Unrelated Allogeneic Hematopoietic Stem Cell Transplantation Research Articles

The Area Under Tacrolimus Concentrations on Day 14-28 Is the Independent Predictor of the Development of Chronic Gvhd in Patients without Severe Acute Gvhd after Unrelated Allogeneic HSCT

Introduction: In unrelated allogeneic hematopoietic stem cell transplantation (UR-SCT), chronic graft-versus-host disease (GVHD) is a critical complication that affects not only patients' quality of life but also post-transplant outcome. Acute GVHD is a major risk factor for the subsequent development of chronic GVHD. The combination of tacrolimus and short-term methotrexate (TAC+sMTX) has been widely used as a GVHD prophylaxis for UR-SCT in Japan. Previous reports have shown that tacrolimus blood concentrations early after transplantation are associated with the development of acute GVHD, but not with that of chronic GVHD. On the other hand, among UR-SCT recipients who did not develop severe acute GVHD, the relationship between tacrolimus blood concentrations and the development of chronic GVHD remains unclear. Methods: To examine the association between tacrolimus blood concentrations and post-transplant outcomes, the area under the tacrolimus concentration on day 0-14 (AUTC 0-14) and day 14-28 (AUTC 14-28) was calculated simply as the sum of the area of the trapezoid for the corresponding period ( Figure). Tacrolimus was initiated by continuous intravenous administration from day -1 in all patients, and no patients were switched to oral administration prior to day 28. Short-term methotrexate was administered at 10 mg/m 2 on day 1 and 7 mg/m 2 on day 3, day 6, and day 11. Among all 151 adult patients with hematopoietic malignancies who underwent first UR-SCT with GVHD prophylaxis of TAC+sMTX between 2010 and 2022 at the Jikei University Hospital, the following were excluded from the analysis: developing grade III-to-IV acute GVHD, using prednisolone or methyl-prednisolone ≥0.5 mg/kg within day 100, engraftment failure, death before day 100, and relapse before day 100. Results: A total of 68 patients were included in the analysis. Median age was 50.5 (range, 16-68) years. Twenty-seven (40%) patients had acute myeloid leukemia, and 18 (27%) had acute lymphoblastic leukemia. Fifty-five (81%) were in complete remission/chronic phase/early stage. The donor source consisted of 42 (62%) bone marrow transplantation (BMT), 20 (29%) cord blood transplantation (CBT), and 6 (9%) peripheral blood stem cell transplantation (PBSCT). BMT recipients transplanted from 22 (52%) HLA 8/8 matched donor, 19 (45%) HLA 7/8 matched donor, and one (3%) HLA 6/8 matched donor. CBT recipients transplanted from 15 (75%) HLA 4/6 matched donor and 5 (25%) HLA 5/6 matched donor. PBSCT recipients transplanted from 5 (83%) HLA 8/8 matched donor and one (17%) HLA 7/8 matched donor. Fifteen (22%) patients were administered additional low-dose anti-thymocyte globulin (ATG) as GVHD prophylaxis. Fifteen male patients transplanted from female donors (22%). Thirty-nine (57%) patients received myeloablative conditioning regimen. The median time from UR-SCT to neutrophil engraftment was 19 days (range, 11-34). Regarding acute GVHD, 46 patients (68%) developed none, 13 patients (19%) developed grade I, and 9 patients (13%) developed grade II. The median observation period for all 68 patients was 48.2 months (4.0 years). The 4-year cumulative incidence (CI) of chronic GVHD was 51%, of which 24% were moderate-to-severe. The CI of moderate-to-severe chronic GVHD was not associated with age, disease status, donor source, HLA incompatibility, ATG use, female to male, intensity of conditioning regimen, and grade I-to-II acute GVHD development. AUTC 14-28 <200 was the only risk factor (AUTC 14-28<200: 32% vs AUTC 14-28≥200: 11%; p=0.047). Multivariate analysis also showed that AUTC 14-28 <200 was the independent factor for development of moderate-to-severe chronic GVHD ( p=0.04). In all 68 patients, 4-year CI of relapse was 20%, 4-year CI of non-relapse mortality was 10%, 4-year GVHD-free, relapse-free, survival (GRFS) was 50%, and 4-year Overall survival was 80%, all of which did not differ between AUTC 14-28 <200 and AUTC 14-28 ≥200 groups. Conclusion: In UR-SCT, our data showed that AUTC 14-28 <200 may be an independent risk factor for developing moderate-to-severe chronic GVHD, even in patients who did not develop severe acute GVHD.

