Graft-Versus-Host Disease (GVHD) After Double-Unit Cord Blood Transplantation (DCBT) Is Associated with Unique Clinical Features Including a Higher Incidence of Grade III-IV Acute GVHD in Children

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3044-3044
Author(s):  
Doris M Ponce ◽  
Anne Marie Gonzales ◽  
Marissa N Lubin ◽  
Hugo Castro-Malaspina ◽  
Sergio A Giralt ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Treatment Response ◽  
Acute Gvhd ◽  
High Rate ◽  
Hematopoietic Stem ◽  
Systemic Corticosteroids ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Unit Unit ◽  
Grade Iii

Abstract Abstract 3044 While the GVHD incidence after unrelated donor CBT is lower than expected for the degree of human leukocyte antigen (HLA)-mismatch, GVHD can be a serious complication and at our center has been the second most common cause of transplant-related mortality after DCBT. However, relatively little is known about DCBT GVHD manifestations, treatment response, and risk factors. Therefore, we evaluated 108 DCBT recipients (median 37 years, range 0.9–69) transplanted for hematologic malignancies. The majority had acute leukemia and high-risk disease. Patients received either myeloablative (n = 81) or non-myeloablative (n = 27) conditioning and 4–6/6 HLA-matched grafts. GVHD prophylaxis consisted of a calcineurin-inhibitor with mycophenolate mofetil, and no patient received anti-thymocyte globulin (ATG). With a median follow-up of 28 months (range 9–64), the cumulative incidences of day 180 grade II-IV and III-IV acute GVHD (aGVHD) were 52% (95%CI :42–62) and 24% (95%CI :15–32), respectively. The median onset was 40 days (range 14–161); the gut was most commonly affected (43/54, 80%) followed by skin (35/54, 65%). Twenty-five patients with mainly grade II gut aGVHD were treated with budesonide alone, 26 patients with predominantly grade III-IV aGVHD received systemic corticosteroids, and complete or partial treatment response was achieved in over 80% by day 56 of therapy. However, 41 patients had active GVHD after day 100 with the majority (25/41, 61%) having aGVHD (persistent, recurrent or late onset), particularly of the gut. Overlap syndrome and classical chronic GVHD were uncommon. Only 1 patient had oral ulceration, and no patient had moderate or severe ocular or sclerotic skin involvement, joint, or pulmonary GVHD manifestations. Univariate analysis of the association between patient/ graft characteristics and grade III-IV aGVHD showed the only significant factor associated with a higher severe aGVHD incidence was age 0–15 years (Figure). Diagnosis, patient ancestry, cytomegalovirus seropositivity, conditioning intensity, and infused cell doses/kg (total graft and engrafting-unit nucleated cell, CD34+ and CD3+) were not significant. A higher engrafting unit-recipient HLA-match of 8–9/10 was associated with a lower incidence of severe aGVHD, and a better unit-unit HLA-match of 6–10/10 was associated with a higher incidence of severe aGVHD, although these differences were not significant (p = 0.128 and 0.266, respectively). To further investigate these findings multivariate Cox regression analysis was performed (Table). Younger age was independently associated with a higher incidence of severe aGVHD (p = 0.042) whereas better engrafting unit-recipient match at 8–9/10 HLA-alleles was protective (p = 0.053). There was a trend toward better unit-unit HLA-match being associated with a higher incidence of grade III-IV aGVHD, but, surprisingly, total infused TNC/kg had no relationship. The 2-year PFS of 72% (95%CI :51–94) in children was higher than the 56% (95%CI :45–66) in adults despite their greater incidence of severe aGVHD. Nine patients (all adult) have died of GVHD including 5 patients initially treated with systemic corticosteroids and 4 with budesonide. We conclude that aGVHD after DCBT is common in the absence of ATG, predominantly affects the gut, and has a high rate of treatment response. Furthermore, GVHD after day 100 frequently has acute features. While the GVHD incidence does not preclude a high rate of survival, improved prophylaxis and treatment are needed. Notably, in contrast to single-unit CBT and adult hematopoietic stem cell transplantation, children receiving DCBT are at a higher risk for severe disease. A possible approach to reduce aGVHD in pediatric DCBT recipients with adequate CB units doses would be to prioritize high resolution HLA-match. Moreover, our data does not currently support an upper limit of infused TNC/kg in DCBT recipients. Further investigation of the biology underlying these unique observations (including the role of specific cellular subsets) should be a major priority. Disclosures: Off Label Use: Mycophenolate Mofetil as GvHD prophylaxis.

scholarly journals A Prospective Multicenter Study of Nonmyeloablative Conditioning with TBI or Fludarabine/TBI for HLA-Matched Related Hematopoietic Cell Transplantation for Treatment of Hematologic Malignancies with Post Grafting Immunosuppression with Tacrolimus and Mycophenolate Mofetil: 10-Year Experience

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1949-1949
Author(s):  
Huiying Qiu ◽  
Brenda M. Sandmaier ◽  
Barry E. Storer ◽  
Thomas Chauncey ◽  
Finn Petersen ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematologic Malignancies ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Autologous Hct ◽  
Grade Iii

