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Brenda M Sandmaier - One of the best experts on this subject based on the ideXlab platform.
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reversal of low donor chimerism after hematopoietic cell transplantation using Pentostatin and donor lymphocyte infusion a prospective phase ii multicenter trial
Biology of Blood and Marrow Transplantation, 2018Co-Authors: Merav Bar, Mary E.d. Flowers, Thomas R Chauncey, Rainer Storb, Barry E Storer, Michael A Pulsipher, Monica S Thakar, Wolfgang Bethge, David G Maloney, Brenda M SandmaierAbstract:Abstract In a multicenter, prospective, phase II study we evaluated the safety and efficacy of Pentostatin followed by donor lymphocyte infusion (DLI) in patients with low donor Tcell chimerism after allogeneic hematopoietic cell transplantation (HCT). Thirty-six patients with low donor blood CD3 chimerism were enrolled in this study. Thirty-five patients received a total of 41 DLIs after a dose of Pentostatin, and 1 patient received Pentostatin only. Median donor CD3 chimerism prompting the initiation of Pentostatin and DLI was 28% (range, 5% to 47%). Responses (defined by increases in donor CD3 chimerism ≥10% maintained to day 56 post-DLI) were seen in 16 patients (44.4%) with a median rise in CD3 donor chimerism to 64% (range, 48% to 100%). There was a trend for better responses among 21 patients who received first treatment within 100 days after transplant (57% response rate) compared with15 patients who received first treatment more than 100 days after HCT (27% response rate, P = .07). Fourteen patients (39%) developed grades II to IV acute graft-versus-host disease (GVHD) at a median of 10 days (range, 0 to 83) after DLI. Ten patients (28%) developed extensive chronic GVHD. Seventeen patients (47%) developed new grade 4 cytopenias after DLI. There was no difference in relapse between nonresponders and responders. Twenty-eight patients (78%) died, most (n = 21) because of relapse. Five of 16 responders (31%) are alive, all disease-free, at a median of 60 months (range, 21 to 132) after DLI. Six of 20 nonresponders (30%) are alive at a median of 47 months (range, 16 to 100) after DLI, 3 in complete remission. Pentostatin and DLI had acceptable toxicity and appeared to increase low donor CD3 chimerism after HCT but had no impact on mortality.
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extracorporeal photopheresis combined with Pentostatin in the conditioning regimen for canine hematopoietic cell transplantation does not prevent gvhd
Bone Marrow Transplantation, 2014Co-Authors: Wolfgang Bethge, Brenda M Sandmaier, Rainer Storb, Fabio R Kerbauy, Erlinda B Santos, Ted GooleyAbstract:Extracorporeal photopheresis (ECP) and the purine analog Pentostatin exert potent immunomodulatory effects. We evaluated the use of these treatment modalities to prevent GVHD in a canine model of unrelated dog leukocyte Ag-mismatched hematopoietic cell transplantation, after conditioning with 920 cGy TBI. We have shown previously in this model that 36/40 dogs given MTX alone as postgrafting immunosuppression engrafted and that 25 of 40 dogs had severe GVHD and median survival of 21 days. In the current study, nine dogs received conditioning with 920 cGy TBI and postgrafting MTX either with ECP on days -2 to -1 alone (n=5) or ECP on days -6 and -5 combined with two doses of Pentostatin (days -4 to -3) (n=4). Seven of nine dogs achieved engraftment. Six dogs developed severe acute GVHD (four in the group with ECP alone and two with Pentostatin and ECP). We failed to demonstrate a positive impact of ECP and Pentostatin for the prevention of GVHD compared with historical control dogs.
