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1.
Genotype, Oxidase Status, and Preceding Infection or Autoinflammation Do Not Affect Allogeneic HCT Outcomes for CGD
Leiding, J. W., Arnold, D. E., Parikh, S. H., Logan, B. R., Marsh, R. A., Griffith, L. M., Wu, R., Kidd, S., Mallhi, K. K., Chellapandian, D., et al
Blood. 2023
Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections and inflammatory conditions. Hematopoietic cell transplantation (HCT) is the definitive treatment for CGD, but questions remain regarding patient selection and impact of active disease on transplant outcomes. We performed a multi-institutional retrospective and prospective study of 391 patients with CGD treated either conventionally (non-HCT;n=151) enrolled from 2004-2018 or who underwent HCT (n=240) from 1996-2018. Median follow-up post-HCT was 3.7 years with a 3-year overall survival of 82% and event-free survival of 69%. In multivariate analysis, Lansky/Karnofsky score <90 and use of HLA-mismatched donors negatively impacted survival. Age, genotype, and oxidase status did not impact outcomes. Pre-HCT, patients had higher infection density, higher frequency of non-infectious lung and liver disease, and more steroid use compared to conventionally-treated patients, yet these issues did not adversely affect HCT survival. Presence of pre-HCT inflammatory conditions was associated with chronic graft versus host disease. Graft failure or receipt of second HCT occurred in 17.6% and was associated with melphalan-based conditioning and/or early mixed chimerism. By 3-5 years post-HCT, patients had improved growth and nutrition, resolved infections and inflammatory disease, and lower rates of anti-microbial prophylaxis or corticosteroid use compared to both their baseline and to conventionally-treated patients. HCT leads to durable resolution of CGD symptoms and lowers burden of disease. Patients with active infection or inflammation are candidates for transplant; HCT should be considered prior to the development of co-morbidities that could impact performance status. Clinical trial # NCT02082353.
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2.
Age Impacts Risk of Mixed Chimerism Following RIC HCT for Non-SCID Inborn Errors of Immunity
Fitch, T., Lane, A., McDonnell, J., Bleesing, J., Jordan, M., Kumar, A., Khandelwal, P., Khoury, R., Marsh, R., Chandra, S.
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Alemtuzumab, fludarabine and melphalan containing reduced intensity conditioning (RIC) is commonly used in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for definitive treatment of high-risk inborn errors of immunity (IEI). Although survival is favorable, there is increased risk of mixed chimerism leading to secondary graft failure. OBJECTIVES Evaluate factors associated with risk of developing mixed chimerism, particularly the influence of age in patients undergoing allogeneic HCT for non-SCID IEI who received a uniform RIC regimen that included intermediate schedule alemtuzumab, fludarabine and melphalan. We hypothesized that age would impact incidence of mixed chimerism. STUDY DESIGN We retrospectively reviewed records of patients who underwent HCT for non-SCID IEIs with a uniform RIC regimen that included intermediate schedule alemtuzumab (1 mg/kg divided over days -14 to - 10), fludarabine (150 mg/m2 or 5 mg/kg if weight <10 kg divided over days -9 to -4), and melphalan (140 mg/m2 or 4.7 mg/kg if weight <10 kg on day-3) between 2010 and 2020 at our institution. Mixed chimerism was defined as <95% donor on 2 or more consecutive occasions on whole blood. RESULTS Ninety-three patients who underwent RIC-HCT for non-SCID IEI using intermediate schedule alemtuzumab, fludarabine, and melphalan were evaluated and categorized into 3 groups: <1, 1-5, and > 5 years of age. Forty-nine patients (52.7%) developed mixed chimerism at a median of 34 days post-HCT (range, 10-1396 days). Mixed chimerism developed in 88.9 % (n=16/18) for <1 year, 57.1% (n=20/35) for 1-5 years, and 35% (n=14/40) for those >5 years. Patients <5 years of age were significantly more likely to develop mixed chimerism (X(2) (3, N = 93) = 14.8, p =0.001). We observed a significantly increased cumulative incidence of developing mixed chimerism if < 1 year of age (p=0.0002). Competing risk regression analysis demonstrated an increase in odds of development of mixed chimerism for age <1 (OR 3.72, p = 0.006, 95% CI 1.46-19.46) compared to age >5 years and decrease in odds of mixed chimerism in patients who developed acute GVHD prior to any intervention (OR 0.24, p=0.005, 95% CI 0.09-0.65) There was no significant association between mixed chimerism and graft source, graft type, CD34+ or CD3+ cell dose, HLA match or underlying disease (HLH vs non-HLH). Additionally, the need for secondary intervention was evaluated; 27 patients (29.0%) required one or more secondary intervention(s) (DLI, CD34 Boost, or second HCT). Patients <1 year of age with mixed chimerism were significantly more likely to require secondary intervention for mixed chimerism than patients > 5 years (p =0.004). CONCLUSION Our study demonstrates that young age <5 years, especially age <1 year is associated with an increased risk of developing mixed chimerism in patients undergoing RIC-HCT for non-SCID IEI using intermediate schedule alemtuzumab, fludarabine, and melphalan. Our data suggest tailoring regimen intensity based on age to reduce the incidence of mixed chimerism. Children <5 years, particularly those <1 year of age, require a higher intensity regimen. Possible strategies include adding thiotepa or using a busulfan-based reduced toxicity regimen.
