Nonmyeloablative Hematopoietic Stem Cell Transplantation Research Articles

COVID-19 impact in Crohn’s disease patients submitted to autologous hematopoietic stem cell transplantation

BACKGROUND Severe acute respiratory syndrome coronavirus 2 is the virus responsible for coronavirus disease 2019 (COVID-19), a disease that has been blamed for inducing or exacerbating symptoms in patients with autoimmune diseases. Crohn's disease (CD) is an inflammatory bowel disease that affects genetically susceptible patients who develop an abnormal mucosal immune response to the intestinal microbiota. Patients who underwent hematopoietic stem cell transplantation (HSCT) are considered at risk for COVID-19. AIM To describe for the first time the impact of COVID-19 in CD patients who had undergone autologous, non-myeloablative HSCT. METHODS In this descriptive study a series of 19 patients were diagnosed with positive COVID-19. For two patients there were reports of the occurrence of two infectious episodes. Parameters related to HSCT, such as time elapsed since the procedure, vaccination status, CD status before and after infection, and clinical manifestations resulting from COVID-19, were evaluated. RESULTS Among the patients with COVID-19, three, who underwent Auto HSCT less than six months ago, relapsed and one, in addition to the CD symptoms, started to present thyroid impairment with positive anti-TPO. Only one of the patients required hospitalization for five days to treat COVID-19 and remained in CD clinical remission. Nine patients reported late symptoms that may be related to COVID-19. There were no deaths, and a statistical evaluation of the series of COVID-19 patients compared to those who did not present any infectious episode did not identify significant differences regarding the analyzed parameters. CONCLUSION Despite the change in CD status in three patients and the presence of nine patients with late symptoms, we can conclude that there was no significant adverse impact concerning COVID-19 in the evaluated patients who underwent HSCT to treat CD.

Non-myeloablative allogeneic HSCT in adult patients with sickle cell disease: Multiple take-home points from the Saudi Arabia experience.

Non-myeloablative allogeneic HSCT in adult patients with sickle cell disease: Multiple take-home points from the Saudi Arabia experience.

Favorable outcome of non-myeloablative allogeneic transplantation in adult patients with severe sickle cell disease: A single center experience of 200 patients.

Allogeneic hematopoietic stem cell transplant (HSCT) for adults with severe sickle cell disease (SCD) is potentially curative but not commonly utilized therapy due to complications such as graft failure (GF) and organ toxicity. Herein, we are reporting our long-term outcome data of non-myeloablative (NMA) HSCT in adults with severe SCD with emphasis on factors predicting event free survival (EFS). Adults with severe SCD undergoing NMA match-related donor allogeneic HSCT from 2015 to 2021 with at least 12 months of follow-up were included. A total of 200 patients were included with a median age of 26 years (14-43) and 56% were male. The median infused CD34 dose was 13.7 (5.07-25.8), respectively. Median absolute neutrophil count engraftment was 19 (13-39) days with 51% of patients receiving GCSF to expedite recovery. A total of 17 patients experienced GF; 3 as primary and 14 as secondary within a median time of 204 days (40-905). A 76% successfully discontinued sirolimus at the last follow-up. Median follow-up for the cohort is 29.2 (2.1-71.4) months. Estimated 3-year EFS and OS were 88.2% (81.9-92.5) and 94.6% (89.2-97.3). At multivariable analysis, minor ABC incompatibility hazard ratio (HR) 4 (1.3-12.1; 0.014) and allo-antibody against non-ABO donor antigens HR 4.3 (1.3-14.1; 0.016) were significant for EFS. No clonal evolution or myeloid malignancies were seen. This largest single-center report of NMA HSCT in adults with severe SCD further delineated its feasibility, potential toxicities, and fertility outcomes. GF remains a major impediment and appears dependent on ABO matching and non-ABO antibodies.

Post-Transplant Maintenance in AML and MDS Patients Undergoing Non-Myeloablative Peripheral Blood Stem Cell Transplant with Post-Transplant Cyclophosphamide