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extracorporeal photopheresis in addition to Pentostatin in conditioning for canine hematopoietic cell transplantation role in engraftment
Bone Marrow Transplantation, 2011Co-Authors: Wolfgang Bethge, Brenda M Sandmaier, Rainer Storb, Fabio R Kerbauy, Erlinda B Santos, Ted GooleyAbstract:Extracorporeal photopheresis in addition to Pentostatin in conditioning for canine hematopoietic cell transplantation: role in engraftment
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dla haploidentical stem cell allografts after anti cd44 therapy and nonmyeloablative conditioning the impact of donor lymphocyte infusion dli Pentostatin and graft composition on donor chimerism and rejection
Blood, 2005Co-Authors: Fabio R Kerbauy, Brenda M Sandmaier, Rainer Storb, Erlinda B Santos, Ted Gooley, Takahiro Fukuda, Hilary StempelAbstract:Background: We previously reported that engraftment across a dog leukocyte antigen (DLA) haplotype-mismatched barrier could be achieved after nonmyeloablative conditioning with 200 cGy total body irradiation (TBI) plus post-grafting mycophenolate mofetil (MMF) /cyclosporine (CSP) when anti-CD44 monoclonal antibody (MAb), S5, is added to the regimen. However, 50% of dogs rejected their grafts after discontinuation of MMF/CSP. Here, we studied the influence of donor lymphocyte infusion (DLI), Pentostatin, and graft composition in achievement of sustained full donor chimerism and prevention of rejection. Methods: Twenty-nine dogs were administered MAb S5 (0.2 mg/kg/day) from days -7 to -2, before 200 cGy TBI. Unmodified G-CSF-mobilized peripheral blood stem cells (PBSC) from DLA-haploidentical donors were infused followed by immunosuppression with MMF (5-10 mg/kg BID SQ) and CSP (15 mg/kg BID PO). Dogs in group 1 (n=8) were not given DLI and dogs in group 2 (n=5) were given 6 doses of Pentostatin (4 mg/m2/dose) before TBI and no DLI. Dogs in group 3 (n=10) and 4 (n=6) received escalating doses of DLI on days +35, +63, +92. In addition, dogs in group 4 received Pentostatin (4 mg/m2) 2 days prior to each infusion of DLI. Results: All dogs achieved initial engraftment between 1 to 2 weeks after transplant and survived 5 weeks or longer with mononuclear cell chimerism ranging from 2% to 98% (median 37%) on day +35. Higher cell subset levels in the PBSC graft were associated with stable donor engraftment: total nucleated cells (p=0.03), CD4+ (p=0.01), CD8+ (p=0.03) and CD14+ (p=0.009) cells. Also, there was a trend in the number of CD34+ (p=0.10) and CD3+(p=0.07) cells. Graft rejection was seen in 7 of 13 dogs without DLI (groups 1 and 2) and in 7 of 16 dogs that received DLI (groups 3 and 4). There was no statistically significant association between DLI and rejection (p=0.44). Six of 16 dogs who received DLI and 1 of 13 dogs with no DLI achieved full donor chimerism (p=0.18), yet there was no statistically significant association between the four groups (p=0.52). There was a trend for higher counts of CD4+ and CD8+ cells (p=0.08) and achievement of full donor chimerism. However, the use of Pentostatin before each DLI (group 4) did not impact achievement of full donor chimerism (p>0.95). Duration of mixed chimerism was associated with higher cell subset levels of infused PBSC; CD34+ (p=0.06), CD4+ (p=0.02), CD14+ (p=0.05), CD3+ (p=0.09), CD8+ (p=0.08). Conclusions: The use of DLI with or without prior infusion of Pentostatin after initial engraftment of DLA-haploidentical donor graft did not facilitate conversion to full donor chimerism, sustain mixed chimerism, or prevent graft rejection. However, the infusion of haploidentical donor PBSC graft with higher numbers of TNC, CD34+, CD3+, CD4+, CD8+ and CD14+ cells could prolong donor chimerism and prevent graft rejection.