Abstract Background: Nonmyeloablative conditioning with 2-Gy TBI alone or in combination with fludarabine (FLU/TBI) and HLA-matched related donor peripheral blood allografts followed by cyclosporine (CSP) and mycophenolate mofetil (MMF) for the prophylaxis of graft-versus-host disease (GVHD) is an effective therapy for many hematologic malignancies with reliable engraftment and moderate toxicity. The major causes of non-relapse mortality (NRM) are the development of acute and chronic GVHD. Several studies have demonstrated that tacrolimus may offer advantages compared with CSP for the prevention of GVHD in patients treated with myeloablative conditioning. The combination of tacrolimus and MMF, which has been used for GVHD prophylaxis after myeloablative hematopoietic cell transplantation (HCT), was well tolerated with low toxicity. Pilot data suggested an improved and perhaps superior GVHD prophylaxis with tacrolimus/MMF compared to our extensive historical experience using CSP/MMF with nonmyeloablative HCT. The purpose of this study is to evaluate the incidence of grade III-IV and II-IV acute GVHD, extensive chronic GVHD, along with the rate of NRM, relapse/progression, and overall survival after nonmyeloablative conditioning and post-grafting immunosuppression with tacrolimus and MMF. Methods: In a phase II multicenter clinical trial we evaluated the effect of post grafting immunosuppression with tacrolimus and MMF for the prophylaxis of GVHD following nonmyeloablative conditioning with 2-Gy TBI alone or in combination with 90mg/m2 FLU (FLU/TBI) for patients with hematologic malignancies. Patients at low risk of graft rejection (preceding autologous HCT within 6 months) received TBI alone (n=50) while the remaining patients received FLU/TBI conditioning (n=100). Tacrolimus was administered orally (0.06 mg/kg, Q12 hr) from days -3 to +56 and in the absence of GVHD tapered off by day +180. Tacrolimus was targeted to 15-20 ng/ml for the first 28 days and 10-20 ng/ml subsequently while on full dose. MMF was given orally (15 mg/kg, Q12 hr) from day 0 until day 27. Results: 150 patients were enrolled from 2004 to 2013 and received peripheral blood stem cells (median doses of 8.1×106 CD34+ cells/kg and 3.5×108 CD3+ cells/kg) from HLA-matched related donors. Diagnosis at transplant included AML (n=42), ALL (n=6), CLL (n=2), MDS/MPD (n=12), NHL (n=25), HL (n=8), and MM (n=55). Median patient age was 56 (range 19-74) years. Sixty-one percent of patients had an HCT comorbidity index (HCT-CI) score of greater than 2. Five percent of patients had failed a prior autologous HCT in FLU/TBI group. Median follow-up was 5.2 years. One graft failure was observed in the FLU/TBI group and no patients rejected their graft. The early NRM at day 100 was 1%. The cumulative incidences of grade II-IV and grade III-IV acute GVHD at 120 days were 26% (FLU/TBI 25%; TBI 28%) and 4% (FLU/TBI 2%; TBI 8%), respectively. Only one patient developed grade IV acute GVHD. Forty-eight percent of patients had chronic GVHD by 5 years (FLU/TBI 44%; TBI 54%). Five-year NRM was low at 12%. The overall cumulative incidence of relapse/progression at 5 years was 52%. Five-year overall and progression-free survivals were 51% and 37%, respectively. Conclusions: Post-grafting immunosuppression and GVHD prophylaxis with tacrolimus/MMF resulted in a low risk of acute and chronic GVHD, which compares favorably with our experience in a concurrent trial using CSP/MMF with FLU/TBI conditioning (46% grades II-IV acute and 72% chronic GVHD with CSP/MMF, respectively; BBMT, 2013, 19: 1340-1347). Furthermore, we recently reported that the active metabolite of MMF (MPA) concentration at steady state (MPA Css) was lower in patients who received concomitant CSP than patients receiving tacrolimus. Low total MPA Css was associated with an increased risk of severe acute GVHD following nonmyeloablative HCT (BBMT 2013, 19: 1159-1166). Together these data warrant consideration of a randomized phase III trial to investigate the role of tacrolimus/MMF versus CSP/MMF in nonmyeloablative HCT. Figure 1. Cumulative incidences of grade II to IV acute GVHD (A) and chronic GVHD (B) Figure 1. Cumulative incidences of grade II to IV acute GVHD (A) and chronic GVHD (B) Disclosures Maloney: Seattle Genetics: Honoraria; Juno Therapeutics: Research Funding; Janssen Scientific Affairs: Honoraria; Roche/Genentech: Honoraria.

Post-Transplantation High Dose Cyclophosphamide As Gvhd Prophylaxis in 9/10 HLA-Matched Unrelated Donors Hematopoietic Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3135-3135 ◽  
Author(s):  
Rohtesh S. Mehta ◽  
Rima M Saliba ◽  
Julianne Chen ◽  
Gabriela Rondon ◽  
Aimee E Hammerstrom ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hla Class I ◽  
Conventional Group ◽  
Unrelated Donor ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Grade Iii