Disease relapse remains a major cause of mortality for patients with AML and MDS undergoing allogeneic hematopoietic stem cell transplant (HSCT). Several trials have evaluated the use of hypomethylating agents (HMA) like azacitadine or decitabine as post-transplant maintenance with its use not currently recommended. Here we review our experience with AML and MDS patients undergoing non-myeloablative (NMA) peripheral blood stem cell transplant using post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis and in whom post-transplant maintenance was used. We retrospectively reviewed AML and MDS patients who had a NMA HSCT from January 2015 until December 2022. All patients received fludarabine, cyclophosphamide and TBI200 or TBI300 as conditioning regimen with tacrolimus, mycophenolate mofetil and PTCy as GVHD prophylaxis (Table 1). Sixty patients received TBI200 and 28 patients received TBI300. Median age at transplant was 65.5 years in the TBI200 group vs 69 years in the TBI300 group. Haploidentical donors were used in 59 (98%) of patients in the TBI200 group and 18 (64%) of patients in the TBI300 group. Minimal residual disease (MRD) was present 35 (58%) of patients receiving TBI200 and 12 (43%) of patients receiving TBI300. Post-transplant therapy was given in 46 (77%) of patients in the TBI200 group and 23 (82%) in the TBI300 group. The majority of patients in both groups received azacitadine. The median cycles of HMAs was 4 (range 1-12). We found no difference in OS, PFS, relapse, or NRM comparing Flu/Cy/TBI200 and Flu/Cy/TBI300 (not shown). We evaluated the use of post-transplant maintenance on survival endpoints and found no difference in endpoints. In addition, post-transplant maintenance had no effect on OS, PFS, relapse, NRM or grade II-IV aGVHD regardless of MRD status at time of transplant. While, this is a small retrospective series, it warrants further investigation into the use of post-transplant maintenance in the setting of NMA HSCT using PTCy. While the use of HMA's did not increase NRM, their efficacy and perhaps combination with other drugs needs to be more closely studied in NMA PTCy transplants to decrease relapse.

Longitudinal neurocognitive effects of nonmyeloablative hematopoietic stem cell transplant among older adolescents and adults with sickle cell disease: A description and comparison with sibling donors

ABSTRACT Sickle cell disease (SCD) is associated with increased risk of neurocognitive deficits. However, whether functioning changes following nonmyeloablative hematopoietic stem cell transplant (HSCT) remains unclear. This study aimed to examine changes in neuropsychological functioning pre- to post-transplant among patients with SCD and compare patients and siblings. Adults with SCD (n = 47; M age = 31.8 ± 8.9) and their sibling stem cell donors (n = 22; M age = 30.5± 9.2) enrolled on a nonmyeloablative HCST protocol completed cognitive and patient-reported outcome assessments at baseline and 12 months post-transplant. Path analyses were used to assess associations between pre-transplant variables and sibling/patient group status and post-transplant function. Mean patient cognitive scores were average at both timepoints. Patient processing speed and somatic complaints improved from baseline to follow-up. Baseline performance predicted follow-up performance across cognitive variables; patient/sibling status predicted follow-up performance on some processing speed measures. Results suggest that patients with SCD demonstrate slower processing speed than siblings. Processing speed increased pre- to post-HSCT among patients and siblings, and on some measures patients demonstrated greater improvement. Thus, HSCT may improve processing speed in patients, although further confirmation is needed. Findings provide promising evidence that neurocognitive functioning remains stable without detrimental effects from pre- to 12-months post nonmyeloablative HSCT in individuals with SCD.

A multimodal interdisciplinary rehabilitation programme (HAPPY) for patients undergoing allogeneic non-myeloablative haematopoietic stem cell transplantation: A feasibility study.

To evaluate the feasibility of the multimodal interdisciplinary rehabilitation programme HAPPY, targeting patients with haematological malignancy and undergoing allogeneic non-myeloablative haematopoietic stem cell transplantation (NMA-HSCT). A single arm longitudinal design was applied to test the feasibility of the 6-month HAPPY programme, which consisted of motivational interviewing dialogues, individual supervised physical exercise training, relaxation exercises, nutritional counselling, and home assignments. The feasibility measures included acceptability, fidelity, exposure, practicability, and safety. Descriptive statistics were conducted. From November 2018 to January 2020, thirty patients (mean age (SD) 64.1 (6.5)) were enrolled in HAPPY, of whom 18 patients completed the programme. Acceptance was 88%; attrition 40%; fidelity was 80%-100% for all HAPPY elements except phone calls; exposure of HAPPY elements at the hospital reflected individual differences but was acceptable, whereas exposure of HAPPY elements at home was low. Planning of HAPPY for the individual patient was time consuming, and patients were dependent of reminders and incites from the health care professionals. Most elements of the rehabilitation programme HAPPY were feasible. Yet, HAPPY will benefit from further development and simplifications before an effectiveness study can be conducted, especially regarding improvement of the intervention elements supporting patients at home.

Triple-Drug Graft-versus-Host Disease Prophylaxis after HLA-Matched Unrelated Donor Nonmyeloablative Allogenic Hematopoietic Stem Cell Transplantation