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conversion of low donor chimerism following nonmyeloablative conditioning for hematopoietic cell transplantation hct using Pentostatin and donor lymphocyte infusion dli
Blood, 2004Co-Authors: Brenda M Sandmaier, Thomas R Chauncey, Michael A Pulsipher, David G Maloney, Michael B Maris, Wolfgang A. BethgeAbstract:Nonmyeloablative allogeneic HCT from both related or unrelated HLA-matched donors after pretransplant conditioning with 2 Gy TBI with or without fludarabine and with posttransplantation CSP/MMF has resulted in initial mixed donor/host chimerism in the majority of recipients. While the risk of rejection of HLA-matched related or unrelated donor grafts was 40%. Among patients receiving DLI for disease, those with disease responses had chimerism levels >90% after DLI, supporting the concept that full chimerism was necessary to eradicate malignant cells and exert graft-vs-tumor effects. Therefore, a protocol was developed to evaluate safety and efficacy of the immunosuppressive drug Pentostatin given before DLI to reverse pending graft rejection. Patients considered at risk for rejection had low ( 20%) donor CD3 chimerism and persistent or stable (including CR) malignant disease; they had no ongoing acute grades II-IV GVHD nor chronic extensive GVHD. Eight patients have been treated a median of 100 (range 54–339) days after HCT. They were originally conditioned for HCT with 2 Gy TBI with (n=7) or without (n=1) fludarabine (30 mg/m2 per day x 3 days) and given both donor and host immunosuppression with MMF and CSP after HCT. Donors were HLA-matched related (n=6) or unrelated (n=2). Diagnoses included NHL (n=2), CLL (n=2), AML (n=1), CML (n=1), and multiple myeloma (n=1); median patient age was 54.5 (range 44–66) years. The patients received Pentostatin (4 mg/m2) 2 days before DLI (107 CD3 cells/kg); no post-DLI immunosuppression was given. The median donor CD3 chimerism level before Pentostatin and DLI was 29.5 (range 5–34)%. Five patients developed neutropenia and the median number of days of ANC
Daniel Catovsky - One of the best experts on this subject based on the ideXlab platform.
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long term follow up after purine analogue therapy in hairy cell leukaemia
Best Practice & Research Clinical Haematology, 2015Co-Authors: Monica Else, Claire Dearden, Daniel CatovskyAbstract:Since 2006 when we last reviewed the literature concerning the use of purine analogues in hairy cell leukaemia (HCL), results from several new and updated series have been published. Here we examine these reports and consider their implications for patient management. The two purine analogues Pentostatin and cladribine remain the first-line treatments of choice for all patients with HCL. Although they have not been compared in randomised trials, they appear to be equally effective. A complete response is important for the long-term outcome and we look at how best this can be achieved. Evidence is emerging which supports the use of either purine analogue plus an anti-CD20 monoclonal antibody after relapse, though questions remain concerning the scheduling of the monoclonal antibody. Patients refractory to the purine analogues may require alternative agents.
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alemtuzumab therapy in t cell prolymphocytic leukemia comparing efficacy in a series treated intravenously and a study piloting the subcutaneous route
Blood, 2011Co-Authors: Claire Dearden, Amit Khot, Monica Else, Mike Hamblin, Effie Grand, Ashok Roy, Saman Hewamana, Estella Matutes, Daniel CatovskyAbstract:Intravenous alemtuzumab is an effective and well-tolerated treatment for T-cell prolymphocytic leukemia (T-PLL). Alemtuzumab given intravenously as first-line treatment in 32 patients resulted in an overall response rate of 91% with 81% complete responses. Studies in B-cell chronic lymphocytic leukemia have shown subcutaneous alemtuzumab to be equally as effective as intravenous alemtuzumab. The UKCLL05 pilot study examined the efficacy and toxicity of this more convenient method of administration in 9 previously untreated patients with T-PLL. Only 3 of 9 patients (33%) responded to treatment. Furthermore, 2 of 9 patients (22%) died while on treatment. Recruitment was terminated because of these poor results. After rescue therapy with intravenous alemtuzumab and/or Pentostatin, median progression-free survival and overall survival were similar to the intravenous group. Alemtuzumab delivered intravenously, but not subcutaneously, remains the treatment of choice for previously untreated T-PLL.
