Significantly Increased Risk of Grade II-IV Acute Gvhd in Adolescent and Young Adult (AYA) Recipients (ages ≥13 years) Vs Childhood Recipients (ages 2-12 years) with Acute Leukemia Following Matched Unrelated Donor (MUD) Stem Cell Transplantation (SCT): The Children's Oncology Group Experience

Abstract Calcineurin inhibitors form the backbone of graft versus host disease (GVHD) prophylaxis in hematopoietic stem cell transplantation. In the adult literature tacrolimus was demonstrated superior to cyclosporine in preventing grade II–IV acute GVHD in both related and unrelated donor transplants; however, there is no data comparing their efficacy in the pediatric population. In a multi-institutional trial, we prospectively evaluated the clinical data on 102 patients receiving either cyclosporine/methotrexate or tacrolimus/methotrexate based prophylactic regimens for 6/6 matched unrelated donor, transplant. Conditioning regimens were fully ablative; no T-cell depletion was permitted; cord blood donors were excluded. Patients were required to receive either cyclosporine or tacrolimus, but the choice was per investigator preference. The two arms were reasonably balanced: 59.8% of patients received cyclosporine and 40.2% of patients received tacrolimus. Rates for maximum grade II–IV acute GVHD were 37.7% for cyclosporine and 39% for tacrolimus (p = 0.89). Rates for maximum grade III–IV acute GVHD were 19.6% for cyclosporine and 24.4% for tacrolimus (p = 0.57). Incidence of chronic GVHD in 97 evaluable patients was 37.9% in 58 patients who received cyclosporine and 35.8% in 39 patients who received tacrolimus (p = 0.84). Survival at 1 year post-transplant was similar in both groups: 59.2% for cyclosporine and 51.2% for tacrolimus (p= 0.31). Toxicity analysis is ongoing. In pediatric matched unrelated donor transplantation, the efficacy of tacrolimus/methotrexate and cyclosporine/methotrexate based regimens for prophylaxis of GVHD are not significantly different.

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Pre-Engraftment Serum C-Reactive Protein (CRP) Value as a Predictor of Acute Graft-Versus-Host Disease and Non-Relapse Mortality.

Blood ◽

10.1182/blood.v110.11.1968.1968 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1968-1968

Author(s):

Shigeo Fuji ◽

Sung-Won Kim ◽

Takahiro Fukuda ◽

Shin-ichiro Mori ◽

Satoshi Yamasaki ◽

...

Keyword(s):

Stem Cell ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Unrelated Donor ◽

Primary Role ◽

Host Disease ◽

Graft Versus Host ◽

Increased Risk ◽

Grade Ii ◽

Acute Graft

Abstract Background: In a mouse model, it has been shown that inflammatory cytokines play a primary role in the development of acute graft-versus-host disease (GVHD). Here, we evaluated whether the pre-engraftment CRP value, which is used as a surrogate marker of inflammation, could predict post-transplant complications including GVHD. Methods: The medical records of 224 adult patients (median age, 47 years; range, 18–68 y), who underwent conventional (CST, n=105) or reduced-intensity (RIST, n=119) allogeneic stem cell transplantation between January 2002 and July 2006 were reviewed retrospectively. Their diagnosis included AML (n=94), ALL (n=23), NHL (n=62), MDS (n=27) and others (n=18). Stem cell sources included bone marrow (n=108), peripheral blood stem cells (n=98) and cord blood cells (n=18). Patients were categorized according to the maximum CRP value during the pre-engraftment neutropenic period: the “low CRP” group (CRP < 15 mg/dL) included 157 patients and the “high CRP” group (CRP≥15 mg/dL) included 67 patients. We assessed the occurrence of acute GVHD, non-relapse mortality (NRM) and overall survival. Results: The incidence of documented infections during neutropenia was higher in the high CRP group (34% vs 17%, P=0.004). The CRP value was significantly lower after RIST than after CST (P=0.017) or after related than after unrelated transplantation (P<0.001). A multiple logistic regression analysis showed that male sex, unrelated donor and HLA-mismatched donor were associated with high CRP values. The high CRP group developed significantly more grade II-IV acute GVHD, grade III-IV acute GVHD and NRM as shown in Figure 1 and 2. A multivariate analysis showed that a high CRP level was associated with an increased risk of grade II-IV acute GVHD, poor OS and high NRM. Conclusion: The present findings suggest that the CRP value may reflect the net degree of tissue damage due to the conditioning regimen, inflammation, infection and allogeneic immune reactions, all of which lead to subsequent acute GVHD and NRM. Future clinical studies to evaluate the feasibility of earlier intervention and adjustment of GVHD prophylaxis based on monitoring of the early CRP value are warranted. Fig 1 grade II-IV acute GVHD Fig 1. grade II-IV acute GVHD Fig 2 non-relapse mortality Fig 2. non-relapse mortality