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3.
Haematopoietic Stem Cell Transplantation (HSCT) for Primary Immune System Disorders in Children: A Single Centre Experience
Kerio, A. A., Khattak, T. A., Ghafoor, T., Yousaf, M., Shahbaz Br, N., Chaudary, Q. U. N.
Journal of the College of Physicians and Surgeons--Pakistan : JCPSP. 2023;33(3):341-345
Abstract
OBJECTIVE To determine the outcomes of allogeneic HSCT in children with primary immune system disorders (PID). STUDY DESIGN Descriptive Cross-sectional study. Place and Duration of the Study: Armed Forces bone marrow transplant centre / National Institute of Bone Marrow Transplant (AFBMTC / NIBMT), Rawalpindi, Pakistan, from October 2012 to December 2021. METHODOLOGY Data of all cases undergoing HSCT for immune system disorders were analysed for variables affecting outcome and overall survival in the first 180 days after allogeneic HSCT. All patients presenting to AFBMTC / NIBMT with PID, age <12 years. Patients with organ dysfunction secondary to repeated infections were excluded from the study. Data of all patients and their donors undergoing HSCT for immune system disorders were analysed for variables affecting outcome and overall survival in the first 180 days after allogeneic bone marrow transplant. Neutrophil engraftment was defined as absolute neutrophil count ≥0.5 × 109/L for 3 consecutive days, while platelet engraftment as platelet count ≥20 × 109/L without platelet transfusion for one week. Overall survival (OS) was taken as time from the date of HSCT till day + 180 post-transplant. RESULTS A total of 42children including 29 boys and 13 girls underwent HSCT for PID. The mean age was 2.1±2.8 years. Underlying diagnosis was haemophagocytic lymphohistiocytosis (HLH), severe immune deficiency (SCID), leukocyte adhesion defect (LAD), X-linked agammaglobulinemia, chronic granulomatous disease (CGD) and Job's syndrome in 18 (42.9%), 16 (38.1%), 3(7.1%), 2 (4.8%), 2 (4.8%) and 1 (2.4%) patients respectively. Thirty-one (73.8%) children had fully HLA-matched donors while 11 (26.2%) had haplo-matched donors. Major immediate post-transplant complications were febrile neutropenia, mucositis and SOS/VOD in 31 (73.8%), 9 (21.4%) and 4 (10.0%) cases, respectively. Eight (19.0%) had CMV reactivation, acute GVHD was seen in 17 (40.4%) cases, while 1 (2.3%) case had chronic GVHD. Twelve (28.6%) patients died, out of which 5 had graft failure, 3 had VOD, 2 had pneumonia, 1 had severe GVHD, and 1 died due to seizures. Overall survival (OS) in this study was 71.4% with survival reaching up to 80.6% in fully matched HSCT. CONCLUSION HLH and SCID were the commonest immune disorders requiring HSCT. Graft failure leading to neutropenic sepsis was the commonest cause of mortality. OS was better in fully matched HSCT as compared to haplo-identical HSCT. KEY WORDS Immune deficiency, Severe combined immunodeficiency, Haematopoietic stem cell transplantation.