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long term results for Pentostatin and cladribine treatment of hairy cell leukemia
Leukemia & Lymphoma, 2011Co-Authors: Claire Dearden, Monica Else, Daniel CatovskyAbstract:Over the past 25 years we have collected data at our institution from 242 patients with hairy cell leukemia (HCL), treated with Pentostatin (n = 188) or cladribine (n = 54), with a median follow-up of 16 years. From this we have been able to conclude that there is no significant difference in outcome between the two agents either at first or subsequent lines of therapy. Overall, the complete response (CR) rate is 81% and the median disease-free survival (DFS) is 16 years. After relapse or non-response patients can be successfully retreated with Pentostatin or cladribine achieving a lower rate of CRs with each line of therapy, although these remain equally durable. Complete response and pretreatment counts of hemoglobin >10 g/dL together with platelets >100 × 109/L are associated with the longest DFS. Importantly, for patients achieving a CR the DFS is five times as long as for those achieving a partial response (PR). Patients still in CR at 5 years have only a 25% risk of relapse by 15 years. Outcomes for...
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the role of rituximab in combination with Pentostatin or cladribine for the treatment of recurrent refractory hairy cell leukemia
Cancer, 2007Co-Authors: Monica Else, Claire Dearden, Estella Matutes, Nnenna Osuji, Andrew Wotherspoon, Ilaria Del Giudice, Francesco Forconi, Francesco Lauria, Daniel CatovskyAbstract:BACKGROUND: The purine analogs Pentostatin and cladribine have revolutionized the treatment of hairy cell leukemia (HCL) with overall responses in greater than 85% of patients and a median progression-free survival of up to 15 years. They continue to be effective at second- and even third-line therapy; however, alternative treatments are needed for patients who are or have become refractory to these agents or whose remissions are shorter with each course of therapy. METHODS: The authors conducted a retrospective review of 8 patients who received Pentostatin or cladribine combined concurrently (n = 6 patients) or sequentially (n = 2 patients) with rituximab at second-line therapy (n = 3 patients) and at subsequent lines of therapy (n = 5 patients). Results from a previously reported database of 219 patients with HCL (73 patients who received second-line therapy and 20 patients who received third-line therapy) were used as a historic control group against which to measure benefit. RESULTS: All 8 patients responded to therapy, with 7 complete responses (CRs) (87.5%) and minimal toxicity. All patients who had CRs were negative for minimal residual disease (MRD). At a median follow-up of 29 months (range, 5-39 months) 1 patient developed recurrent disease, and the estimated 2-year recurrence rate was 20% (0% after second-line therapy and 25% after subsequent lines of therapy). In the historic control group, the CR rates were 70% after second-line therapy and 45% after third-line therapy, and the recurrence rates at 2 years were 15% and 33%, respectively. CONCLUSIONS: The combination of purine analogs with rituximab was safe and effective for patients with recurrent and/or refractory HCL, and the current results suggested an added benefit compared with standard treatment.
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t cell large granular lymphocyte leukemia a report on the treatment of 29 patients and a review of the literature
Cancer, 2006Co-Authors: Nnenna Osuji, Estella Matutes, Andrew Wotherspoon, John Swansbury, Geir E Tjonnfjord, Henri Grech, Ilaria Del Giudice, Daniel CatovskyAbstract:BACKGROUND: To the authors' knowledge, there is no standard treatment for patients with T-cell large granular lymphocyte (LGL) leukemia. Available data are limited by patient numbers and coexisting pathologies. METHODS: The authors report on the use of immunosuppressants (cyclosporin A [CSA] and low-dose oral methotrexate [MTX] given continuously) and cytotoxic agents in the treatment of 29 patients with T-cell LGL leukemia age over the past 20 years. RESULTS: The overall response rate (ORR) to MTX (n = 8 patients) was 85.7% (complete hematologic response [CHR] rate, 14.3%; partial response [PR] rate, 71.4%) with dose-dependent responses observed and safe usage of doses >10 mg/m2 per week in 2 patients. The ORR to CSA (n = 23 patients) was 78.2% (CHR rate, 30.4%; PR rate, 47.8%). The median time to response for both agents was 1 month. Toxicity, although it was minor in most patients and was more common in the CSA group, included second malignancies in 5 patients. An ORR of 67% (all CHR) was attained with Pentostatin (n = 4 patients); recurrences developed after a median of 4.6 years. Successful retreatment with Pentostatin was possible but with increasing drug resistance. Cyclophosphamide induced CHR that lasted >7 years with bone marrow clearance in 1 of 4 patients. Alemtuzumab induced a PR in 1 patient who had refractory disease. CONCLUSIONS: Both MTX and CSA were efficacious in the treatment of T-cell LGL leukemia but generally required long-term maintenance therapy. The authors highlight the risks of second malignancies and persistence of bone marrow disease. Although MTX and CSA were effective as first-line therapy, alemtuzumab and Pentostatin merit further investigation, particularly for refractory disease.