Adding sirolimus to graft-versus-host disease (GVHD) prophylaxis with cyclosporin and mycophenolate mofetil (MMF) reduced the risk of grade II-IV acute GVHD after nonmyeloablative (NMA) allogenic hematopoietic stem cell transplantation (HSCT) with an HLA-matched unrelated donor in a randomized clinical trial. We analyzed real-life data to investigate the impact of implementing the triple-drug regimen with cyclosporin, MMF and sirolimus as standard GVHD prophylaxis after NMA HSCT with an HLA-matched unrelated donor at our institution. We studied all adult patients (age ≥18 years) who underwent NMA HSCT with an HLA-matched unrelated donor at Rigshospitalet, Copenhagen University Hospital, Denmark between 2018 and 2021 and received GVHD prophylaxis with cyclosporin, MMF and sirolimus (triple-drug group [TDG]). Comparisons were made with a historical cohort who received tacrolimus and MMF as GVHD prophylaxis after HLA-matched unrelated donor NMA HSCT between 2014 and 2017 (control group [CG]). Outcomes were grade II-IV and grade III-IV acute GVHD, chronic GVHD, relapse, nonrelapse mortality (NRM) andoverall survival (OS). A total of 264 patients were included (TDG, n = 137; CG, n = 127). Median age was 66 years (interquartile range [IQR], 58 to 69 years) in the TDG and 63 years (IQR, 57 to 68 years) in the CG. Acute myeloid leukemia and myelodysplastic syndrome were the most frequent indications for HSCT in both groups (TDG, 33% and 23%, respectively; CG, 36% and 22%, respectively). The cumulative incidence at day +110 of grade II-IV GVHD was 17% (95% confidence interval [CI] 11% to 23%) in the TDG versus 29% (95% CI, 21% to 37%) in the CG (P = .02, Gray's test) and that of grade III-IV acute GVHD was 3% (95% CI, 0 to 6%) versus 5% (95% CI, 1% to 8%), respectively (P = .4, Gray's test). In a Cox regression model adjusted for age, donor age and female donor to male recipient the risk of grade II-IV acute GVHD was lower in the TDG compared to the CG (hazard ratio [HR], .51; 95% CI .30 to .86; P = .01). The 2-year OS was 77% (95% CI, 70% to 84%) in the TDG and 69% (95% CI, 61% to 77%) in the CG (P = .04), and this difference remained significant after adjustment for age and Karnofsky Performance Status (HR, .65; 95% CI, .42 to .99; P = .04). The 2-year cumulative incidences of chronic GVHD, relapse and NRM were 60% (95% CI, 51% to 69%), 21% (95% CI, 13% to 28%), and 12% (95% CI, 6% to 17%), respectively, in the TDG and 62% (95% CI, 54% to 71%), 27% (95% CI, 19% to 35%) and 14% (95% CI, 8% to 20%), respectively, in the CG. Multivariable analyses revealed no difference in the risk of chronic GVHD (HR, .91; 95% CI, .65 to 1.26; P = .56), relapse (HR, .70; 95% CI, .42 to 1.15; P = .16) or NRM (HR, .56; 95% CI, .31 to 1.05; P = .07). After changing the standard GVHD prophylaxis in patients undergoing NMA HSCT with an HLA-matched unrelated donor from tacrolimus and MMF to cyclosporin, MMF and sirolimus, we observed a reduction in the incidence of grade II-IV acute GVHD and improved 2-year OS.

Human Hematopoietic Stem/Progenitor Cells in Type One Diabetes Mellitus Treatment: Is There an Ideal Candidate?

Type 1 diabetes mellitus (T1DM) is a highly prevalent autoimmune disease causing the destruction of pancreatic islet β-cells. The resulting insulin production deficiency leads to a lifelong need for insulin re-placement therapy, systemic complications, and reduced life quality and expectancy. Cell therapy has been extensively attempted to restore insulin independence (IID), and autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) has appeared to give the most promising results, but with a highly variable quote of patients achieving IID across the studies. We performed a comprehensive review of the trials involving stem cells, and in particular AHST, for the treatment of T1DM. We then pooled the patients enrolled in the different trials and looked for the patient characteristics that could be associated with the achievement of IID. We found a significantly higher probability of achieving IID in older patients (OR 1.17, 95%CI 1.06-1.33, p = 0.002) and a significantly lower probability in patients with a history of ketoacidosis (OR 0.23, 95%CI 0.06-0.78, p = 0.023). This suggests that there could be a population of patients more likely to benefit from AHST, but further data would be required to depict the profile of the ideal candidate.

Optimizing Management of the Central Nervous System in Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Stem Cell Transplantation