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HLA-DRB3/4/5 mismatches are associated with increased risk of acute GVHD in 10/10 matched unrelated donor hematopoietic cell transplantation

American Journal of Hematology ◽

10.1002/ajh.25133 ◽

2018 ◽

Vol 93 (8) ◽

pp. 994-1001

Author(s):

Stéphanie Ducreux ◽

Valérie Dubois ◽

Kahina Amokrane ◽

Ibrahim Yakoub-Agha ◽

Myriam Labalette ◽

...

Keyword(s):

Cell Transplantation ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Unrelated Donor ◽

Matched Unrelated Donor ◽

Increased Risk

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Killer Immunoglobulin-Like Receptor and NOD2/CARD15 Polymorphisms Independently Influence Survival after Allogeneic Hematopoietic Stem Cell Transplanation.

Blood ◽

10.1182/blood.v110.11.2167.2167 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2167-2167

Author(s):

Sebastian Giebel ◽

Aleksandra Holowecka-Goral ◽

Izabela Nowak ◽

Tomasz Czerw ◽

Jerzy Wojnar ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Kir Genes ◽

Increased Risk ◽

Grade Ii ◽

Card15 Gene ◽

Grade Iii

Abstract Background: Activating and inhibitory killer immunoglobulin-like receptors (KIRs) regulate function of NK cells and a subset of T cells. KIR genotype, in particular the content of activating KIR genes is highly polymorphic. NOD2/CARD15 protein is broadly expressed in APCs and lymphocytes. Single nucleotide polymorphisms (SNPs) of this gene have been reported to impair the pathogen elimination and trigger pathologic immunologic reactions like GvHD. The goal of this prospective study was to evaluate the impact of donor’s and recipient’s KIR and NOD2/CARD15 genotypes on outcome after allogeneic hematopoietic stem cell transplantation (alloHSCT). Pateints and methods: One-hundred-two consecutive patients with hematological malignancies, aged 32(18–58)y, treated with alloHSCT from HLA-matched related (n=34) or matched unrelated donor (MUD) (n=68) were included. The conditioning regimen was myeloablative, GVHD prophylaxis consisted of CsA, Mtx, and, in case of MUD-HSCT, pre-transplant ATG. Donors and recipients were tested for 11 KIR genes as well as SNP8,12,13 of the NOD2/CARD15 gene. In addition, immune reconstitution including KIR expression on T cells, was analyzed on days +28, +56, +100, +180, and +360. Results: Overall survival (OS) rate at 2y was significantly lower in alloHSCT with at least one activating KIR mismatch compared to transplants with full compatibility (62% vs. 86%, p=0.01). In particular, the presence of at least one activating KIR in the donor with its absence in the recipient (D+R−) was associated with decreased probability of OS (60% vs. 78%, p=0.01) and DFS (58% vs. 82%, p=0.005), as well as increased incidence of non-relapse mortality (NRM) (27% vs. 7%). KIR2DS1 and KIR3DS1 D+R− mismatches resulted in increased risk of grade II–IV acute GvHD, whereas KIR2DS3 and KIR2DS2 D+R− mismatches were associated with increased risk of chronic GvHD. The presence of at least one activating KIR D+R− mismatch was associated with increased CD8+/CD4+ T cell ratio up to day +100. In all cases of incompatibility regarding KIR2DS1, KIR2DS2 and KIR3DS1, T cells with expression of respective receptors could be detected up to 360 days after alloHSCT. The presence of SNP8 of the NOD2/CARD15 gene in the recipient was associated with decreased probability of OS (20% vs. 70%, p=0.005) and DFS (20% vs. 70%, p=0.01) as well as increased incidence of NRM (60% vs. 17%) and grade III–IV acute GvHD (67% vs. 8%). In a multivariate analysis including KIR and NOD2/CARD15 polymorphisms together with other potential risk factors, increasing number of D+R− activating KIR mismatches as a linear variable appeared to independently influence OS (HR: 1.3, p=0.02), DFS (HR: 1.3, p=0.008), NRM (HR: 1.4, p=0.02), grade II–IV acute GvHD (HR: 1.4, p=0.001), and chronic GvHD (HR: 1.2; p=0.02). Recipient SNP8 of NOD2/CARD15 was predictive for OS (HR: 5.5, p=0.003), DFS (HR: 4.4, p=0.008), NRM (HR: 5.9, p=0.006), grade III–IV acute GvHD (HR: 6.1, p=0.02), and chronic GvHD (HR: 3.7; p=0.03). Conclusions: Both activating KIR D+R− mismatches and recipient SNP8 of NOD2/CARD15 appear to enhance alloreactivity and independently influence survival after alloHSCT. Evaluation of these polymorphisms may contribute to better donor selection and optimization of the alloHCT procedure.