Rainer Storb - One of the best experts on this subject based on the ideXlab platform.
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reversal of low donor chimerism after hematopoietic cell transplantation using Pentostatin and donor lymphocyte infusion a prospective phase ii multicenter trial
Biology of Blood and Marrow Transplantation, 2018Co-Authors: Merav Bar, Mary E.d. Flowers, Thomas R Chauncey, Rainer Storb, Barry E Storer, Michael A Pulsipher, Monica S Thakar, Wolfgang Bethge, David G Maloney, Brenda M SandmaierAbstract:Abstract In a multicenter, prospective, phase II study we evaluated the safety and efficacy of Pentostatin followed by donor lymphocyte infusion (DLI) in patients with low donor Tcell chimerism after allogeneic hematopoietic cell transplantation (HCT). Thirty-six patients with low donor blood CD3 chimerism were enrolled in this study. Thirty-five patients received a total of 41 DLIs after a dose of Pentostatin, and 1 patient received Pentostatin only. Median donor CD3 chimerism prompting the initiation of Pentostatin and DLI was 28% (range, 5% to 47%). Responses (defined by increases in donor CD3 chimerism ≥10% maintained to day 56 post-DLI) were seen in 16 patients (44.4%) with a median rise in CD3 donor chimerism to 64% (range, 48% to 100%). There was a trend for better responses among 21 patients who received first treatment within 100 days after transplant (57% response rate) compared with15 patients who received first treatment more than 100 days after HCT (27% response rate, P = .07). Fourteen patients (39%) developed grades II to IV acute graft-versus-host disease (GVHD) at a median of 10 days (range, 0 to 83) after DLI. Ten patients (28%) developed extensive chronic GVHD. Seventeen patients (47%) developed new grade 4 cytopenias after DLI. There was no difference in relapse between nonresponders and responders. Twenty-eight patients (78%) died, most (n = 21) because of relapse. Five of 16 responders (31%) are alive, all disease-free, at a median of 60 months (range, 21 to 132) after DLI. Six of 20 nonresponders (30%) are alive at a median of 47 months (range, 16 to 100) after DLI, 3 in complete remission. Pentostatin and DLI had acceptable toxicity and appeared to increase low donor CD3 chimerism after HCT but had no impact on mortality.