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4.
Hematopoietic Cell Transplantation for Adenosine Deaminase Severe Combined Immunodeficiency-Improved Outcomes in the Modern Era
Ghimenton, E., Flinn, A., Lum, S. H., Leahy, T. R., Nademi, Z., Owens, S., Williams, E., Flood, T., Hambleton, S., Slatter, M., et al
Journal of clinical immunology. 2022;42(4):819-826
Abstract
Current treatment for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) includes enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplant (HSCT), or ex vivo corrected autologous hematopoietic stem cell gene therapy. Historic data show HSCT survival is superior using unconditioned matched sibling and family compared to matched unrelated and haploidentical donors. Recent improvement in HSCT outcomes prompted us to retrospectively examine HSCT survival and long-term graft function in ADA-SCID transplanted at our center. Thirty-three ADA-deficient patients received HSCT between 1989 and 2020, with follow-up data to January 2021. Chemotherapy conditioning regimens were defined as myeloablative (MAC-busulfan/cyclophosphamide), reduced-toxicity myeloablative (RT-MAC-treosulfan-based, since 2007), or no conditioning. Serotherapy used included alemtuzumab (with or without other conditioning agents) or antithymocyte globulin (ATG). ERT was introduced routinely in 2010 until commencement of conditioning. Median age at HSCT was 3.2 (0.8-99.8) months. Twenty-one (63.6%) received stem cells from unrelated or haploidentical donors. Seventeen (51.5%) received chemotherapy conditioning and 16 (48.5%) received alemtuzumab. Median follow-up was 7.5 (0.8-25.0) years. Overall survival (OS) and event-free survival (EFS) at 8 years were 90.9% (95% CI: 79.7-100.0%) and 79% (55-91%), respectively. OS after 2007 (n = 21) was 100% vs 75% before 2007 (n = 12) (p = 0.02). Three (9.1%) died after HSCT two from multiorgan failure and one from unexplained encephalopathy. There were no deaths after 2007, among those who received ERT and treosulfan-based conditioning pre-HSCT. Ten (30.3%) developed acute GvDH (3 grade II, 2 grade III); no chronic GvHD was observed. In the modern era, conditioned HSCT with MUD has a favorable outcome for ADA-deficient patients.
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5.
Nutritional status and prognosis in children with immunodeficiencies undergoing hematopoietic stem cell transplantation
Dos Santos Nunes Pereira, A. C., Chahin, B. M., Tarzia, A., Vilela, R. M.
Clinical nutrition ESPEN. 2022;52:1-11
Abstract
BACKGROUND Primary immunodeficiencies (PID) are diseases resulting from genetic dysfunctions in the immune system, which can result in recurrent infections, autoimmunity and even malignancy. It is estimated that approximately one-third of the PID described have gastrointestinal components or symptoms involved and may present an increased risk of weight loss and failure to thrive. It is also known that, in patients with other diagnoses, malnutrition may be associated with worse outcomes after hematopoietic stem cell transplantation (HSCT). OBJECTIVE to characterize the nutritional status of pediatric patients with PID at the time of admission for HSCT and to establish the relationship between baseline nutritional status measures and post-HSCT clinical outcomes. METHODS a retrospective analytical observational study, based on data from pediatric patients, of both sexes and all ethnicities, with PID, submitted to HSCT in the period from 2004 to 2019. The risk factors analyzed were the Z-scores of weights for age (W/A), height for age (H/A), BMI for age (BMI/A) and Sum score, obtained by through the sum of the W/A and H/A scores. The primary outcomes were overall survival at 6 months, occurrence of acute Graft Versus Host Disease (aGVHD) at 6 months, and occurrence of chronic Graft Versus Host Disease (cGVHD) at 1 year. Secondary outcomes were occurrence and degree of mucositis, length of stay, and total number of infectious episodes. As statistical analysis, the ANOVA model, the Tukey test, ROC curves and Kaplan Meier and Log-Rank analysis were used. Multivariate survival and logistic regression models were also performed. RESULTS The study showed important indicators of malnutrition in patients with PID, especially those diagnosed with Severe Combined Immunodeficiency Syndrome (SCID) and Hemophagocytic Syndromes (HS). Among those with SCID, 60% had low or very low weight for their age, 52% had low or very short stature for their age, and 44% were classified as being thin or very thin. Among patients with HS, 75% had short or very short stature for their age. Multivariate analysis only demonstrated association between W/A score with extensive cGVHD, controlling for diagnosis, compatibility, conditioning and immunoprophylaxis. Lower W/A values were associated with higher occurrences of these events. Although W/A was only associated with cGVHD and H/A had no association with chronic or acute GVHD, when Sum scores were used, the lower values the higher rates of severe aGVHD and total cGVHD according to multivariate controlled models for diagnosis, compatibility, conditioning and immunoprophylaxis. CONCLUSIONS Our study characterized the nutritional status of children with PID undergoing HSCT and found alarming rates of underweight and short stature in patients with SCID and HS. We also demonstrated a relationship between anthropometric parameters and outcomes such as mortality, the occurrence of GVHD and severe mucositis after HSCT. In this sense, W/A and Sum score measures would be good prognostic methods for these outcomes. Henceforth, prospective studies are needed to confirm these findings and establish new nutritional assessment criteria for this population.