Abstract Background: Post-transplantation cyclophosphamide (PTCy) is an effective strategy to prevent GVHD after haploidentical or HLA-matched related or unrelated donor hematopoietic stem cell transplantation (HSCT). Our study aim was to determine its efficacy in HLA-mismatched unrelated donor (MMUD) HSCT. Methods: We included 113 consecutive adult patients with high risk hematological malignancies who underwent one-antigen MMUD (9/10-matched) bone marrow (BM) or peripheral blood (PB) HSCT after myeloablative or reduced-intensity conditioning at our institution from 2009-2013. Outcomes were compared between (a) conventional GVHD group (n=71) that received in-vivo T-cell depletion with ATG, tacrolimus and methotrexate and (b) PTCy group (n=41) that received PTCy (50 mg/kg/day IV on days 3 and 4) with tacrolimus and MMF. After exclusion of 29 patients with isolated HLA-DQ mismatches, a separate analysis was performed in 84 patients with 7/8 HLA-MUD HSCT; 38 patients received PTCy while 46 patients received conventional prophylaxis. Results: Patients in the conventional group were marginally older (median 54 years; range 19-74) than those in the PTCy group (median 50 years; range 20-64). PB was used more frequently as a graft source in the conventional group (38% vs 17%, p=0.02). PTCy group included more patients with HLA class-I mismatches (87.8%) compared to conventional group (56.9%). There were no other differences between the groups. Incidence of grade II-IV (37% vs 36%, p=0.8) or grade III-IV (17% vs 12%, p=0.5) acute GVHD at day 100 post-transplant was not different between the groups. [Figure 1] Incidence of grade II-IV acute GVHD at day 30 was significantly lower after PTCy compared with conventional prophylaxis (0% vs 15%, p <0.001). Correspondingly, incidence of grade III-IV GVHD at day 30 was 0% in the PTCy group and 8% in the conventional group (p=0.08). Cumulative incidence of chronic GVHD was similar between the two groups at 6 months (20% vs 15%), 1-year (30% vs 31%) or 2-years (30% vs 42%). Risk factors analysis showed that use of PTCy was the sole independent predictor of lower risk of grade II-IV acute GVHD at day 30 (p=0.01). None of the risk factors evaluated, including PTCy use, were shown to predict the rate of grade II-IV acute GVHD within day 100. Two-year cumulative incidences of NRM (35% vs 25%), disease progression (20% vs 31%), DFS (42% vs 38%) and OS (52% vs 40%) were similar in the PTCy and the conventional groups, respectively. [Figure 1] Median times to neutrophil (18 vs. 12 days, p<0.001) and platelet (25.5 vs. 18 days, p=0.05) engraftment were prolonged in PTCy group. Disease recurrence/persistence was the leading cause of death in both groups, accounting for about 46% of all deaths. Subgroup analysis restricting to patients with BM grafts produced similar findings. In patients with HLA class-I mismatch, PTCy was associated with significantly reduced risk of grade II-IV, but not grade III-IV, acute GVHD at day 30 (p=0.01). However, there were no differences in acute grade II-IV GVHD (HR 1.1, 95% C.I. 0.5-2.5, p=0.7) or acute grade III-IV GVHD (HR 1.5, 95% C.I. 0.4-5.4, p=0.5) by day 100 between the groups. Comparing patients with 7/8-HLA-MUD HSCT, no patient in PTCy group developed acute GVHD at day 30 compared with 8 patients in conventional group (p=0.005). There were no differences in incidence of grade II-IV (HR 1, 95% C.I. 0.5-2.1, p=0.9) or grade III-IV (HR 1.1, 95% C.I. 0.3-3.3, p=0.9) acute GVHD at day 100, chronic GVHD at 6 months (HR 0.8, 95% C.I. 0.2-2.9, p=0.7), 1-year (HR 0.8, 95% C.I. 0.3-2.2, p=0.6) or 2-years (HR 0.7, 95% C.I. 0.2-1.9, p=0.5) between the groups. Conclusion: Our results demonstrate that PTCy, tacrolimus and MMF for GVHD prophylaxis is safe and produced similar results as conventional prophylaxis in patients with one antigen HLA-MMUD HSCT. Disclosures Alousi: Therakos, Inc: Research Funding.

scholarly journals Pilot Study of Telmisartan (Micardis) for Prevention of Acute Graft Vs. Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation: Interim Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4546-4546
Author(s):  
Sujatha Iyengar ◽  
Scott D. Rowley ◽  
Caixin Zhan ◽  
Michele L. Donato ◽  
Themba Nyirenda ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Adverse Reactions ◽  
Acute Gvhd ◽  
Medical Center ◽  
Hematopoietic Stem ◽  
Graft Vs Host Disease ◽  
Grade Ii ◽  
Pre Treatment ◽  
Historical Controls ◽  
Grade Iii

Telmisartan (TMS) is an angiotensin receptor blocker with anti-inflammatory properties and little or no clinical immunosuppressive effect. We undertook an unblinded, single arm, pilot study of TMS (160 mg/d p.o.) for prevention of acute graft vs. host disease (aGvHD) in recipients of HLA matched allogeneic hematopoietic stem cell transplants (HSCTs). Primary endpoints of Grade II or >Grade III aGvHD (1994 Consensus Conference on Acute GVHD Grading) were compared with 178 similar HSCT historical controls over the preceding 3 yrs at our institution: 26% >Grade III, 74% Grade II. Safety endpoints included engraftment, relapse/progression by day (d) 180, non-relapse mortality by d 180, and serious drug-related adverse reactions. Experimental data were collected on blood endotoxin levels and stool microbiome composition. The study was powered to detect 20% or 50% reduced rates of, respectively, Grade II or >Grade III. We report results from a planned interim analysis triggered when the first 22 evaluable patients (pts) reached d 100. Of 27 evaluable pts, 24 were beyond d 180 by completion of this interim analysis. The study was designed to treat pts for two days prior to, and day of HSCT, and for an additional 98 days post-transplant, but pts were considered evaluable if they completed >14 days of post- transplant TMS, including pre-determined dose reductions. One enrollee received TMS for 13 days post-HSCT and was excluded from analysis. Five pts received 14-24 days of drug (4 by choice, 1 died of sepsis). More than half the evaluable patients (17/27) completed >94 days of post-HSCT therapy, including 6 who experienced an episode of hypotension. Almost half (13/27) received >80% of the full 101 day dose (16,160 mg), including 5 who experienced hypotension. Of the 6 enrollees receiving <24 days of drug, two had documented hypotension. No other serious drug-attributed adverse reactions were reported. Reasons cited for pts choosing to discontinue TMS were inconvenience of taking pills, and home stool sampling. Safety Endpoints: All pts engrafted promptly (ANC >500/uL, platelet >20,000/uL). Peripheral donor CD3+ T cell median and range of chimerism on days 28 and 84 were 99.5% (37-100) and 100.0% (36-100); bone marrow donor CD34+ cell chimerism was 97.0% (62-100). There was a single NRM during the 180 d study, and no graft rejection or increase in relapse or progression. Four relapses occurred within 180 days, and 2 more after d 180, resulting in two relapse deaths (d 370, and d 600). Primary Endpoints:A single individual developed hyperacute Grade III skin GvHD on day 7 p-HSCT. Another 12 of 27 patients developed Grade 2 aGvHD, one after the conventional 100 d window (d 141). Compared with historical controls, the incidence of aGvHD was significantly reduced for Grade II (p < 0.005) and Grade >III (p = 0.01), using the two-tailed Z-test of proportions. Experimental Endpoints: Acute GvHD is associated with increased gut permeability, bacterial translocation, and loss of gut microbiome diversity. Endotoxemia, an indicator of intestinal integrity, as measured by the endotoxin activity assay (EAA, Spectral Medical) reached septic levels in 40% of patients during pre-transplant conditioning (d -3 - d 0), and subsequently returned to, or maintained, non-septic levels from week 5 onward in 90% of patients, with an overall downward group trend of EAA scores during 180 days of follow up. Genotyping and analysis of bacterial V4 16S ribosomal DNA from weekly stool samples of the first 10 evaluable patients revealed no decrease in OTU richness or Shannon diversity at any time point pre- vs. post- treatment. Among the 5 most abundant phyla, Bacteroidetes was significantly less abundant post-treatment compared to pre-treatment. Among the 8 most abundant families, Bacteroidaceae significantly decreased post- vs. pre- treatment. While historic microbiome controls from our institution are not available, our finding of increased Bacteroidetes is in contrast to reported decreased Bacteroidetes in allogeneic HSCTs not receiving TMS, but may resemble changes after autologous HSCT. This trial, funded by the Gateway Foundation, is ongoing. Preliminary results indicate TMS is well tolerated, with a beneficial impact on aGvHD and no increased relapse or NRM, with excellent engraftment, and preservation of anti-tumor effect, intestinal barrier integrity, and gut microbial diversity. Disclosures Iyengar: Hackensack University Medical Center: Patents & Royalties: Telmisartan use patent.. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Schwartz:Hackensack University Medical Center: Patents & Royalties: Telmisartan use patent. OffLabel Disclosure: Telmisartan. Indicated for treatment of hypertension.