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reversal of low donor chimerism following hematopoietic cell transplantation using Pentostatin and donor lymphocyte infusion
Blood, 2016Co-Authors: Mary E.d. Flowers, Merav Bar, Thomas R Chauncey, Barry E Storer, Michael A Pulsipher, Monica S Thakar, Wolfgang Bethge, Rainer StorbAbstract:Objectives: Low donor chimerism after hematopoietic cell transplantation (HCT) is associated with increased risk of post transplant relapse. Our group has shown that donor lymphocyte infusion (DLI) was ineffective for converting 90% elicited GVT effects (Blood 2004;103:790). To facilitate effectiveness of DLI for patients (pts) with low or declining donor CD3chimerism, a prospective multicenter trial assessing the safety and efficacy of addingPentostatin was developed. Patients and Methods: Pts at risk for rejection after HCTs, defined as low ( 5%) donor CD3 chimerism and with stable/in remission disease, were included. Pts were excluded if they had evidence of relapse/progression, ongoing grades II-IV acute (a)GVHD, or extensive chronic (ec)GVHD. Between 2003 and 2014, 36 pts were treated on the study; 35 pts received a total of 41 DLIs following a dose of Pentostatin, and 1 pt received Pentostatin only. Diagnoses included AML (n=13), NHL (n=4), CLL (n=7), CML (n=2), MDS (n=6), MPD (n=2), MM (n=1), NHL and MDS (n=1). Pts received nonmyeloablative (n= 35) or ablative (n=1) conditioning, followed by PBSCs from HLA-matched related (n=17) or unrelated (n=17) donors, or 1-allele mismatched unrelated donor (n=2). Median age at HCT was 58 (34-72) years. DLI was given at a median of 96 (54-339) days after HCT. A dose of Pentostatin was given 2 days before infusing 1x107 CD3 cells/kg (n=26), 2x107 CD3 cells/kg (n=1), or 3x107 CD3 cells/kg (n=14). Per protocol, prophylactic immunosuppression (IS) with cyclosporine and MMF was given after DLI to the last 6 pts on study. Results: Median donor CD3chimerism beforePentostatin/DLI was 28 (5-47)%. Efficacy, defined by increases in donor CD3chimerism>10% maintained to day 56 post-DLI, was seen in 16 pts (44.4%) with a median CD3 donorchimerism of 64 (48-100)%. There was a trend for better efficacy among the 21 pts who received first treatment within 100 days after transplant (57%) compared to the 15 pts who received first treatment more than 100 days after HCT (27%) (p=0.07). Six pts received 2nd treatment ofPentostatin/DLI; among them 1 responded. Fifteen pts (12 responders) developedaGVHD after DLI [grade I (n=2), II (n=9), III (n=3), IV (n=1)] at a median of 10 (0-83) days after DLI. One pt developed skinGVHD, grade II, afterPentostatin administration and DLI was aborted. Of the 16 pts who developedaGVHD afterPentostatin/DLI, 3 had a prior history of GVHD after transplant. Thirteen pts developedcGVHD, ofwhom 10 developedecGVHD at a median of 112 (13-347) days after DLI. One pt developedecGVHD with no prioraGVHD. Among the 6 pts who received prophylaxis IS after DLI 1 pt developedaGVHD grade II, and none developedcGVHD. However, only 2 of those 6 pts responded. Seventeen pts developed grade 4cytopenia after DLI; 9 pts developed both neutropenia and thrombocytopenia, 4 pts developed neutropenia, and 4 pts developed thrombocytopenia. Among the 13 patients who developed grade 4 neutropenia, 9 (69%) were non-responders. Median time between DLI and lowest ANC count was 22 (2-100) days, and neutropenia lasted for median of 7 (1-52) days. Twelve pts received platelet transfusions started at median of 33 (1-98) days after DLI. Nineteen pts relapsed at a median of 91 (26-777) days after DLI. Among the 20 non-responders 12 relapsed (60%), compared to 7 of 16 responders (44%) (HR 0.64 (0.3-1.6), p=0.35). Ten of the 17 pts (59%) who developedcytopenia relapsed, 6 ofwhom (60%) were non-responders. Median number of significant infections was 2 (0-10) per pt. Twenty-eight pts died at a median of 522 (67-2028) days after DLI. Causes of death were relapse (n=21), respiratory failure/infections (n=4), grade IV GVHD (n=2), or other causes (n=1). Five of the 16 responders (31%) are alive, all in CR. Six of the 20 non-responders (30%) are alive, only 3 in CR (Figure 1). Summary:Pentostatin/DLI increased donor CD3chimerism in pts after HCT if was given within 100 days after transplant, and it was well tolerated. Response was associated with GVHD. Delayed treatment after HCT and prophylactic IS after DLI were associated with decreased efficacy. There was a trend for higher relapse rate among the non-responders and pts who developed cytopenia, but the differences were not statistically significant. Disclosures Pulsipher:Novartis: Consultancy, Other: Advisory Board, Steering Committee for Phase II Study; Jazz Pharmaceutical: Consultancy, Other: Advisory Board; Chimerix: Consultancy, Other: Advisory Board ; Medac: Other: Travel support for a study group.