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Outcomes of Allogeneic Stem Cell Transplantation with Individualized Dosing of Antithymocyte Globulin

Blood ◽

10.1182/blood-2020-141350 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 41-42

Author(s):

Amany R. Keruakous ◽

George Selby ◽

Sarah A. Schmidt ◽

Jennifer Holter-Chakrabarty ◽

Mohamad O. Khawandanah ◽

...

Keyword(s):

Logistic Regression ◽

Stem Cell ◽

Acute Gvhd ◽

Unrelated Donor ◽

Matched Unrelated Donor ◽

Lymphoid Malignancies ◽

Stem Cell Source ◽

Individualized Dosing ◽

Cell Source ◽

Donor Transplant

Background: Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative procedure for a variety of hematologic malignancies. However, relapse disease and graft-versus-host disease (GVHD) remain to be the main obstacle for a successful HCT. Thus, adequate immune suppression to minimize the risk of high-grade GVHD while not over suppression of donor immunity to allow graft versus tumor effect is crucial. Matched unrelated donor transplant has a higher rate of GVHD as compared to matched sibling donor transplant due to minor histocompatibility mismatch. Rabbit antithymocyte globulin (ATG), a polyclonal antibody produced by immunizing rabbits with human thymocytes, has been utilized as prophylaxis against GVHD. ATG dosing by weight has been the standard. Recent pharmacokinetic (PK) studies revealed that ATG levels and clearance vary significantly among patients receiving weight-based dosing of ATG. Recipient lymphocyte count before receiving ATG has been described as a modulator of both ATG PK and clinical outcomes after ATG-conditioned HCT. The Parachute-Study utilizing an individualized ATG dosing approach has shown more rapid immune reconstitution without affecting the incidence of acute GVHD and graft failure. In this study, we are comparing the outcomes of individualized dosing of ATG versus weight-based dosing. Method: This is a single institutional study carried out at the Bone Marrow Transplant Program at the University of Oklahoma Health Science Center. It was started as a case-control cohort study in July 2018 when individualized dosing of ATG was initiated, and continues as a historically controlled non-randomized prospective clinical study investigating individualized versus weight-based dosing of ATG. Subjects over 18 years of age who are undergoing matched unrelated donor (MUD) stem cell transplant, with myeloablative or reduced-intensity conditioning, peripheral blood or bone marrow stem cell source, for myeloid or lymphoid malignancies were included in the study. We excluded subjects with HLA mismatch or sibling donors. Individualized dosing was based on the previously validated PK model with cumulative doses varying between 2 to 10 mg/kg, based on weight, recipient lymphocyte counts before the first dose of ATG, and stem cell source, starting day -9; while the standard weight-based dosing of ATG is 4 mg/kg divided into 3 days pre-transplant. The study endpoints are to evaluate the difference between treatment groups on (1) GVHD and its severity; (2) relapse-free survival (RFS) and (3) overall survival (OS). Univariate logistic regression analysis was used to evaluate the probabilities of GVHD in both treatment arms. Multivariable analysis was done to adjust for all covariates between study arms using adjusted logistic. OS and RFS were computed using the Kaplan-Meier curves. Results: The study included 38 subjects undergoing MUD HCT for myeloid or lymphoid malignancies. Subjects included are in 2 cohorts, 19 subjects in the intervention arm using individualized targeted ATG (tATG group), and 19 subjects in the matched control arm using weight-based dosing ATG (ATG group). In a univariate unadjusted logistic regression analysis, the risk of developing GVHD is numerically higher in the ATG group than in the tATG group (OR=1.339, p=0.70). However, the proportion of acute GVHD is significantly higher in the tATG group than the ATG group (73.68% vs 31.58%, p=0.022). Also, the proportion of higher grade acute GVHD is significantly higher in the tATG group than the ATG group (31.58% vs 0%, p=0.020). RFS is longer in the tATG group than the ATG group, tending statistical significance (p=0.063). However, there is no difference in OS between study arms (p=0.645). [Figures 1 and 2] In a multivariable-adjusted logistic regression, adjusting for age at HCT, diagnosis, disease status at HCT, prior lines of therapy, and stem cell source, no confounder was found to be significantly associated with GVHD. Conclusion: Individualized targeted dosing of ATG (tATG), based on weight, recipient lymphocyte counts and stem cell source, increases the risk of acute GVHD when compared to standard fixed-dosing method, however, it improves RFS, implying possibly better immune reconstitution providing improved graft versus leukemia effect. Disclosures No relevant conflicts of interest to declare.