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

Blood ◽  
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.

Randomized Phase II Trial Comparing Cyclosporine (CSP) and Tacrolimus (TAC) for Methotrexate (MTX)-Free Graft-Versus-Host Disease (GVHD) Prophylaxis after Allogeneic Transplantation from a Matched Related Donor (MRD) with a Reduced-Intensity Regimen Containing Cladribine and Busulfan

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1170-1170 ◽  
Author(s):  
Sung-Won Kim ◽  
Takahiro Fukuda ◽  
Shotaro Hagiwara ◽  
Tsunehiko Komatsu ◽  
Tetsuya Goto ◽  
...  
Keyword(s):  
Whole Blood ◽  
Acute Gvhd ◽  
Trough Level ◽  
Chronic Gvhd ◽  
Gvhd Prophylaxis ◽  
Starting Dose ◽  
Grade Ii ◽  
Reduced Intensity ◽  
Grade Iii ◽  
Neutrophil Engraftment

Abstract Background: Although GVHD prophylaxis without MTX might enhance a graft-versus-leukemia effect, no randomized controlled trial (RCT) of GVHD prophylaxis has investigated this possibility in a reduced-intensity stem cell transplantation (RIST) setting. Therefore, we conducted a prospective randomized trial to compare CSP and TAC without MTX as GVHD prophylaxis in RIST from a MRD. Methods: Patients with hematological malignancies in complete remission or with a chemosensitive status were eligible for this study if they were either older than 50 years or had significant medical contraindications for conventional transplantation. The primary endpoint was the incidence of grade II-IV acute GVHD on day 100. Regimen-related toxicities (RRT) between day −8 and day 28 were assessed by NCI-CTC ver 2.0. The conditioning regimen consisted of cladribine (0.11 mg/kg × 6 days) and oral busulfan (4 mg/kg × 2 days). All patients received unmanipulated G-CSF-mobilized peripheral blood stem cells from a MRD. CSP (starting dose 3 mg/kg/day, target whole blood conc. 250–350 ng/mL, target trough level 150–250 ng/mL) or TAC (starting dose 0.03 mg/kg/day, target whole blood conc. 10–20 ng/mL, target trough level 5–10 ng/mL) was given as GVHD prophylaxis from day −1. G-CSF was administered from day +6 until neutrophil engraftment. Results: Sixty-eight patients were enrolled between 2/2003 and 2/2008, but 3 were removed before transplant because of disease progression or infection. The diagnoses included lymphoma (n=27; 10 FL, 6 DLBCL, 6 PTCL and 5 HL), AML (n=14), MDS (n=12), MM (n=5), MPD (n=4) and ALL (n=3). The median age of the patients (56 y vs. 55 y) and the median number of CD34+ cells infused (3.7 ×106/kg vs. 3.1 ×106/kg) were similar in the CSP and TAC arms. The median day of neutrophil engraftment in both arms was day 11. The proportion of patients in the CSP or TAC arm who achieved complete chimerism in CD3+ cell fraction on days 28, 56 and 90 was, respectively, 61% vs. 48%, 80% vs. 76% and 80% vs. 97%. Grade 4 RRT was hepatic disease (n=1, CSP arm), and grade 3 RRT included cardiac (n=1, CSP), renal (n=1, CSP), hepatic (n=2, CSP), oral mucosal (n=1, TAC) and gastrointestinal disease (n=4, CSP vs. n=3, TAC). The incidence of grade II–IV acute GVHD in the TAC arm was significantly lower than that in the CSP arm (Table & Figure). The incidences of grade III–IV acute GVHD and extensive chronic GVHD were not significantly different between the two arms. The non-relapse mortality (NRM) in the TAC arm was significantly lower than that in the CSP arm. The causes of death that contributed to NRM were infection in 6 (CSP arm), GVHD in one (CSP), ARDS in one (TAC) and lung cancer in one (CSP). The relapse rate and relapse-related mortality were not significantly different between the two arms. The median follow-up for surviving patients was 1295 days (169–1954). The overall survival (OS) and progression-free survival (PFS) rates in the TAC arm tended to be higher than those in the CSP arm. Figure Figure Conclusions: A regimen with TAC alone without MTX as GVHD prophylaxis was associated with significantly lower rates of grade II–IV acute GVHD and NRM compared to a regimen with CSP alone after RIST from a MRD. OS and PFS with TAC alone tended to be higher than those with CSP alone. Nevertheless, these results must be considered with care due to the small number of patients, and the optimal use of both drugs is still under investigation. A large-scale RCT to identify suitable GVHD prophylaxis in the RIST setting is warranted. Table: Study Outcomes CSP arm (n=33) TAC arm (n=32) P P value was evaluated with logrank test or Wilcoxon test*. Grade II–IV acute GVHD 64% 39% 0.040 Grade III–IV acute GVHD 30% 23% N.S Extensive chronic GVHD 63% 61% N.S 1-year/3-year NRM 26%/38% 0%/5% 0.008 1-year/3-year relapse 35%/43% 25%/49% N.S 1-year/3-year relapse mortality 27%/33% 10%/42% N.S 1-year/3-year OS 57%/45% 90%/56% 0.135 (0.039*) 1-year/3-year PFS 48%/35% 75%/48% 0.120 (0.047*)