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extracorporeal photopheresis combined with Pentostatin in the conditioning regimen for canine hematopoietic cell transplantation does not prevent gvhd
Bone Marrow Transplantation, 2014Co-Authors: Wolfgang Bethge, Brenda M Sandmaier, Rainer Storb, Fabio R Kerbauy, Erlinda B Santos, Ted GooleyAbstract:Extracorporeal photopheresis (ECP) and the purine analog Pentostatin exert potent immunomodulatory effects. We evaluated the use of these treatment modalities to prevent GVHD in a canine model of unrelated dog leukocyte Ag-mismatched hematopoietic cell transplantation, after conditioning with 920 cGy TBI. We have shown previously in this model that 36/40 dogs given MTX alone as postgrafting immunosuppression engrafted and that 25 of 40 dogs had severe GVHD and median survival of 21 days. In the current study, nine dogs received conditioning with 920 cGy TBI and postgrafting MTX either with ECP on days -2 to -1 alone (n=5) or ECP on days -6 and -5 combined with two doses of Pentostatin (days -4 to -3) (n=4). Seven of nine dogs achieved engraftment. Six dogs developed severe acute GVHD (four in the group with ECP alone and two with Pentostatin and ECP). We failed to demonstrate a positive impact of ECP and Pentostatin for the prevention of GVHD compared with historical control dogs.
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extracorporeal photopheresis in addition to Pentostatin in conditioning for canine hematopoietic cell transplantation role in engraftment
Bone Marrow Transplantation, 2011Co-Authors: Wolfgang Bethge, Brenda M Sandmaier, Rainer Storb, Fabio R Kerbauy, Erlinda B Santos, Ted GooleyAbstract:Extracorporeal photopheresis in addition to Pentostatin in conditioning for canine hematopoietic cell transplantation: role in engraftment
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dla haploidentical stem cell allografts after anti cd44 therapy and nonmyeloablative conditioning the impact of donor lymphocyte infusion dli Pentostatin and graft composition on donor chimerism and rejection
Blood, 2005Co-Authors: Fabio R Kerbauy, Brenda M Sandmaier, Rainer Storb, Erlinda B Santos, Ted Gooley, Takahiro Fukuda, Hilary StempelAbstract:Background: We previously reported that engraftment across a dog leukocyte antigen (DLA) haplotype-mismatched barrier could be achieved after nonmyeloablative conditioning with 200 cGy total body irradiation (TBI) plus post-grafting mycophenolate mofetil (MMF) /cyclosporine (CSP) when anti-CD44 monoclonal antibody (MAb), S5, is added to the regimen. However, 50% of dogs rejected their grafts after discontinuation of MMF/CSP. Here, we studied the influence of donor lymphocyte infusion (DLI), Pentostatin, and graft composition in achievement of sustained full donor chimerism and prevention of rejection. Methods: Twenty-nine dogs were administered MAb S5 (0.2 mg/kg/day) from days -7 to -2, before 200 cGy TBI. Unmodified G-CSF-mobilized peripheral blood stem cells (PBSC) from DLA-haploidentical donors were infused followed by immunosuppression with MMF (5-10 mg/kg BID SQ) and CSP (15 mg/kg BID PO). Dogs in group 1 (n=8) were not given DLI and dogs in group 2 (n=5) were given 6 doses of Pentostatin (4 mg/m2/dose) before TBI and no DLI. Dogs in group 3 (n=10) and 4 (n=6) received escalating doses of DLI on days +35, +63, +92. In addition, dogs in group 4 received Pentostatin (4 mg/m2) 2 days prior to each infusion of DLI. Results: All dogs achieved initial engraftment between 1 to 2 weeks after transplant and survived 5 weeks or longer with mononuclear cell chimerism ranging from 2% to 98% (median 37%) on day +35. Higher cell subset levels in the PBSC graft were associated with stable donor engraftment: total nucleated cells (p=0.03), CD4+ (p=0.01), CD8+ (p=0.03) and CD14+ (p=0.009) cells. Also, there was a trend in the number