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Low Incidence of Grade II-IV Acute GVHD Following Tacrolimus and q8h Mycophenolate Mofetil (MMF) Prophylaxis in Pediatric and Young Adult Recipients of Allogeneic Stem Cell Transplantion (AlloSCT)

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2014.11.595 ◽

2015 ◽

Vol 21 (2) ◽

pp. S369-S370

Author(s):

Olga Militano ◽

M Fevzi Ozkaynak ◽

Daniel Mitchell ◽

Karen Wolownik ◽

Sandra Fabricatore ◽

...

Keyword(s):

Stem Cell ◽

Mycophenolate Mofetil ◽

Young Adult ◽

Acute Gvhd ◽

Grade Ii ◽

Low Incidence

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Transplant CD34+ Cell Dose Affects Outcomes Following Allogeneic Peripheral Blood Stem Cell Transplantation from a Matched Unrelated Donor.

Blood ◽

10.1182/blood.v106.11.2056.2056 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2056-2056

Author(s):

Ryotaro Nakamura ◽

Joycelynne Palmer ◽

Roberto Rodriguez ◽

Pablo Parker ◽

David Senitzer ◽

...

Keyword(s):

Peripheral Blood ◽

Acute Gvhd ◽

Unrelated Donor ◽

Matched Unrelated Donor ◽

Relapse Risk ◽

Cell Dose ◽

Grade Ii ◽

Full Intensity ◽

The Impact ◽

Reduced Intensity

Abstract Peripheral blood stem cells (PBSC) have been increasingly used in the matched unrelated donor (MUD) transplant setting, but the impact of CD34 cell dose on outcomes following MUD-PBSC transplant have not been well characterized. Between 8/00-12/04, a total of 181 patients underwent MUD-PBSC transplantation at our institution under IRB-approved protocols. Patient’s age at transplant ranged from 1 to 67 years (median 44). Eighty-two were female and 99 were male. The cohort consisted of 68 patients with AML, 38 with ALL, 18 with CML, 18 with NHL, 17 with MDS, and the remaining 22 with other diagnosis (CLL, MM, MPD, etc.). Of 181 patients, 35 were considered to have low-risk disease (acute leukemias in CR1 or CML-CP). Patients were conditioned with either full-intensity regimen (TBI+Cy or VP16, or BuCy: n=83) or reduced-intensity regimen (fludarabine+melphalan or busulfan: n=98). GVHD prophylaxis consisted of tacrolimus+methotrexate for full-intensity transplants and cyclosporine+mycophenolate+/− methotrexate for reduced-intensity transplants. Median (range) CD34+ cell, lymphocyte (Ly), and mononuclear cell (MNC) doses were 6.7 (0.6–28) x106/kg, 440 (40–2640) x106/kg, and 710 (50–5060) x106/kg respectively. A strong correlation exists between Ly and MNC doses (r2=. 52, p<0.01), but not between CD34+ cell and Ly or MNC doses. The median time to ANC≥500/uL was 16 days (range: 7–52) and platelet≥20k/ul at 20 days (range: 12–98). After a median follow up of 18 months (range: 3–49), 103 patients are alive. The two-year overall survival (OS), disease-free survival (DFS), relapse, and transplant-related mortality (TRM) probabilities were 54%, 46%, 30%, and 31% respectively. Grade II–IV acute GVHD occurred in 64% of patients (grade 3–4: 31%). Chronic GVHD was observed in 64% of evaluable patients. By univariate analysis, a CD34+ cell dose ≥ 4.2x106/kg (the lowest quartile) was associated with significantly lower relapse risk (Hazard Ratio=0.4; p=0.02), and a trend for improved DFS (HR=0.6; p=0.06) and OS (HR=0.64; p=0.08). After adjusting for the patient’s age at transplant, disease risk classification, and conditioning regimen (full-intensity vs. reduced intensity), the impact of CD34+ cell dose (≥ 4.2x106/kg) remained significant for relapse (HR=0.4; p<0.01), DFS (HR=0.6; p=0.05), with a trend for OS (HR=0.6; p=0.07). CD34+ cell dose ≥6.7x106/kg (median) was associated with a trend for reduced relapse risk (HR= 0.5; p=0.06) without impact on DFS, OS, or TRM. A CD34+ cutoff at 9.5 x106/kg (the highest quartile) had no impact on OS, DFS, relapse, or TRM. There was no association between the CD34 cell dose and acute GVHD (grade II–IV or III–IV). In conclusion, within the range of CD34 doses in our study, the CD34+ cell dose ≥ 4.2x106/kg was associated with better transplant outcomes in MUD-PBSC transplants. We observed no adverse effect of receiving CD34+cell dose > 9.5 x106 (the highest quartile) in transplant outcomes including acute GVHD and TRM.