PurposeTo evaluate clinical outcomes and patterns of failure, specifically in regards to the central nervous system (CNS), in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT) using total body irradiation (TBI)-based conditioning regimens. Methods and MaterialsAll adult patients (aged ≥18 years) with ALL undergoing allogeneic HSCT using TBI-based conditioning regimens treated from 1995 to 2020 at Duke University Medical Center were evaluated. Various patient, disease, and treatment-related factors were collected, including CNS prophylaxis and treatment interventions. Clinical outcomes, including freedom from CNS relapse, were calculated using the Kaplan-Meier method for patients with and without CNS disease at presentation. ResultsOne hundred and fifteen patients with ALL were included the analysis (myeloablative, 110; nonmyeloablative, 5). Of the 110 patients undergoing a myeloablative regimen, most (n = 100) did not have CNS disease before transplant. For this subgroup, peritransplant intrathecal chemotherapy was administered in 76% (median of 4 cycles) and 10 received a radiation boost to the CNS (cranial irradiation, 5; craniospinal, 5). Only 4 failed in the CNS after transplant, none of whom received a CNS boost, with freedom from CNS relapse at 5 years of 95% (95% confidence interval (CI), 84-98%). Freedom from CNS relapse was not improved with a radiation therapy boost to the CNS (100% vs 94%, P = .59). Overall survival, leukemia-free survival, and nonrelapse mortality at 5 years were 50%, 42%, and 36%, respectively. Among the 10 patients with CNS disease before transplant, 10 of 10 received intrathecal chemotherapy and 7 received a radiation boost to the CNS (cranial irradiation, 1; craniospinal, 6) and none subsequently failed in the CNS. A nonmyeloablative HSCT was pursued for 5 patients because of advanced age or comorbidities. None of these patients had prior CNS disease or received a CNS or testicular boost, and none failed in the CNS after transplant. ConclusionsA CNS boost may not be necessary in patients with high-risk ALL without CNS disease undergoing a myeloablative HSCT using a TBI-based regimen. Favorable outcomes were observed with a low-dose craniospinal boost in patients with CNS disease.

Anti-Thymocyte Globulin (ATG)-Free Nonmyeloablative Haploidentical PBSCT Plus Post-Transplantation Cyclophosphamide Is a Safe and Efficient Treatment Approach for Pediatric Acquired Aplastic Anemia

Most cases of acquired aplastic anemia (AA) arise from autoimmune destruction of hematopoietic stem and progenitor cells. Human leukocyte antigen (HLA)-haploidentical nonmyeloablative hematopoietic stem cell transplantation (HSCT) plus post-transplantation cyclophosphamide (PTCy) is increasingly applied to salvage AA using bone marrow as graft and anti-thymocyte globulin (ATG) in conditioning. Herein, we characterize a cohort of twelve AA patients clinically and molecularly, six who possessed other immunological disorders (including two also carrying germline SAMD9L mutations). Each patient with SAMD9L mutation also carried an AA-related rare BCORL1 variant or CTLA4 p.T17A GG genotype, respectively, and both presented short telomere lengths. Six of the ten patients analyzed harbored AA-risky HLA polymorphisms. All patients recovered upon non-HSCT (n = 4) or HSCT (n = 8) treatments. Six of the eight HSCT-treated patients were subjected to a modified PTCy-based regimen involving freshly prepared peripheral blood stem cells (PBSC) as graft and exclusion of ATG. All patients were engrafted between post-transplantation days +13 and +18 and quickly reverted to normal life, displaying a sustained complete hematologic response and an absence of graft-versus-host disease. These outcomes indicate most AA cases, including of the SAMD9L-inherited subtype, are immune-mediated and the modified PTCy-based regimen we present is efficient and safe for salvage.

G-CSF Improves Stable Engraftment in Adults with Sickle Cell Disease Undergoing Nonmyeloablative Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) is curative in patients with sickle cell disease (SCD). HSCT using nonmyeloablative conditioning leads to a mixed chimerism that improves the SCD phenotype but may be complicated by the continued need for immunosuppression and graft loss. Granulocyte colony stimulating factor (G-CSF) may stimulate progenitor cells and is used post-HSCT to reduce the duration of neutropenia and the risk of neutropenic fever. G-CSF has been generally avoided in patients with SCD due to its risk of promoting vaso-occlusion (PMID 19513902). Starting in 7/2016, our institution administered G-CSF after day +5 post-HSCT on the days when the ANC was < 500 x103/µL. In this study, we evaluated whether G-CSF is safe and can improve the duration of neutropenia, infection risk, and donor chimerisms in adults with SCD undergoing non-myeloablative HSCT. We included 34 adults with SCD that underwent allogeneic HSCT from an HLA-matched sibling donor in our institution and were conditioned with alemtuzumab and total body irradiation (TBI) (PMID 33534948) between 11/2011 and 8/2021. Medical records were individually reviewed for data extraction. Linear and categorical outcomes were compared by G-CSF use with the Kruskal-Wallis and chi-square test, respectively. We also compared the Kaplan-Meier curves for discontinuation of immunosuppression with the log-rank method. Median and interquartile range (IQR) are provided. The median age of our cohort was 33 years (IQR, 26 - 45 years), 18 (53%) patients were female, and 30 (88%) had hemoglobin SS genotype. We did not observe statistically significant differences in baseline characteristics between the SCD patients that received G-CSF versus did not receive G-CSF for median age (37 years vs. 32 years), female gender (69% vs. 43%), hemoglobin SS genotype (85% vs. 90%) or median CD34+ dose (8.6 vs. 8.1 x 106/kg), respectively. In the 13 SCD patients that received G-CSF, the median day when it was initiated was day +10 (IQR, 7 - 17) and for a median of 3 days (IQR, 2 - 7 days). The maximum pain score during hospitalization was not significantly different in the SCD group that received G-CSF (median 8, IQR, 7 - 10) compared to those that did not receive G-CSF (median 10, IQR, 9 - 10). Median time to neutrophil engraftment (G-CSF: day 16 vs. no G-CSF: day 22) and duration of neutropenia (G-CSF: 7 days vs. no G-CSF: 9 days) were relatively similar between the 2 groups, while the incidence of neutropenic fevers trended lower with G-CSF treatment (8% vs. 29%, respectively, P=0.1). Whole blood or myeloid chimerism values were significantly higher in the SCD patients that received G-CSF at day +30, +90, +180, and 1 year post-HSCT (Figure 1A). Secondary graft loss was not observed after we implemented G-CSF while 4 out of 21 (19%) of patients experienced secondary graft failure who did not receive post-HSCT G-CSF. Furthermore, in those patients with stable engraftment, we observed a trend for more patients who received G-CSF being successfully tapered off immunosuppression (11/13, 85%) versus those that did not receive G-CSF (10/17, 59%) (Figure 1B). In conclusion, administration of G-CSF to patients with SCD undergoing HSCT conditioned with alemtuzumab/TBI was associated with significantly higher whole blood or myeloid donor chimerism values. This benefit was achieved without a significant increase in pain scores during the hospitalization for HSCT and was associated with trends for a greater proportion of patients discontinuing immunosuppression and less secondary graft loss. Future studies investigating the effects of G-CSF on donor myeloid progenitor cells and on T-cell clearance may guide strategies to improve outcomes for curative therapies in adults with SCD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Increased incidence of hematologic malignancies in SCD after HCT in adults with graft failure and mixed chimerism