Impact Of Prophylaxis With Defibrotide On The Occurrence Of Acute GvHD In Allogeneic HSCT

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4591-4591
Author(s):  
Selim Corbacioglu ◽  
Simone Cesaro ◽  
Maura Faraci ◽  
Bernd Gruhn ◽  
Jaap J Boelens ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Controlled Study ◽  
Control Group ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Adjusted Risk ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
And Control ◽  
The Impact

Background Acute GvHD (aGvHD) remains one of the most significant complications of allogeneic hematopoietic stem cell transplantation (HSCT) with a persistently high incidence despite a plethora of prophylactic approaches. The medical need for effective drugs to prevent aGvHD remains substantial. Methods A prospective, randomized, open-label controlled study has been conducted in 356 children at high-risk for hepatic VOD post-HSCT to demonstrate efficacy of prophylaxis with defibrotide (DF) to reduce the incidence of VOD (180 in the DF arm and 176 in the control arm [Corbacioglu, Lancet 2012]). A secondary objective of the study was to analyze the impact of DF prophylaxis on the incidence and severity of aGvHD. Among children undergoing allogeneic HSCT (allo-subset) 122 patients received DF prophylaxis and 117 were in the control arm. Results Demographic and baseline characteristics were similar in the DF and control arm of the allo-subset. Mean age (± SD) was 6.47±5.28 and 6.54±5.49 in DF arm and in the controls respectively, with 29% and 30% being <2 years; 64% and 58%, respectively, were males. Busulfan was used in conditioning in 62% and 64% of patients in the two arms, and melphalan in 60% and 53%, respectively. Grafts were from related donors in 40% and 30%, respectively, in DF and control arm. Prophylaxis with DF was shown to significantly reduce the occurrence and severity of aGvHD. At day+100 post-HSCT the incidence of aGvHD was 47% in the DF arm vs. 65% in the control group (p=0.0046). DF did not seem to affect the incidence of aGvHD grade I (25% vs 28%, respectively). However, Defibrotide showed a consistent reduction of the more severe grade II–IV aGvHD from 37% to 22% (p=0.0130). Of note the use of corticosteroids was significantly lower in patients receiving DF prophylaxis (37% vs 48% in control arm, p=0.0363), likely reflecting the lower incidence of aGvHD in the DF arm. This has also previously been observed in the treatment studies [Richardson, ASH 2012]. Standard GvHD prophylaxis was allowed according to best practice and was generally comparable (cyclosporine A: 81% vs. 89%; methotrexate: 46% vs. 56%; in DF and control arm, respectively). However, there was a difference in patients who received antithymocyte globulin (ATG) in the DF arm compared to controls (55% vs 70%). Exploratory analysis performed adjusting for ATG as covariate confirmed the significant effects of defibrotide [Adjusted Risk Difference (DF vs control) for aGvHD grade II–IV: -0.1470 (95%CI: -0.2618; -0.0322), p =0.0121]. Defibrotide did not seem to interfere with a graft-versus-leukemia effect. Relapse rates of combined leukemias were 8% (ALL 1.5%, AML 5%, others 1.5%) in DF group compared with 10% (ALL 3%, AML 7%) in controls by day +100; while 10% (ALL 1.5%, AML 7%, others 1.5%) patients in DF group relapsed by day +180 compared with 13% (ALL 8%, AML 5%) in the control arm. Conclusions The study shows that DF prophylaxis can reduce the incidence and severity of aGvHD in children undergoing allogeneic HSCT. This reduction observed with defibrotide is additional to standard GvHD prophylaxis that was fully implemented in these patients. Defibrotide has been reported to protect endothelial cells from damage as well as to downregulate heparanase activity. These clinical data would therefore suggest a benefit of defibrotide to reduce the incidence and severity of aGvHD. Further studies may be conducted to strengthen preclinical and clinical evidence for the role of defibrotide in aGvHD prevention. Ref: Corbacioglu S et al, Lancet 2012; 379:1301-9. Richardson PG et al, Blood 2012; 120:738. Disclosures: Corbacioglu: Gentium : Consultancy. Cesaro:Pfizer SpA: Honoraria; Gilead: Honoraria; Merck: Honoraria. Tudone:Gentium : Employment. Ballabio:Gentium : Employment. Heringa:Gentium S.p.A.: Employment.

