis. Clinicians should be vigilant for VOD/SOS even in non-HCT patients. Defibrotide is approved for post-HCT VOD/SOS but there is no approved therapy for non-HCT VOD/SOS; future trials should focus on diagnosis and treatment outside the HCT setting, which represents a significant unmet need. A limitation of the current work is the suboptimal reporting and low methodological quality in some primary studies.[Table: see text]

Randomized Controlled Trial of Isha Kriya versus Observation to Improve Quality of Life in Hematopoietic Cell Transplantation Recipients

Hematopoietic cell transplantation (HCT) impacts its recipients' quality of life (QoL). Few mindfulness-based interventions (MBI) in HCT recipients have shown feasibility, but heterogeneous practices and outcome measures have questioned the real benefit. We hypothesize that a self-guided meditation as a mobile app will improve QoL in the acute HCT setting. This single-center, open-label, randomized controlled trial was conducted in 2021-2022. The study was cleared by Institutional Ethics Committee and registered at the Clinical Trial Registry of India. Recipients were included after obtaining written informed consent. Recipients without access to smartphones or regular practitioners of yoga, meditation, or other mind-body practice were excluded. Autologous + allogeneic HCT recipients of age ≥ 18 years were included in the study. Recipients were randomized to the control arm or Isha kriya arm in a 1:1 ratio stratified by type of transplant. Patients in the Isha kriya arm were recommended to perform the kriya twice daily from pre-HCT to day+30 post-HCT. Isha Kriya is 12-minute guided meditation based on the principles of yoga, focussing on breath, awareness, and thought. The primary endpoint was the QoL summary scores assessed by the Functional Assessment of Cancer Therapy - Bone Marrow Transplantation (FACT-BMT) and the Patient-Reported Outcomes Measurement Information System–Global Health (PROMIS-GH) questionnaires. The secondary endpoints were the difference in QoL domain scores. The validated questionnaires were self-administered before the intervention, day +30, and day +100 after HCT. The analysis of endpoints was done on an intention-to-treat basis. Domain and summary scores were calculated for each instrument as recommended by the developers. A p-value <0.05 was used for statistical significance, and cohen's d effect size determined clinical significance. A total of 72 HCT recipients were randomized to the Isha kriya and the control arm. Patients in both arms were matched for age, gender, diagnosis, and type of HCT. Both arms had no difference in the pre-HCT QoL domain, summary, and global scores. Post-HCT at day+30, there was no difference in the mean FACT-BMT total scores (112.9 ± 16.8 vs.101.2 ± 13.9, p = 0.2) and the mean global health scores (Global mental health 45.1 ± 8.6 vs. 42.5 ± 7.2, p = 0.5, global physical health 44.1 ± 6.3 vs. 44.1 ± 8.3, p = 0.4) in the two groups. There was similarly no difference in the physical, social, emotional, and functional domain scores. However, the mean BMT-subscale scores, which addresses BMT-specific quality-of-life concerns, were statistically and clinically significantly higher in the Isha kriya arm than the control arm (27.9 ± 5.1 vs. 24.4 ± 9.2, p = 0.03, Cohen's d 0.5, medium effect size). This effect was transient as the day+100 scores showed no difference (28.3 ± 5.9 vs. 26.2 ± 9.4, p = 0.3). Isha kriya did not improve the FACT-BMT total and global health scores in the acute HCT setting. However, practicing Isha kriya for a month did show a transient improvement in the FACT-BMT subscale scores on day +30 but not on day +100 post-HCT.

Day 4 collection of granulocyte colony-stimulating factor-mobilized HLA-matched sibling donor peripheral blood allografts demonstrates no long-term increase in chronic graft-versus-host disease or relapse rates