The Psychosocial Transplant Evaluation Rating Scale (TERS) Prospectively Predicts Inferior Overall Survival Outcome for High Risk Scoring Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Several studies have begun to examine the relationship between psychosocial variables and outcome in hematopoietic stem cell transplantation (HSCT). Previous studies have also looked at the relationship between the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) and disease risk on overall survival in HSCT. Research has shown that disease risk and HCT-CI may have a negative relationship with outcome in HSCT. In this study, psychosocial data was collected prospectively on 437 patients undergoing related and unrelated allogeneic HSCT. All patients were assessed using the Transplant Evaluation Rating Scale (TERS). Based on the patient’s TERS score, each patient was stratified into one of two groups (low/moderate risk (n=371) vs. high risk (n=66)) based on their predicted psychosocial risk for problems during transplant. The 1-year overall survival (OS) for the low/mod risk TERS group versus the high TERS risk group was 78% and 61%, respectively (p=.005). Stratification by CIBMTR disease risk identified 261 patients with low and intermediate risk disease of which 228 had low/mod risk TERS score and 33 had high risk TERS score. The is a significant survival advantage for Low/Mod Risk TERS patients vs. High Risk TERS patients at 100 day, 1 year and overall survival being 97% vs 79% (P=.01), 85% vs 58% (P=.002) and 68% vs 42% (P=.002) with a median follow up of 48 months (graph attached). An adjusted logistic regression analysis showed that psychosocial factors have a significant impact on overall survival despite all patients being required to have 24 hour caregiver support, a pre-transplant psychosocial evaluation and post-transplant psychosocial intervention. The analysis controlled for other variables such as age, gender, performance status, disease risk and transplant type. These results highlight the impact of psychosocial factors on HSCT outcome, as those patients who are expected to do well based on their low/intermediate disease risk may not perform as expected due to psychosocial risk factors. These results suggest the need to perform careful psychosocial assessments on all HSCT patients in order to predict mortality risks for the individual patient and to help the transplant team strategize how to better manage the high risk psychosocial patient. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis

AbstractFrom 2007 to 2011, 66 patients with primary myelofibrosis or myelofibrosis (MF) preceded by essential thrombocythemia or polycythemia vera were enrolled into a prospective phase 2 clinical trial of reduced-intensity allogeneic hematopoietic stem cell transplantation (AHSCT), Myeloproliferative Disorder Research Consortium 101 trial. The study included patients with sibling donors (n = 32) receiving fludarabine/melphalan (FluMel) as a preparative regimen and patients with unrelated donors (n = 34) receiving conditioning with FluMel plus anti-thymocyte globulin (ATG). Patient characteristics in the 2 cohorts were similar. Engraftment occurred in 97% of siblings and 76% of unrelated transplants, whereas secondary graft failure occurred in 3% and 12%, respectively. With a median follow-up of 25 months for patients alive, the overall survival (OS) was 75% in the sibling group (median not reached) and 32% in the unrelated group (median OS: 6 months, 95% confidence interval [CI]: 3, 25) (hazard ratio 3.9, 95% CI: 1.8,8.9) (P < .001). Nonrelapse mortality was 22% in sibling and 59% in unrelated AHSCT. Survival correlated with type of donor, but not with the degree of histocompatibility match, age, or JAK2V617F status. In patients with MF with sibling donors, AHSCT is an effective therapy, whereas AHSCT from unrelated donors with FluMel/ATG conditioning led to a high rate of graft failure and limited survival. This trial was registered at www.clinicaltrials.gov as #NCT00572897.