Outcomes after Double Umbilical Cord Blood Transplantation in Children: A Survey on Behalf of Eurocord and PDWP-EBMT

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2570-2570
Author(s):  
Federica Giannotti ◽  
Annalisa Ruggeri ◽  
Gerard Michel ◽  
Jean-Hugues Dalle ◽  
Tracey O'Brien ◽  
...  
Keyword(s):  
Single Unit ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Median Number ◽  
Cell Dose ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Grade Iii

Abstract Double UCBT (dUCBT) has been used in adults to reach an acceptable cell dose. For most children a single unit with a total nucleated cell (TNC) dose >3x107/Kg can be easily identified, but that is not always the case for heavier patients (pts). Use of dUCBT might decrease relapse and increase graft-versus-host-disease (GvHD). Data on dUCBT in children are scarce in the literature. A recent randomized study in children has described similar outcomes after double compared to single UCBT. Our study provides an overview of the use of dUCBT in the pediatric population reported to Eurocord. We retrospectively analyzed the outcomes of unrelated dUCBT in 177 children transplanted between 2002 and 2012 in 61 EBMT centres. Analysis was performed separately for pts with malignant (n=139) and non-malignant (NM, n=38) diseases. Among pts with malignancies, 76 had ALL, 40 AML, 6 MDS, 2 CML, 11 NHL, 3 Hodgkin Lymphoma and 1 Multiple Myeloma. Median age at dUCBT was 15 years (1.3-17.9) and median weight was 55 kg (13-97). Disease status at dUCBT was 1st complete remission (CR) (36%), ≥2nd CR (34%) or advanced (25%), and missing in 5% of the pts. In this group, 117pts received a myeloablative conditioning (MAC) and 22 a reduced intensity regimen (RIC). Cyclophosphamide+fludarabine+TBI was administered to 41% of the pts; 55% received ATG in the conditioning. Median number of collected TNC was 5.7x107/kg (3,6-12,8). Considering the unit with the higher number of HLA incompatibilities with the recipient, 56% had 2 mismatches. GvHD prophylaxis was cyclosporine-A (CSA) based in 93% of the pts (58% received CSA + mycofenolate mofetil). Median follow-up was 31 months. Cumulative incidence (CI) of neutrophil (PMN) and platelet (PLT) engraftment was 88% at 60 days and 64% at 180 days after dUCBT, and it was achieved with a median time of 24 and 45 days, respectively. Among the 122 pts with PMN engraftment, 85/94 with available data on chimerism were full donor and, of these, 20% had dual chimerism. CI of acute GvHD grade II-IV and grade III-IV at 100 days was 51% and 26%, respectively; it was significantly higher in pts who did not receive ATG (grade II-IV: 35% vs 67%, p=0.004; grade III-IV: 12% vs 37%, p=0.0075). Chronic GvHD was observed in 24/104 pts at risk (60% extensive; 2-year (yr) CI: 18%). The 2-yr CI of relapse was 31%. In univariate analysis, RIC, advanced stage at transplantation and a collected TNC dose lower than the median, were significantly associated with higher rates of relapse.The 2-yr CI of transplant related mortality (TRM) was 27%. Overall, 73 pts died: 35 of relapse, 15 of infections, 9 of GvHD and 14 of other causes. The 2-yr disease free survival (DFS) and overall survival (OS) were 42% and 45%, respectively. Among pts with NM disorders, 24 had bone marrow failure syndrome (BMFS) (10 Fanconi Anemia, 13 Acquired Aplastic Anemia and 1 other inherited BMFS), 2 hemoglobinopathies, 7 immune deficiencies and 5 metabolic disorders. Median age at dUCBT was 11 years (0.7-17.9) and the median weight was 40 kg (13-70). In this group, 27 pts received a RIC (40% TBI based), 10 a MAC (90% busulfan based), and 1 no conditioning regimen. ATG was administered to 82% of the pts and GvHD prophylaxis was CSA-based in 77%. The median number of collected TNC was 8.4x107/kg (1,2-11,2) and 60% of the grafts had ≥2 HLA mismatches with the recipient. Median follow-up was 39 months. Overall, 28 pts achieved PMN engraftment and 16 PLT engraftment, with a median time of 23 and 61 days, respectively. In univariate analysis, pts with BMFS compared to others had a significantly lower CI of PMN engraftment (58% vs 100%, p=0.002). Among the 10 pts who did not engraft, 3 had autologous reconstitution and 3 had a subsequent allogeneic HSCT. Forteen pts developed acute GvHD grade II-IV and 10/25 pts at risk had chronic GvHD (3 extensive). Overall 21 pts died (17 with BMFS): 9 of infections, 5 of GvHD and 7 of other causes. The 2-yr OS was 42% and it was significantly lower in pts with BMFS compared to those affected by other NM disorders (28% vs 70%, p=0.03). In pts with malignancies, despite a higher incidence of acute GvHD, DFS and OS seem to be comparable to those reported in the literature for single UCBT or HSCT from other alternative stem cell sources. In the NM disorders group, despite the high cell dose, dUCBT did not seem to improve results in pts with BMFS. This survey suggests that dUCBT is feasible in children and should be considered when a single unit with an adequate cell dose is not available. Disclosures No relevant conflicts of interest to declare.