Background aimsIn a previous pilot study of HLA-matched sibling donor hematopoietic cell transplantation (HCT), the authors determined the feasibility of day 4 versus day 5 granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell (PBSC) collection compared with a historical cohort. Given identified differences in the PBSC product (day 4 cohort with significantly lower infused total nucleated, mononuclear and CD3 cells compared with other collection cohorts), the authors performed a follow-up study to determine long-term post-HCT outcomes, including detailed characterization of chronic graft-versus-host disease (GVHD). MethodsThis was a prospective observational study, and the authors collected data on chronic GVHD, staging, sites of involvement and treatments. Performance status, incidence of relapse, overall survival and duration of immunosuppressive therapy (IST) were also evaluated. Data were examined retrospectively. To account for differences in length of follow-up among cohorts, the authors also determined performance status and chronic GVHD staging, sites and treatment at 2 years post-HCT. ResultsAt 2 years post-HCT, the overall survival rate was 71.7% in the day 4 cohort compared with 61.5%, 52% and 56% in the day 5, 2-day and historical cohorts, respectively (P = 0.283). The cumulative incidence of chronic GVHD was 65.2% in the day 4 cohort versus 46.4% in the day 5 cohort, 51.1% in the 2-day cohort and 65% in the historical cohort (P = 0.26). There was no significant difference in the maximum overall stage of chronic GVHD (P = 0.513), median number of sites involved (P = 0.401) or cumulative incidence of discontinuation of IST (P = 0.32). Death from chronic GVHD was less common in the day 4 and day 5 cohorts compared with the 2-day and historical cohorts, though this did not reach statistical significance. ConclusionsThe authors’ preliminary results demonstrated that collection of allogeneic matched sibling donor PBSCs on day 4 of G-CSF was feasible, reduced donor exposure to growth factor and was associated with an initial cost savings. Importantly, the authors now demonstrate that transplantation of day 4 mobilized PBSCs is not associated with any adverse outcomes post-HCT, including late effects such as chronic GVHD. Further investigation of donor G-CSF collection algorithms is merited in other HCT settings, including unrelated and mismatched related donors.

Early vascular endothelial complications after hematopoietic cell transplantation: Role of the endotheliopathy in biomarkers and target therapies development.

This work aims to review the role of endothelial dysfunction underlying the main complications appearing early after autologous and allogeneic hematopoietic cell transplantation (HCT). The endothelial damage as the pathophysiological substrate of sinusoidal obstruction syndrome (SOS) is well established. However, there is growing evidence of the involvement of endothelial dysfunction in other complications, such as acute graft-versus-host disease (aGVHD) and transplant-associated thrombotic microangiopathy (TA-TMAs). Moreover, HCT-related endotheliopathy is not only limited to the HCT setting, as there is increasing evidence of its implication in complications derived from other cellular therapies. We also review the incidence and the risk factors of the main HCT complications and the biological evidence of the endothelial involvement and other linked pathways in their development. In addition, we cover the state of the art regarding the potential use of the biomarkers of endotheliopathy in the prediction, the early diagnosis, and the follow-up of the HCT complications and summarize current knowledge points to the endothelium and the other linked pathways described as potential targets for the prevention and treatment of HCT-complications. Lastly, the endothelium-focused therapeutic strategies that are emerging and might have a potential impact on the survival and quality of life of post-HCT-patients are additionally reviewed.

A Phase 1b Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of an Investigational Microbiome Therapeutic, SER-155, in Adults Undergoing Hematopoietic Stem Cell Transplantation

Background: In patients undergoing allogeneic hematopoietic cell transplantation (HCT), loss of gastrointestinal microbial diversity is associated with risk of bloodstream infections (BSI), acute graft-versus-host disease (aGvHD), and death. SER-155 is an investigational cultivated microbiome therapeutic rationally designed to improve clinical outcomes in HCT by restoring colonization resistance to potential pathogens, promoting epithelial barrier integrity, and reducing colonic inflammation. SER-155-001 is a Phase 1b study to evaluate the efficacy, safety, and pharmacokinetics (PK) of SER-155 in adults undergoing HCT that is currently enrolling at 4 sites. Study Design and Methods: This study will enroll approximately 70 subjects ≥ 18 years in an open-label Cohort 1 (n = 10) followed by a double-blind, placebo-controlled Cohort 2 (n = 60) randomized 1:1 to SER-155 or placebo and stratified by conditioning regimen intensity. Exclusion criteria include history of severe colitis or active inflammatory bowel disease or total colectomy, umbilical cord blood or ex vivo T-cell depletion, exposure to fecal microbiota transplant or any live microbial therapeutic within 3 months prior to screening, and evidence of relapse or progression of hematologic malignancy (minimal residual disease is allowed). Following screening, subjects in both cohorts will receive 2 treatment courses (before and after HCT), each comprised of microbiome conditioning with oral vancomycin or placebo followed by SER-155 or placebo, and a conditional 3rd treatment course if the subject receives antibiotics (Table 1; Figure 1). Safety outcomes will be followed through 52 weeks post HCT. The primary endpoint is to evaluate the incidence and severity of adverse events, serious adverse events, and adverse events of special interest. Secondary endpoints include rates of BSI, gastrointestinal infections, aGvHD, febrile neutropenia and overall survival in placebo vs SER-155 arms. Microbiome related endpoints include engraftment of SER-155 bacterial strains in the gastrointestinal tract (PK endpoint) and fecal microbiome diversity, composition and metabolites. In April 2022, the SER-155 Data and Safety Monitoring Committee met as part of a planned review of available safety data from Cohort 1 and supported continuation of Cohort 1 enrollment. Summary: In this Phase 1b study, the feasibility, safety, and clinical efficacy of SER-155 is being assessed in the setting of allogeneic HCT. This trial will add to the expanding clinical experience of microbiome-directed interventions in allogeneic HCT recipients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association between Patient-Reported Social Determinant of Health Outcomes and a Social Genomics Profile in Allogeneic Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis