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6.
CD34+ Stem Cell Selection and CD3+ T Cell Add-Back from Matched Unrelated Adult Donors in Children with Primary Immunodeficiencies and Hematological Diseases
Porta, F., Comini, M., Soncini, E., Carracchia, G., Maffeis, M., Pintabona, V., Bolda, F., Beghin, A., Schumacher, R. F., Lanfranchi, A.
Transplantation and cellular therapy. 2021;27(5):426.e1-426.e9
Abstract
Less than 25% of children who require hematopoietic stem cell transplantation (HSCT) for primary immunodeficiencies (PIDs) or genetic hematological diseases have an HLA-identical sibling. For them, a matched unrelated donor (MUD), although baring a greater risk of graft failure, delayed engraftment and immune reconstitution, and severe graft-versus-host disease (GvHD), represents a valid alternative. The stem cell source is also important, as unprocessed peripheral blood stem cells (PBSCs) contain 5 to 10 times more T cells than bone marrow (BM)-derived grafts, a major risk especially for small children with PID. A CD34+ positive selection can mitigate HLA compatibility issues, but the resulting CD3+ T cell depletion hampers engraftment and facilitates infections. To mitigate those problems, we decided to add back a certain number of T cells (30 × 10(6) cells/kg body weight [BW]) to the positive CD34+ selection derived from MUD BM or PBSCs and report the results in terms of time to engraftment and immune reconstitution, GvHD incidence, infections, and survival. Our aim was to show not only the feasibility and clinical efficacy of this addback but also that PBSC-derived CD34+ selected grafts with calibrated T cell addback would be equivalent to BM-derived grafts. We analyzed retrospectively our single-center cohort of 76 children (median age, 1.9 years) affected by PID (61) and hematological diseases (15) who received a total of 79 MUD HSCTs with CD34+ selection and addback of 30 × 10(6) CD3+ cells/kg BW between 2001 and 2019. We used descriptive and analytic statistics (chi-square, Student's t-test, Mann-Whitney U test, as appropriate) and constructed Kaplan-Meier curves using the log-rank test to compare patients grafted with BM or PBSC-derived inocula. The two groups showed no statistically significant differences in terms of age, sex, HLA-mismatch, or amount of CD3+ cells/kg BW added back to the CD34+ selection. However, the latter being higher in the PBSC group (P = .0001). Overall engraftment rate was 96% (73/76) and occurred faster in the PBSC group than in BM recipients: polymorphonuclear cells, 16 versus 21 days (P = .006); platelets, 15 versus 22 days (P = .001). GvHD incidence was low. No acute GvHD was diagnosed in 24 children, whereas grades I, II, III, and IV occurred in 19, 28, five, and three children, respectively (P not significant). Chronic GvHD was seen in only two children. The CD4+ count at six months after HSCT was higher in PBSC recipients as compared to those receiving BM (184 versus 88 CD4+ cells; P = .003). Overall survival for the whole cohort was 80% at 10 years, with no significant difference between the two stem cell sources (P not significant). Viral infections occurred among five of the PBSC grafted children and 14 in the BM group (P not significant), and no patient suffered from post-transplant lymphoproliferative disorder (PTLD). The results we present show that an addback of 30 × 10(6) donor CD3+ cells/kg recipient BW to a MUD BM or PBSC-derived CD34+ selection gives promising results in infants and young children undergoing HSCT for PID or hematological diseases. Furthermore, with this manipulation the inherent limits of PBSC-derived grafts can be overcome, allowing both swift engraftment and immune reconstitution without an increase in GvHD, infections, or PTLD.