HLA-DP Mismatches Increase the Risk of Acute GVHD after Unrelated Donor Hematopoietic Transplantation (UDT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3125-3125 ◽  
Author(s):  
Marcos de Lima ◽  
Simrit Parmar ◽  
Ping Liu ◽  
Poliana A. Patah ◽  
Pedro Cano ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Unrelated Donor ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Reduced Intensity ◽  
Grade Iii

Abstract The HLA class II DP locus encode for both subunits of DPB1 heterodimers, which have low levels of expression on the cell surface of antigen presenting cells. We hypothesized that donor-recipient HLA-DP mismatch would lead to an increased incidence of acute (a) graft-versus-host disease (GVHD), and that 2 mismatches would likely be even more significant. Methods: We studied 84 consecutive patients (pts) with myeloid leukemias in complete remission (CR) transplanted from 01/02 to 02/06. Preparative regimens were ablative IV Busulfan-based (n=58) or Cy/TBI (n=2), and reduced intensity (Fludarabine (Flu)/Bu 130 mg/m2/2 doses plus Gleevec (n=8), and Flu/Melphalan 140 mg/m2 (n=16). Stem cell (SC) source was bone marrow (n=70) or peripheral blood (n=14). ATG was given in 78 cases. GVHD prophylaxis was tacrolimus and mini-methotrexate in all cases, with additional pentostatin in 31 pts. High-resolution typing was sequence-based for HLA-A, B, DRB1; SSP was used for DRB3/4/5, DQB1 and DPB1, and SBT/SSOP for HLA-C. A Cox proportional hazards regression model was used to study aGVHD-free and relapse-free (RFS) survival. Variables with a p-value <0.25 by univariate analysis were included in the multiple regression analysis (MV). Variables were age, gender, weight, conditioning regimen, GVHD prophylaxis, diagnosis, cytogenetics, SC source, ABO group, infused CD34 and CD3 cell dose, and HLA matching. AGVHD-free survival was calculated from transplant date to date of development of grade II–IV GVHD or completion of 100 days of follow-up. Results: Median age was 48 yrs (range, 14–72). Diagnoses were MDS (n=5), AML (n=58), and CML (n=21). 54 pts (64%) were beyond 1st CR; all CML pts were in >1st chronic phase (CP). Sixty-one pts were 10/10 HLA match (A, B, C, DRB1, DQB1), and 23 had one or more mismatches. All but one pt engrafted neutrophils at a median of 13 days. 33 pts (39%) and 13 pts (15%) developed grade II–IV and III–IV aGVHD, respectively. Chronic GVHD incidence was 51%. With a median follow-up of 18 mo. (range,1.3–52) 60 pts are alive; 40 pts have relapsed or died. Median survival has not been reached. Number of DP mismatches and incidence of aGVHD is shown in the table. The following covariates influenced aGVHD-free survival by MV analysis: Flu-based regimen (P=0.005; HR 0.25 (95%CI 0.1–0.66), reduced intensity regimens (p=0.02; HR 0.35 (95%CI 0.15–0.83) and presence of 2 DPB1 mismatches (p=0.02; HR 3.07 (95%CI 1.19–7.95). Presence of 1 DPB1 mismatch was not significantly associated with aGVHD. There was no statistically significant correlation between presence of 2 DP mismatches and RFS (P=0.17;HR 0.3 (95%CI 0.06–1.65);HR 0.75 for 1 mismatch) or with cGVHD. Actuarial 2-yr survival for 10/10 matched pts without DP mismatches (12/12) versus those with DP mismatches is 82% versus 71%(P=0.6). In the 10/10 matched group, GVHD was the cause of death only among recipients of 2 DP mismatches transplants (n=4). Conclusion: Mismatching at HLA-DPB1 may increase the risk of aGVHD following UDT. The role of DP in the development of GVHD and GVL effects merits future study. Incidence of acute GVHD 10 of 10 matches number of DP mismatches grade II–IV grade III–IV 0 8% 0% 1 23% 8% 2 45% 18% < 10 of 10 matches number of DP mismatches grade II–IV grade III–IV 0 45% 15% 1 82% 36% 2 80% 40%

Donor Lymphocyte Infusion Management and Impact on Transplant Outcome after Reduced Intensity Conditioning Allogeneic Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2305-2305
Author(s):  
Mauricette Michallet ◽  
Quoc-Hung Le ◽  
Anne-Sophie Michallet ◽  
Anne Thiebaut ◽  
Emannuelle Tavernier ◽  
...  
Keyword(s):  
Retrospective Analysis ◽  
Prospective Studies ◽  
Acute Gvhd ◽  
Mixed Chimerism ◽  
Reduced Intensity Conditioning ◽  
Acute Leukemias ◽  
Hematopoietic Stem ◽  
Grade Ii ◽  
Reduced Intensity ◽  
Grade Iii