Introduction Patient-reported outcomes (PROs) capture the subjective experience of a patient's social and environmental context, providing a firsthand account of this and other social determinants of health (SDOH). An individual's socioenvironmental context is linked to a wide array of health outcomes, including for patients undergoing hematopoietic cell transplantation (HCT) [1, 2]. Social genomics, the study of socioenvironmental effects on human gene expression, offers a framework for understanding these complex biobehavioral relationships [3]. The conserved transcriptional response to adversity (CTRA) is a genomic biomarker characterized by increased expression of pro-inflammatory genes and decreased innate anti-viral gene expression [4]. The CTRA profile has been associated with psychosocial adversity and is predictive of clinical outcomes in HCT, and thus may be a means to map the biologic sequelae of social hardship [2, 4]. The objective of this study was to examine the association of pre-transplant CTRA profile with psychosocial PROs in allogeneic HCT recipients. Methods A cross-sectional analysis of data from a subset of participants enrolled on a prior CIBMTR study testing the feasibility of centralized collection of PROs in allogeneic HCT [5] was completed. For the present analysis, eligible patients from this larger cohort were those aged >18 years with baseline (pre-HCT) PRO measures and available pre-transplant banked biospecimens. PROs included the 36-Item Short Form Health Survey (SF-36) and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT). Descriptive analyses of patient-, disease-, and transplant-related characteristics were prepared. CTRA was derived from banked whole blood specimens using RNA sequencing. Transcript-per-million values of the 47 indicator genes were log2 transformed and analyzed using mixed effects linear regression models testing relative average gene expression levels to standardized PRO score controlling for age, sex, race, malignant versus non-malignant disease, and performance status. Results A total of n=140 patients representing 8 transplant centers in the United States were included. Patient characteristics are depicted in Table 1. The median age was 55 years (range 18-75y), 44% were female, and 90% identified as White. A majority (96%) of patients had a hematologic malignancy diagnosis, with acute myelogenous leukemia (AML) being most common (35%). There were statistically significant associations between lower CTRA gene expression and higher FACT-BMT total scores (β-coefficient -0.041 difference in log2 CTRA RNA abundance/SD PRO score, p-value=0.003) social well-being (β-coefficient -0.058 difference in log2 CTRA RNA abundance/SD PRO score, p-value=0.0001), physical well-being, (β-coefficient -0.031 difference in log2 CTRA RNA abundance/SD PRO score, p-value=0.031) and FACT-G scores (β-coefficient -0.042 difference in log2 CTRA RNA abundance/SD PRO score, p-value=0.003) as depicted in Figure 1. This corresponds to a 10.7%, 14.8%, 8.2%, and 11.1% difference, respectively, in CTRA gene expression per 4-SD range of variation in each PRO. Conclusions Patient reports of socioenvironmental experience were associated with the CTRA immunoregulatory pattern in adult allogeneic HCT recipients, with social well-being emerging as the most significant domain. This finding is consistent with prior literature and supports the importance of social well-being and community context in the setting of allogeneic HCT. Heightened CTRA expression could provide a potential molecular mechanism for social gradients in HCT outcomes, although this was not experimentally tested in this study. Further research and intervention that targets this pathway could support optimal multidimensional outcomes in this high-risk population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Persistence of Mixed Full Donor Chimerism after Double Cord Blood Transplantation. Example of Tolerance in Allogeneic Hematopoietic Cell Transplantation Setting