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A Comparison of Stem Cell Source in Recipients of T-Cell Depleted Myeloablative Transplants for Leukaemia: No Difference in Mortality Using BM or PBSC.

Blood ◽

10.1182/blood.v110.11.46.46 ◽

2007 ◽

Vol 110 (11) ◽

pp. 46-46

Author(s):

B.E. Shaw ◽

Nigel H. Russell ◽

A. Pagliuca ◽

J. Apperley ◽

G. Cook ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Stem Cell Source ◽

Increased Risk ◽

Significant Difference ◽

Cell Source ◽

The Impact

Abstract The use of GSCF-mobilised Peripheral Blood Stem Cells (PBSC) for unrelated donor (UD) transplantation has increased dramatically since 2000. The association of PBSC with more rapid engraftment and with an increase in chronic Graft versus Host Disease (GvHD), compared to bone marrow (BM) has been reported in a number of studies. More recently the use of PBSC has been associated with an increase in transplant related mortality (TRM) and decrease in survival (OS) in T-cell replete transplants. We sought to analyse the impact of PBSC compared to BM in a cohort of UD transplant recipients, where T-cell depleting agents (in-vivo campath in >90%) were included in the transplant conditioning. The study included 145 patients transplanted between January 2000 and March 2006: CML- 35 in 1CP; acute leukaemia (AML in 61, ALL in 49)-110 in CR1 or 2. All had myeloablative conditioning regimens and received grafts with 9–10/10 matched HLA alleles. 86 patients received BM and 59 PBSC. There were no associations between the stem cell source and any transplant variable (including disease and stage). There was a trend to an increased use of PBSC in patients with a single antigen mismatch (p=0.052). All evaluable patients achieved neutrophil engraftment, with a significantly faster time to engraft in recipients of PBSC compared to BM (16 vs 20 days; p=0.0003). The incidence of acute GvHD was 46% (grade I in 50%, II in 41%, III in 8%, IV in 2%). This was significantly higher in recipients of PBSC (60%) compared to BM (36%; p=0.006), however there was no increase in either II/IV (p=0.69) or III/IV (p=0.18) disease in PBSC recipients. In univariate analysis, the presence of a single HLA mismatch (p=0.026) was the only other variable to be associated with an increase in acute GvHD. In a logistic regression model including both these variables, the use of PBSC remained significantly associated with an increase in aGvHD (OR=2.3; 95% CI 1.1,4.7;p=0.020). The TRM was 14%, 27% and 39% at 100 days, 1 and 5 years respectively. At none of these time points was the stem cell source associated with a significant difference in TRM. The 5-year incidence of chronic GvHD was 58% (BM 55%, PBSC 60%; NS), extensive disease in one third, and of relapse was 61% (BM 60%, PBSC 62%; NS). The 5-years OS was 41% with a median follow-up of 3.4 years (0.5–7.1). This was 44% using PBSC and 40% using BM (NS). In conclusion, although we observed an increase in acute GVHD with PBSC this was only of grade 1 disease. We found no association between the use of PBSC and an increased risk of chronic GVHD or of a worse transplant outcome, when compared to BM, in recipients of T-cell depleted myeloablative transplants for leukaemia.