Abstract Management of donor lymphocyte infusions (DLI) after reduced intensity conditioning regimen allogeneic hematopoietic stem cell transplantation (RICT) remains not clear and needs prospective studies. We performed a retrospective analysis on 47 patients (29 males and 18 females) who received 94 DLI among 96 patients who underwent RICT in our institution. Twenty-four patients received 1 DLI (D) [mean dose: 0.3x108 CD3 /Kg (0.01–1)] and 70 escalating doses (ED) [2 DLI (n=10), 3 DLI (n=9), 4 DLI (n=1), 5 DLI (n=1), 6 DLI (n=1) and 8 DLI (n=1)] from 0.1 to 5.6x108 CD3/Kg. The diagnosis pretransplant was acute leukemias (n=10) and myelodysplasia (n=3), chronic myeloid leukemia (n=2), Hodgkin (n=7) and non Hodgkin lymphomas (n=6), multiple myeloma (n=14) and solid tumours (n=5). Twenty patients have already been transplanted before RICT and 9 patients were in complete remission (CR), 19 in partial response (PR), 18 in evolutive disease (EDis). As hematopoietic stem cells, 22 patients received peripheral blood and 25 bone marrow and as conditioning 26 patients received busulfan, fludarabine and anti-thymocytes globulines (ATG), 13 patients TBI 2 grays associated to fludarabine (n=8) and 6 grays associated with cyclophosphamide (n=5), 5 patients received cyclophosphamide and ATG and 3 patients aracytine, idarubicine and fludarabine. After transplant and before any DLI, 21 developped acute GVHD (11 grade I, 8 grade II and 2 grade III). The indications and results after DLI are given in the Table 1. Only 4 patients received DLI for two different indications within time: 2 for relapse firstly and partial chimerism secondly and 2 according to protocol requirement firstly and for relapse secondly. After DLI, we noted 18 acute GVHD (7 grade I, 4 grade II, 6 grade III and 1 grade IV), 9 were resolutive after specific therapy and 18 patients developed chronic GVHD (13 limited and 5 extensive). Probability of overall survival at 2 years of patients who underwent RICT including DLI (n=47) was significantly better than for patients undergoing RICT without DLI (n=57) [43% (95%CI 30.5–60.4) vs 31.5 (95%CI 18.8–52.8) (p=0.01)] but there was no difference when we consider EFS [20.7% (95%CI 11.6–36.8) vs 21.6% (11–42.5) (p=0.49)]. We performed for patients receiving DLI a multivariate analysis stratified on diagnosis studying sex, age, status at transplant and mean dose of infused lymphocytes and we demonstrated that lymphocyte dose had a significant negative impact on EFS (HR= 1.06 95% CI 1.01–1.10) (p=0.01). To better understand the real place of DLI within allogeneic immunotherapy against malignancies, we need more details about the results of DLI in retrospective analysis but principally prospective studies in the future. TABLE 1 Indication of DLI Nb of patients Nb of DLI DLI (D) DLI (ED) Dose x 10 exp8 CD3/Kg Response to DLI Evolutive Disease N = 34 23 2.26 10 13 1.46 EDis 5 1.6 2 3 0.66 CR 6 1.5 2 4 0.45 PR Mixed Chimerism N = 7 6 1.5 5 1 0.7 Total Donor 1 1 1 0 0.7 Mixed Chimerism Protocol N = 6 1 1 1 0 0.1 CR 3 1.6 2 1 0.34 PR 2 2 1 2 0.52 EDis

Megadose CD34-Selected Haplocompatible Donor Stem Cell Transplantation in Children.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5417-5417
Author(s):  
Barbara S. Sleight ◽  
Morton J. Cowan ◽  
Biljana Horn ◽  
Jennifer Jaroscak ◽  
Joseph McGuirk ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Overlap Syndrome ◽  
Malignant Diseases ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Grade Iii

Abstract We report a retrospective review of 18 children receiving haplocompatible related donor hematopoietic peripheral blood SCT and consecutively enrolled at four U.S. transplant centers. The median age was 8 yrs (range 1–20). Patients with malignancy (n=13) included: AML-CR1 (primary induction failure, failed cord blood transplant) [1], CR2 [3]; MDS-RA/RARS [2], RAEB [2]; AML and Fanconi anemia [1]; CML-CP2 [1]; ALL-CR3 [2]; NHL-CR2 [1]. Patients with non-malignant diseases included severe aplastic anemia [n=4] and Wiskott-Aldrich syndrome [n=1]. Thirteen donors were a 3/6 HLA match and 5 were a 4/6 match. CD34 positive selection was used to select stem cells and deplete T lymphocytes. Conditioning for 13 of the patients consisted of TBI 12–14 Gy in 6 fractions, thiotepa, fludarabine and ATG. Fractionated TBI was replaced by single fraction TBI (n=2) or melphalan (n=3). Cyclophosphamide replaced thiotepa for 1 patient with FA. No post-transplant graft-versus-host disease (GVHD) prophylaxis was given. Patients received a median of 18 × 106 CD34+ cells/kg (range 6–28) and 3 × 104 CD3+ cells/kg (range 0.3–11). Sustained primary engraftment occurred in 15/18 (83%) patients. Primary graft failure occurred in one patient. Two patients had immunological rejection following HHV-6 reactivation. Both engrafted after a second transplant; therefore the overall engraftment success was 94%. The median time to an ANC >0.5 × 109/L was 12 days (range 9–21). Platelet recovery occurred in 16/18 at a median of 17 days (range 9–22). Primary (occurring after SCT but prior to DLI) grade II acute GVHD was seen in 4/17 patients (24%). Grade III-IV GVHD was seen in 1 patient (6%) manifest as overlap syndrome in association with HHV-6 reactivation. One pt had primary extensive chronic GVHD. Of nine patients who received DLI and/or stem cell boosts, 4 had grade II GVHD (3/4 had prior acute GVHD), none had grade III-IV GVHD, 2 developed chronic GVHD and 1 developed overlap syndrome. Infections were common but manageable. All patients were at risk for CMV reactivation based on CMV serology: recipient/donor +/+ (9), +/− (3), −/+ (6). Seven patients (39%) reactivated CMV. All cases were responsive to anti-viral therapy and/or DLI. No CMV disease was seen. Seven patients had adenovirus reactivation and 6 had HHV-6 reactivation. EBV reactivation occurred in 5/18 (28%) patients. Rituximab (5) and DLI (2) yielded rapid resolution of EBV in all patients. Four of 13 (31%) at risk patients have relapsed: 1 pt with cytogenetic relapse remains in CR2 > 6 mo later and another who recently relapsed is undergoing salvage therapy. The 100 day and 1 year transplant-related mortality was 11% and 19%, respectively. The overall survival is 72% with a median follow-up of 31 months (range 7–89). Among patients transplanted for malignant diseases (13) and non-malignant diseases (5), overall survival is 69% and 80%, respectively. The K-M 2 year survival was 70% +/− 22%. All survivors were complete donor chimeras by DNA methods. The use of megadose CD34-selected PBSC without post-transplant GVHD prophylaxis yielded rapid engraftment, low 100-day mortality and incidence of severe GVHD, and excellent survival. The overall survival compares favorably with MSD and MUD HSCT.

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