Lawal et al report on a 45-fold increase in secondary hematologic malignancy in 120 patients following hematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD), comparable to what has been reported following gene therapy. Notably, the cohort is enriched for older patients and for haploidentical transplant recipients with mixed chimerism following HSCT. These data further support the idea that pre-existing premalignant myeloid clones undergo clonal selection in the setting of nonmyeloablative HSCT and contribute to secondary malignancy.

Stem cell transplantation for systemic sclerosis.

Stem cell transplantation for systemic sclerosis.

P509: CLONAL HEMATOPOIESIS-ASSOCIATED MUTATIONS AS MEASURABLE RESIDUAL DISEASE MARKERS IN ACUTE MYELOID LEUKEMIA PATIENTS FOLLOWING ALLOGENEIC STEM CELL TRANSPLANTATION

Background: Clonal hematopoiesis (CH)-associated mutations (mut) are frequent in acute myeloid leukemia (AML), appear early in leukemogenesis, and often persist in remission after chemotherapy. Following allogeneic hematopoietic stem cell transplantation (HSCT), which replaces the patients’ hematopoiesis, CH mut may present useful measurable residual disease (MRD) markers. Aims: To evaluate patient specific CH-associated mut as MRD markers in AML patients (pts) after allogeneic HSCT. Methods: We analyzed 31 AML pts with CH-associated mut present at diagnosis (DNMT3A: n=17; SRSF2: n=9; IDH2: n=7; ASXL1: n=4; TET2: n=2, and JAK2: n=1), 23 pts had 1, 7 had 2, and 1 patient had 3 CH mut. All received a myeloablative (36%), reduced-intensity (48%), or non-myeloablative (16%) HSCT (median age 58, range 32-72 years). 84% were transplanted in complete remission (CR) or CR with incomplete recovery (CRi). European Leukemia Net (ELN) risk was 23% favorable, 37% intermediate, and 40% adverse. Mut-specific digital droplet PCR assays were developed using a competitive probe-approach. MRDpos was defined as variant allele frequency (VAF) ≥2% for ASXL1 & ≥0.05% for all other analyzed mut. 209 samples with a median of 6 (range 1-13) blood or bone marrow samples per patient were available after HSCT with a median of 1.2 years follow-up time for pts alive. Results: Prior to HSCT, 89% of pts remained CH-associated mut positive in CR/CRi. 11 pts relapsed after HSCT (35%), all with the same CH-associated mut present at diagnosis (median VAF at relapse 15.6, range 0.2-41.2%). Of those, 6 pts had at least 1 MRD sample available prior to relapse. In 5 pts, impeding relapse was predicted by a CH-associated mut MRD conversion with a median VAF of 0.27 (range 0.06-1.0)% at a median of 103 (range 14-199) days prior to relapse. The lead time was longest for a DNMT3A mut patient (199 days) & shortest for a SRSF2 mut patient (14 days). For the patient relapsing without prior CH MRD positivity, the last available sample was taken 169 days before relapse & was CH MRDneg. 20 pts retained remission during follow-up. Of those, 17 pts remained CH MRDneg in all samples (median samples per analyzed mutation 6, range 1-13). 2 pts had 2 MRDpos samples directly after HSCT but became MRDneg in subsequent samples. 1 patient received Enasidenib maintenance after HSCT with fluctuating CH-MRD values after HSCT (SRSF2 & IDH2, VAFs <0.05-0.34% & <0.05-0.14%, respectively). Of the pts with MRD samples within the first year after HSCT available, pts with at least 1 MRDpos sample after HSCT had a significantly higher cumulative incidence of relapse (CIR, P=.008, Figure 1A) & shorter relapse-free survival (RFS, P=.02, Figure 1B). 8 pts had concurrent NPM1 mut (n=4) or RUNX1 mut (n=4), which showed concordant MRD results in 7 pts (4 remained MRDneg, 3 concurrently converted MRDpos). 1 patient suffered a NPM1 MRDneg relapse which was predicted by 2 re-detected CH-associated mut (DNMT3A mut & IDH2 mut, 112 & 199 days prior to relapse, respectively, Figure 1C). Image:Summary/Conclusion: Prior to HSCT most CH-associated mut remain detectable in pts in CR/CRi. However, pts with at least one CH MRDpos sample following allogeneic HSCT had higher CIR & shorter RFS. All relapsing pts were positive for the same CH-associated mut present at diagnosis. 5 of 6 showed increasing VAFs prior to hematologic relapse & the majority of pts retaining remission remained CH MRDneg. While CH-associated mut in chemotherapy treated AML pts have limited MRD value, these mut are feasible MRD markers after HSCT & may inform relapse preventing therapy decisions.