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CD34-Selected, T Cell-Depleted Alternative Donor Stem Cell Transplantation For Children

Blood ◽

10.1182/blood.v122.21.2064.2064 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2064-2064 ◽

Cited By ~ 1

Author(s):

Andrew Gilman ◽

Michael Eckrich ◽

Stacy Epstein ◽

Carrie Barnhart ◽

Javier Oesterheld ◽

...

Keyword(s):

Stem Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Post Transplant ◽

Primary Graft Failure ◽

Alternative Donor ◽

Mast Cell Leukemia ◽

Grade Ii

Abstract Many children who need a hematopoietic stem cell transplant do not have a matched related or unrelated donor. The use of alternative donors including mismatched family members can provide a donor for almost all patients. The use of such donors is associated with a high risk of graft-versus-host disease (GVHD). We present the results of a prospective study using the CliniMACS® device for CD34-selection of peripheral blood stem cell (PBSC) grafts to prevent GVHD under BB-IND 14045. Patients did not receive immunosuppression after transplant. The approach was also used as a platform for a companion post-transplant immunotherapy study. The study included patients with malignant (MD) and non-malignant (NMD) disorders receiving unrelated donor (UD) and mismatched related donors (MMRD) to evaluate the broad applicability of this approach for GVHD prevention. The primary endpoint was acute GVHD incidence and there was a stopping rule for primary graft failure. Overall survival was a secondary endpoint. Between 2009-2013, 30 children underwent CD34-selected PBSC transplantation from an alternative donor. Fifteen patients had MD (ALL 4, AML 8, JMML 1, acute mast cell leukemia 1, Ewing’s sarcoma 1) and 15 had NMD (sickle cell 6, immunodeficiency 5, bone marrow failure 4). Twenty-three patients had MMRD and 7 had UD (all 7 had NMD). The conditioning regimen consisted of TBI 1200 cGy (MD) or melphalan 140mg/m2 (NMD), thiotepa 5mg/kg x2, fludarabine 40 mg/m2x5, and rabbit-ATG 1.5 (MD) or 2.5 (NMD) mg/kg x4. Seven patients with NMD received rituximab x1 during conditioning. Twenty-two patients received a planned (P) donor lymphocyte infusion (DLI) between days 30 and 42 with methotrexate GVHD prophylaxis on a companion study. Eight patients received a therapeutic (T) DLI for decreasing donor chimerism or viral infection. The median age at transplantation was 10 years (range 0.3-17). Median CD34+ dose was 21 x 10^6/kg (range 10-25) and all patients received < 1 x 10^4 CD3/kg. The ANC was > 500 at median 14 days (range 9-16). Acute GVHD prior to DLI occurred in 1 patient (3%; stage I skin which resolved with a brief course of prednisone). Primary graft failure occurred in 1 patient (3%). The patient subsequently engrafted after a CD34-selected transplant from the other parent. Two patients who had active disease at transplant (mast cell leukemia, Ewing’s) and early relapse are excluded from the following analyses. Twenty-one of 28 patients are alive with median follow-up of 2 years (range 1 mo-4 yrs). The Kaplan-Meier estimated 100 day and 1 year survival is 96% and 74%, respectively. Relapse occurred in 1/10 MD patients with at least 100 days follow-up. Grade II-IV acute GVHD and chronic GVHD occurred only after DLI. Acute GVHD grade II-IV occurred in 21% (3 P, 3 T) and chronic GVHD (3 P) in 11%. Viral reactivation was common, but viral disease was less common - CMV 12% and EBV-related PTLD 11% [at risk patients only] and adenovirus 11%. Invasive fungal infections occurred in 7%. All deaths were due to infection, with thrombotic microangiopathy present in 6/7. All outcomes were similar for MD and NMD and for MMRD and UD except for acute GVHD which occurred in 26% MMRD and 0% UD transplants and for EBV-PTLD which only occurred in NMD patients. EBV-PTLD has been reduced in NMD patients by using rituximab in the conditioning. The use of a CD34-selected, T cell-depleted alternative donor PBSC transplant successfully prevented acute GVHD without the need for post-transplant immunosuppression. The use of this approach and the conditioning regimens employed provided reliable engraftment and a very low incidence of Day 100 transplant-related mortality and relapse (for patients without active disease). Future efforts will focus on approaches for post-transplant immunotherapy to decrease morbidity and mortality due to viral infections. Disclosures: No relevant conflicts of interest to declare.

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