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7.
Poor T-cell receptor ß Repertoire Diversity Early Post-transplant for Severe Combined Immunodeficiency Predicts Failure of Immune Reconstitution
Delmonte, O. M., Castagnoli, R., Yu, J., Dvorak, C. C., Cowan, M. J., Dávila Saldaña, B. J., De Ravin, S. S., Mamcarz, E., Chang, C. K., Daley, S. R., et al
The Journal of allergy and clinical immunology. 2021
Abstract
BACKGROUND Development of a diverse T cell receptor ß (TRB) repertoire is associated with immune recovery following hematopoietic cell transplantation (HCT) for SCID. High-throughput sequencing (HTS) of the TRB repertoire allows evaluation of clonotype dynamics during immune reconstitution. OBJECTIVES We investigated whether longitudinal analysis of the TRB repertoire would accurately describe TCR diversity and illustrate the quality of T cell reconstitution following HCT or gene therapy (GT) for SCID. METHODS We used HTS to study composition and diversity of the TRB repertoire in 27 SCID infants at 3, 6, and 12 months and yearly post-treatment(s). Total RNA from peripheral blood was used as template to amplify TRB rearrangements. RESULTS TRB sequence analysis showed poor diversity at 3 months, followed by significant improvement by 6 months after cellular therapies. Kinetics of development of TRB diversity were similar in patients with a range of underlying gene defects. However, in patients with RAG and DCLRE1C defects, HCT with no conditioning or immune suppression only resulted in lower diversity than HCT with conditioning. HCT from a matched donor correlated with higher diversity than HCT from a mismatched donor. Naïve CD4(+) T cell count at 6 months post-HCT correlated with higher TRB diversity. A Shannon index of diversity of 5.2 or lower 3 months after HCT predicted a need for a second intervention. CONCLUSIONS TRB repertoire after hematopoietic cell therapies for SCID provides a quantitative and qualitative measure of diversity of T-cell reconstitution and permits early identification of patients who may require a second intervention.
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8.
Infections in Infants with SCID: Isolation, Infection Screening, and Prophylaxis in PIDTC Centers
Dorsey, M. J., Wright, N. A. M., Chaimowitz, N. S., Dávila Saldaña, B. J., Miller, H., Keller, M. D., Thakar, M. S., Shah, A. J., Abu-Arja, R., Andolina, J., et al
Journal of clinical immunology. 2020
Abstract
PURPOSE The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children with severe combined immunodeficiency (SCID) in a prospective natural history study of hematopoietic stem cell transplant (HSCT) outcomes over the last decade. Despite newborn screening (NBS) for SCID, infections occurred prior to HSCT. This study's objectives were to define the types and timing of infection prior to HSCT in patients diagnosed via NBS or by family history (FH) and to understand the breadth of strategies employed at PIDTC centers for infection prevention. METHODS We analyzed retrospective data on infections and pre-transplant management in patients with SCID diagnosed by NBS and/or FH and treated with HSCT between 2010 and 2014. PIDTC centers were surveyed in 2018 to understand their practices and protocols for pre-HSCT management. RESULTS Infections were more common in patients diagnosed via NBS (55%) versus those diagnosed via FH (19%) (p?=?0.012). Outpatient versus inpatient management did not impact infections (47% vs 35%, respectively; p?=?0.423). There was no consensus among PIDTC survey respondents as to the best setting (inpatient vs outpatient) for pre-HSCT management. While isolation practices varied, immunoglobulin replacement and antimicrobial prophylaxis were more uniformly implemented. CONCLUSION Infants with SCID diagnosed due to FH had lower rates of infection and proceeded to HSCT more quickly than did those diagnosed via NBS. Pre-HSCT management practices were highly variable between centers, although uses of prophylaxis and immunoglobulin support were more consistent. This study demonstrates a critical need for development of evidence-based guidelines for the pre-HSCT management of infants with SCID following an abnormal NBS. TRIAL REGISTRATION NCT01186913.