P1313: PREDICTING OUTCOMES IN AML PATIENTS CONSOLIDATED BY AN ALLOGENEIC STEM CELL TRANSPLANTATION USING THE KNOWLEDGE BANK APPROACH

Background: Current risk stratification systems in acute myeloid leukemia (AML), e.g. by the European LeukemiaNet (ELN) 2017, help to inform treatment decisions, including those for an allogeneic stem cell transplantation (HSCT) in first remission. Recently Gerstung et al. (Nature Genetics, 2017) developed a knowledge bank (KB)-based algorithm to in order to more precisely predict individual outcomes based on demographic, clinical, and genetic data. Two studies validated the feasibility of the KB prediction in AML patients (pts) consolidated with chemotherapy. However, a validation in a HSCT-treated cohort - crucial with respect to informed decisions towards HSCT - is lacking. Aims: To validate the feasibility of KB outcome prediction in a HSCT-treated cohort. Methods: We analyzed 545 AML pts (median age at diagnosis 62, range 21-77 years) consolidated by reduced-intensity (23%) or non-myeloablative (77%) allogeneic HSCT. 60% of pts were in first remission. All clinical variables included in the KB were available for this cohort, while our gene mutation panel did not cover 17/58 of genes included in the KB. KB predictions 3 years after diagnosis were retrospectively calculated by using the adapted transplant strategy and compared to the observed outcomes using receiver operating characteristics (ROC) curves. Additionally, the measurable residual disease (MRD) status at HSCT - based on NPM1 mutation and BAALC, MN1, and WT1expression - was evaluated by digital droplet PCR in pts with material available. Results: The area under the curve (AUC) to predict 3-year overall survival (OS) produced by the KB value was 0.69 (95% CI 0.62-0.72), not significantly different compared to the AUC based on ELN2017 risk groups (0.66 [95% CI 0.57-0.71], P= 0.23, Figure 1A), and worse compared to the published results in chemotherapy consolidated pts (AUCKB = 0.80, Bill et al, J Hematol Oncol 2021). Still, in a multivariate analysis the KB prediction for 3-year OS significantly impacted OS (OR 6.25, CI 2.9-13.2) after adjustment for the MRD-corrected remission status at HSCT. Aikaike Information criterion comparison with a model including the ELN2017 risk groups and the MRD-corrected remission status at HSCT demonstrated the model containing the KB prediction as preferable. When introducing cut-offs according to the KB value for OS at 3 years similar to Fenwarth et al. (Blood 2021), we observed a clear separation of OS curves according to a KB value of <20, 20-39, and ≥ 40 with higher values indicating a higher likelihood for OS (P< 0.001, Figure 1B). Regarding additional endpoints, the KB algorithm had the highest probability to correctly predict death without previous achievement of a remission (AUCKB = 0.75, Figure 1C, black), restricted prediction for death in first remission (AUCKB = 0.61, Figure 1C, red) or after relapse (AUCKB = 0.63, Figure 1C, blue), but good prediction for being alive in first remission (AUCKB = 0.69, Figure 1D, red) or after relapse (AUCKB = 0.77, Figure 1D, blue). Image:Summary/Conclusion: For HSCT treated AML pts the KB-based outcome prediction was inferior compared to previous studies of pts receiving chemotherapy. The likely reason for this inferiority is the introduction of confounders (e.g donor selection or conditioning regimens), that may impact treatment-related mortality, and are not integrated in and not predictable by the current KB algorithm. Future versions of the KB that also consider HSCT-associated factors might further improve outcome prediction by this promising clinical tool.