Clinical and Immunological Correction of DOCK8 Deficiency by Allogeneic Hematopoietic Stem Cell Transplantation Following a Reduced Toxicity Conditioning Regimen

Dedicator of cytokinesis 8 protein (DOCK8) deficiency is a combined immunodeficiency disorder characterized by an expanding clinical picture with typical features of recurrent respiratory or gastrointestinal tract infections, atopic eczema, food allergies, chronic viral infections of the skin, and blood eosinophilia often accompanied by elevated serum IgE levels. The only definitive treatment option is allogeneic hematopoietic stem cell transplantation (HSCT). We report a patient with early severe manifestation of DOCK8 deficiency, who underwent unrelated allogeneic HSCT at the age of 3 years following a reduced toxicity conditioning regimen. The transplant course was complicated by pulmonary aspergilloma pretransplantation, adenovirus (ADV) reactivation, and cytomegalovirus (CMV) pneumonitis 4 weeks after transplantation. With antifungal and antiviral treatment the patient recovered. Seven months after transplantation the patient is in excellent clinical condition. Eczematous rash, chronic viral skin infections, and food allergies have subsided, associated with normalization of IgE levels and absolute numbers of eosinophils. Chimerism analysis shows stable full donor chimerism. DOCK8 deficiency can be successfully cured by allogeneic HSCT. This treatment option should be considered early after diagnosis, as opportunistic infections and malignancies that occur more frequently during the natural course of the disease are associated with higher morbidity and mortality.

Late Recurrence of Precursor B-cell Acute Lymphoblastic Leukemia 9 Years and 7 Months After Allogeneic Hematopoietic Stem Cell Transplantation

We present the case of a 15-year-old adolescent boy with recurrent precursor B-cell acute lymphoblastic leukemia, which appeared 9 years and 7 months after a first unrelated allogeneic hematopoietic stem cell transplantation (HSCT). The patient received chemotherapy and a subsequent second unrelated allogeneic HSCT, and was free of the disease 3 years after the second HSCT. A molecular study revealed the same rearrangement pattern at IGK@ in both the first relapse and the later relapse, confirming the common origin of the leukemic blasts at different time points. However, a new Vδ2-Dδ3 rearrangement of TRD@ emerged at the later relapse. A subsequent, more sensitive examination revealed a minor subpopulation with rearrangements at both IGK@ and TRD@, even during the first relapse. This finding suggests that the minor clone, related to the major clone, was present at the first relapse, leading to the later recurrence, even though the major clone at the first relapse had been eradicated by the first allogeneic HSCT. Although a later relapse after allogeneic HSCT is a rare phenomenon, clinicians should keep in mind that later relapses can occur, even after allogeneic HSCT.

Increased infection-related mortality in KIR-ligand-mismatched unrelated allogeneic hematopoietic stem-cell transplantation.

Recently, attention has been focused on the role of killer cell immunoglobulin-like receptor (KIR)-ligand incompatibility between donor and recipient in allogeneic hematopoietic stem-cell transplantation (ASCT). Although KIR-ligand mismatch is clearly associated with improved survival in haploidentical ASCT for acute myeloid leukemia, its role in unrelated human leukocyte antigen-mismatched ASCT is more controversial. Here we present a retrospective analysis of KIR-ligand-matched (n=167) and mismatched (n=23) unrelated ASCTs for hematologic malignancies performed at a single center. We observed that KIR-ligand mismatch was associated with increased transplantation-related mortality (P=0.02), leading to decreased overall survival (P=0.01). The increased transplantation-related mortality was a consequence of a higher rate of infections (P=0.01), whereas incidence of graft-versus-host disease and leukemic relapse did not differ significantly between the two groups. These results suggest that the presence of donor-derived, alloreactive natural killer cells may interfere with immunity to infection in the early posttransplantation period.