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9.
Graft Versus Host Disease Following HLA-Matched Sibling Donor Compared with Matched Related Donor for Hematopoietic Stem Cell Transplantation for the Treatment of Severe Combined Immunodeficiency Disease
Al-Saud, B., Al-Saleem, A., Al Rasheed, B., Al-Ghonaium, A., Al-Ahmari, A., Al-Mousa, H., Al-Seraihy, A., Arnaout, R., Al-Jefri, A., Elshorbagi, S., et al
Journal of clinical immunology. 2019
Abstract
BACKGROUND One of the limiting factors for successful hematopoietic stem cell transplantation (HSCT) is graft versus host disease (GVHD). The EBMT/ESID guidelines for HSCT in severe combined immunodeficiency (SCID) recommend no GVHD prophylaxis for a matched sibling donor (MSD). OBJECTIVE To determine the risk of GVHD in MSD HSCT for SCID patients compared to matched related donor (MRD). METHODS This retrospective cohort study compares MSD with MRD and the outcome of GVHD in all SCID patients who underwent HSCT between 1993 and 2013. All statistical analyses were done using IBM SPSS statistics software. RESULTS One hundred forty-five SCID patients underwent 152 HSCTs while 82 (54%) received GVHD prophylaxis. GVHD occurred in 48 patients (31.5%); 20/48 (42%) had GVHD prophylaxis compared to 28/48 (58%) that did not, P = 0.022. Acute GVHD occurred at a higher trend in MSD, 37/120 (30.8%), compared to MRD, 6/32 (18.8%), P = 0.17. We also analyzed the outcome according to the period of HSCT. The first period was 1993 to 2003, 48 HSCTs, 43 MSD, 5 MRD; all patients had GVHD prophylaxis, and there was no difference in GVHD. The second period was 2004 to 2013: of 104 HSCTs, 77 had MSD and 27 had MRD; GVHD prophylaxis was used in 22.1% of MSD and 63% of MRD, P = 0.000. GVHD was significantly higher in the MSD (40.2%) compared to MRD (18.5%) patients, P = 0.041. CONCLUSION GVHD prophylaxis in MSD transplant should be considered in SCID patients.
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10.
Long-term outcome and chimerism in patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation: a retrospective nationwide survey
Iguchi, A., Cho, Y., Yabe, H., Kato, S., Kato, K., Hara, J., Koh, K., Takita, J., Ishihara, T., Inoue, M., et al
International journal of hematology. 2019
Abstract
We analyzed the outcomes of allogeneic stem cell transplantation (SCT) and risk factors for chimerism in 108 patients with Wiskott-Aldrich syndrome (WAS) who were registered with The Japan Society for Hematopoietic Cell Transplantation between January 1985 and December 2016. A preparative conditioning regimen consisting of myeloablative conditioning (MAC) was provided to 76 patients, and reduced-intensity conditioning was provided to 30 patients. Fifty-one patients received prophylaxis against graft-versus-host disease (GVHD) with cyclosporine, and 51 patients received tacrolimus (Tac). Chimerism analyses had been performed in 91 patients. Neutrophil engraftment was achieved in 91 patients (84.3%). The engraftment rate was significantly higher in patients who received Tac for GVHD prophylaxis (p = 0.028). Overall survival rate (OS) was significantly higher in patients with complete chimerism than in patients with mixed chimerism (88.2 +/- 6.1% and 66.7 +/- 9.9%, respectively, p = 0.003). Multivariate analysis showed that the rate of complete chimerism in patients who received MAC including cyclophosphamide (CY) at a dose of 200 mg/kg was significantly higher (p = 0.021) than that in patients who received other conditioning. Thus, MAC including CY at a dose of 200 mg/kg and Tac for GVHD prophylaxis were optimal conditions of SCT for patients with WAS under existing study.