Mismatched Unrelated Donor Hematopoietic Stem Cell Transplantation Rescues Marrow Failure From Acute Leukemia Therapy in a Patient With Previously Undiagnosed Ligase IV Syndrome.

Patients with DNA double-strand breakage repair disorders are at increased risk of malignancy which is often difficult to treat given underlying sensitivity to chemotherapy and radiotherapy, lending an important role to hematopoietic stem cell transplantation. The choice of conditioning regimen used must balance reducing risk of rejection with minimizing excessive toxicity from myeloablative chemotherapy or ionizing radiation. We describe successful engraftment following a nonmyeloablative hematopoietic stem cell transplantation in a patient with Ligase IV syndrome and numerous pretransplant complications including malignancy, cardiac failure, and secondary hemophagocytic lymphohistiocytosis. Congruent with prior reports, a reduced intensity regimen appears efficacious in Ligase IV syndrome patients.

Patients' reflections on undergoing non-myeloablative allogeneic haematopoietic stem cell transplantation and participating in a multimodal interdisciplinary rehabilitation programme: A qualitative study.

To explore participants' experiences and perspectives on the relevance and meaning of participating in the multimodal interdisciplinary rehabilitation programme named 'HAPPY', and the programme's influence on their handling of everyday life during and after non-myeloablative allogeneic haematopoietic stem cell transplantation. A qualitative interview study using Thorne's interpretive description methodology. A semi-structured interview guide and the analysis were inspired by symbolic interactionism. From April to July 2020, individual interviews were conducted with 24 patients who had participated in HAPPY while undergoing non-myeloablative haematopoietic stem cell transplantation. HAPPY contributed to the patients' knowledge building on the basis of three themes: Social Solidarity and Comparison, Processing Mind and Body, and Balancing Disease and Life. HAPPY supported the participants in maintaining their physical functioning and induced a perception of empowerment. Moreover, HAPPY supported patients in their efforts to familiarise themselves with their changed life conditions after the stem cell transplantation. Our findings showed that participation in HAPPY empowered patients to manage and cope with the stresses of everyday life and restore balance in their lives whilst undergoing treatment and confronting their cancer diagnosis. The findings underline the importance of elements of peer support and continuous support and facilitation from the specialist team, and the possibility to rethink the use of online technology to support and ensure a balance between disease and life and to minimise hospital visits.

S105: ADDING AZATHIOPRINE/HYDROXYUREA PRECONDITIONING TO ALEMTUZUMAB/TBI CONDITIONING IMPROVES DONOR CHIMERISM IN MATCHED SIBLING DONOR STEM CELL TRANSPLANTATION IN ADULT SICKLE CELL DISEASE PATIENTS

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only established curative treatment option for sickle cell disease (SCD). In adults, myeloablative conditioning is associated with significant toxicity, primarily due to cumulative organ damage. Matched sibling donor (MSD) transplantation with non-myeloablative conditioning (alemtuzumab/3 Gy total body irradiation (TBI)) has shown promising results in adult SCD patients.1,2 Patients treated with this regimen had their sickle cell phenotype corrected with only mild complications and no reports of graft-versus-host disease (GvHD). However, most of the described patients did not reach complete donor chimerism with graft failure rates of 13%. Furthermore, in almost 10% of patients, immunosuppressives could not be withdrawn because of too low T cell chimerism (<50%).2 We hypothesized that adding azathioprine and hydroxyurea as preconditioning to the alemtuzumab/TBI regimen might improve donor chimerism, reduce the risk of graft failure and improve successful withdrawal of immunosuppressives. Aims: In this study we prospectively investigate the effects of azathioprine/hydroxyurea preconditioning on donor chimerism and graft failure in patients receiving non-myeloablative MSD HSCT for SCD. Methods: Adult SCD patients who had an HLA-identical sibling donor were eligible for this treatment. After 3 months of azathioprine 150mg qd and hydroxyurea 25mg/kg qd, erythrocyte exchange transfusion was performed on day –10, aiming for HbS <30%. Conditioning with alemtuzumab/TBI was started on day –7. Graft versus host disease (GvHD) prophylaxis consisted of sirolimus. Results: As of October 2021, 13 SCD patients (median age 30.6 (range 19–49) years) were transplanted. Twelve patients (92.3%) engrafted successfully. After a median follow-up of 24 months, median donor myeloid and T cell chimerism of engrafted patients were 100% (IQR 84–100%) and 77% (IQR 70.5%-82.5%), respectively. These donor chimerism percentages are higher than previously reported with alemtuzumab/TBI only. All engrafted patients had a corrected SCD phenotype with normalized hemoglobin levels. Patients reaching 1-year post-transplantation were able to stop sirolimus without decreases in chimerism. Summary/Conclusion: Azathioprine/hydroxyurea preconditioning prior to alemtuzumab/TBI results in improved donor chimerism, potentially reducing the risk of graft failure after non-myeloablatieve MSD transplantation in SCD patients. Importantly, all engrafted patients reached donor T cell chimerism >50% at 1-year post-transplantation and were able to stop immunosuppressives as scheduled.