Background Double umbilical cord blood transplantation (UCBT) is recognized as an alternative source of hematopoietic donor cells for allogeneic haematopoietic cell transplantation (HCT), particularly in adult setting. Because of important infectious complications, UCBT are rarely utilized and more and more replaced by haplo-identical cell transplantation for adult patients. Nevertheless, some very good results were observed with a long-term follow-up. In most cases, after several weeks, one unit turns immuno-dominant and thus, the second one is no longer detected. Patients and Methods We reported three cases of long-term mixed full donor chimerism associated to documented complete remission of haematological malignancies after double UCBT. The indications of UCBT were acute myeloid leukaemia for 2 patients [1 AML MRC (female of 65 years) and 1 transformation of Fanconi disease (female of 20 years)] and acute lymphoid leukaemia for 1 patient (female of 22 years). AML received a reduced intensity and ALL a standard conditioning. The general characteristics of recipients and UCB are presented in Table 1. The chimerism follow-up were performed by STR and qPCR techniques with a sensitivity of 5 and 0.2% respectively. Early after transplantation, patient 1 developed a grade I graft-versus-host disease (GVHD), patient 3 a grade II GVHD treated by extracorporeal photopheresis, and patient 2 did not develop any GVHD. The follow-up of these patients were 14, 13 and 8 years respectively after UCBT without any episodes of relapse and at the last follow-up still a total donor mixed chimerism. Results Results of STR and qPCR after transplantation early revealed the presence of the two transplant units with a total donor chimerism (Table 1). Patient 1 presented a perfectly balanced chimerism with 54 % of the majority unit. The other two patients showed an imbalance in the proportions of their two UCB with 83% and 72% of their majority units respectively but a long-term persistence of 17% and 28% of their second UCB. The study of total blood chimerism during their follow-up revealed a stabilization of the proportions of the two units during the first year (Figure 1). A more in-depth study of circulating cell subsets (CD3+, CD15+ and CD19+) chimerism of patient 1 revealed a very strong initial imbalance of the two units, which ended up being balanced at two years after transplantation. In the other two patients, the respective study of CD3+ and CD33+ cells showed a stabilization of the two unit percentage around six months after transplantation. At five years after transplantation, patient 1 had an in-depth study of circulating cells sub-populations (CD4+ T lymphocytes, CD8+ T lymphocytes, B-lymphocytes, natural killer cells, regulatory T cells, monocytes, naive CD4+ and CD8+ T lymphocytes) by flow cytometry, after separation of the two units cells by specific monoclonal antibody directed against HLA mismatching antigen (HLA-A2). This analysis revealed an imbalance in the percentage of NK and monocytes. The immune-dominant unit had three times more NK cells than the other one and this imbalance ratio increased by twenty-two for monocytes. A co-culture study of the CD4+ lymphocytes demonstrated a lack of reactivity of both unit against the other one but a normal ability to react against an allogeneic third-part cell. Conclusions This expected tolerance, highlighted in co-culture experience, showed rare cases of naturally induced graft tolerance. A study of tolerance markers and underlying mechanisms in these special cases of persistent mixed full donor chimerism is necessary to acquire better knowledge and to define more investigations ways for the induction of tolerance in patients receiving hematopoietic cell transplantation or organ transplantations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Infections With Stenotrophomonas maltophilia in Children Undergoing Anticancer Therapy or Hematopoietic Cell Transplantation: A Multicenter Nationwide Study.

Infections caused by Stenotrophomonas maltophilia (SM) have documented high mortality rate in immunocompromised patients. This nationwide multicenter study was performed to analyze the epidemiology of SM infections in children undergoing anticancer therapy (pediatric hematology and oncology [PHO]) or hematopoietic cell transplantation (HCT) over 2012-2019, including incidence and outcome of SM infections, as well as treatment regimens and multidrug resistance. Cumulative incidence of SM infections was calculated using the competing risk analysis from the day of diagnosis (PHO setting) or from the day of transplantation (HCT setting). The Kaplan-Meier method was used to determine survival from infection. During the study period of 8 years, a total number of 1356 HCTs and 7337 children newly diagnosed for malignancy were analyzed. Diagnosis of acute leukemia was a predisposing factor for SM infection. The cumulative incidence of SM infections was comparable in HCT patients in comparison to PHO (0.81% vs. 0.76%). High rate of trimethoprim/sulfamethoxazole susceptibility among SM isolates was observed in both groups of patients (80.8%). Although this was the drug of choice, survival rates from SM infections were significantly lower in HCT than in PHO (45% vs. 85%, P = 0.001, log-rank test). We found the transplant procedure and lack of clinical resolution after 18 days of antibiotic therapy to be independent mortality risk factors. The risk of SM infections and the occurrence of resistant bacterial strains in allo-HCT patients were comparable to PHO patients. Irrespective of target antibiotic therapy, the outcome of SM infections was better in the PHO setting.