Oral Mucositis Association with Periodontal Status: A Retrospective Analysis of 496 Patients Undergoing Hematopoietic Stem Cell Transplantation

Background: Hematopoietic stem cell transplantation (HSCT) can induce serious oral complications, including oral mucositis (OM). The presence of periodontal inflammation before HSCT is believed to be associated with OM. The aim of our study was to determine the prevalence and severity of OM in patients undergoing HSCT and its relation to periodontal status. Patients and methods: This is a retrospective study of patients who underwent HSCT and a detailed dental examination between 2007 and 2015. The dental and periodontal status of all patients was evaluated by clinical and radiographic examination prior to HSCT. Oral health was assessed with the gingival index, the the community periodontal index, presence of plaque-related gingivitis, and marginal periodontitis. During the HSCT period, patients were examined daily for the presence of OM, which was graded according to World Health Organization (WHO) classification if present. The patients were assigned to the groups according to type of transplantation: autologous HSCT, myeloablative allogeneic HSCT, and non-myeloablative allogeneic HSCT. Results: A total of 496 patients were included in the study. OM was present in 314 of 496 patients (63.3%): 184/251 (73.3%) in the autologous group, 100/151 (66.2%) in the myeloablative allogeneic group, and 30/94 (31.9%) in the nonmyeloablative allogeneic group. Significantly more patients suffered from OM in the autologous and myeloablative groups versus the nonmyeloablative conditioning group (p < 0.001). The presence of periodontal inflammation did not significantly differ among the groups. There was only a borderline trend for the higher prevalence of OM in the non-myeloablative allogeneic nonmyeloablative group when periodontal inflammation was present (0.073939). Conclusions: Oral mucositis prevalence and severity after stem cell transplantation is not widely affected by the oral hygiene and periodontal disease presence before HSCT. We confirmed the wide-known connection of the conditioning regimen intensity to the prevalence of OM.

Alemtuzumab clearance, lymphocyte count, and T‐cell chimerism after hematopoietic stem cell transplant in sickle cell disease

AbstractStudy ObjectiveAlemtuzumab is a monoclonal antibody that targets the cell surface antigen CD52 on lymphocytes. Although it is used for the treatment of hematologic malignancies, such as chronic lymphocytic leukemia, and incorporated into many hematopoietic stem cell transplant (HSCT) conditioning regimens, few studies have evaluated the pharmacology of alemtuzumab in adult patients with sickle cell disease (SCD). We therefore examined the pharmacokinetics (PK) and pharmacodynamics (PD) of alemtuzumab in adults with SCD who received a matched related donor HSCT to determine if the clearance of alemtuzumab affects transplant outcomes.DesignPK and PD analysis of patient data from a single‐center clinical trial.SettingClinical research center.PatientsTwenty‐two adult patients with SCD who received one of two nonmyeloablative allogeneic HSCT regimens: alemtuzumab and total body irradiation (Alem‐TBI) or pentostatin, cyclophosphamide, alemtuzumab, and total body irradiation (Pento‐Cy‐Alem‐TBI).Measurements and Main ResultsAlemtuzumab serum concentrations, absolute lymphocyte counts, T‐cell (CD3), and myeloid (CD14/15) chimerism were collected at distinct time points and analyzed. A semi‐mechanistic PK population model was built to understand inter‐individual differences in pharmacology. Alemtuzumab was detectable up to 28 days post‐HSCT. The mean alemtuzumab level 7 days after transplant for patients on Alem‐TBI was 818 ng/ml, significantly lower than the mean level of 1502 ng/ml for patients on Pento‐Cy‐Alem‐TBI (p &lt; 0.001), but this difference decreased as time progressed. The clearance of alemtuzumab was linear, and the half‐life was longer in the Pento‐Cy‐Alem‐TBI group (average half‐life = 61.1 h) compared to the Alem‐TBI group (average half‐life = 44.1 h) (p &lt; 0.001). The CD3 chimerism at 2 and 4 months after transplant positively correlated with alemtuzumab levels collected on day 14 after transplant (R2 = 0.40 and p = 0.004 at 2 months, R2 = 0.36 and p = 0.005 at 4 months), but this significance was lost by 6 months after HSCT. No correlation was seen between alemtuzumab levels and CD14/15 chimerism.ConclusionBetween 2 and 4 months after transplant, higher alemtuzumab levels measured 14 days after transplant correlated with patients having better engraftment, suggesting more lymphodepletion may be needed to reduce graft failure in these two non‐myeloablative matched related donor HSCT regimens.