of CD34+ (p=0.10) and CD3+(p=0.07) cells. Graft rejection was seen in 7 of 13 dogs without DLI (groups 1 and 2) and in 7 of 16 dogs that received DLI (groups 3 and 4). There was no statistically significant association between DLI and rejection (p=0.44). Six of 16 dogs who received DLI and 1 of 13 dogs with no DLI achieved full donor chimerism (p=0.18), yet there was no statistically significant association between the four groups (p=0.52). There was a trend for higher counts of CD4+ and CD8+ cells (p=0.08) and achievement of full donor chimerism. However, the use of Pentostatin before each DLI (group 4) did not impact achievement of full donor chimerism (p>0.95). Duration of mixed chimerism was associated with higher cell subset levels of infused PBSC; CD34+ (p=0.06), CD4+ (p=0.02), CD14+ (p=0.05), CD3+ (p=0.09), CD8+ (p=0.08). Conclusions: The use of DLI with or without prior infusion of Pentostatin after initial engraftment of DLA-haploidentical donor graft did not facilitate conversion to full donor chimerism, sustain mixed chimerism, or prevent graft rejection. However, the infusion of haploidentical donor PBSC graft with higher numbers of TNC, CD34+, CD3+, CD4+, CD8+ and CD14+ cells could prolong donor chimerism and prevent graft rejection.
Wolfgang Bethge - One of the best experts on this subject based on the ideXlab platform.
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reversal of low donor chimerism after hematopoietic cell transplantation using Pentostatin and donor lymphocyte infusion a prospective phase ii multicenter trial
Biology of Blood and Marrow Transplantation, 2018Co-Authors: Merav Bar, Mary E.d. Flowers, Thomas R Chauncey, Rainer Storb, Barry E Storer, Michael A Pulsipher, Monica S Thakar, Wolfgang Bethge, David G Maloney, Brenda M SandmaierAbstract:Abstract In a multicenter, prospective, phase II study we evaluated the safety and efficacy of Pentostatin followed by donor lymphocyte infusion (DLI) in patients with low donor Tcell chimerism after allogeneic hematopoietic cell transplantation (HCT). Thirty-six patients with low donor blood CD3 chimerism were enrolled in this study. Thirty-five patients received a total of 41 DLIs after a dose of Pentostatin, and 1 patient received Pentostatin only. Median donor CD3 chimerism prompting the initiation of Pentostatin and DLI was 28% (range, 5% to 47%). Responses (defined by increases in donor CD3 chimerism ≥10% maintained to day 56 post-DLI) were seen in 16 patients (44.4%) with a median rise in CD3 donor chimerism to 64% (range, 48% to 100%). There was a trend for better responses among 21 patients who received first treatment within 100 days after transplant (57% response rate) compared with15 patients who received first treatment more than 100 days after HCT (27% response rate, P = .07). Fourteen patients (39%) developed grades II to IV acute graft-versus-host disease (GVHD) at a median of 10 days (range, 0 to 83) after DLI. Ten patients (28%) developed extensive chronic GVHD. Seventeen patients (47%) developed new grade 4 cytopenias after DLI. There was no difference in relapse between nonresponders and responders. Twenty-eight patients (78%) died, most (n = 21) because of relapse. Five of 16 responders (31%) are alive, all disease-free, at a median of 60 months (range, 21 to 132) after DLI. Six of 20 nonresponders (30%) are alive at a median of 47 months (range, 16 to 100) after DLI, 3 in complete remission. Pentostatin and DLI had acceptable toxicity and appeared to increase low donor CD3 chimerism after HCT but had no impact on mortality.
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reversal of low donor chimerism following hematopoietic cell transplantation using Pentostatin and donor lymphocyte infusion
Blood, 2016Co-Authors: Mary E.d. Flowers, Merav Bar, Thomas R Chauncey, Barry E Storer, Michael A Pulsipher, Monica S Thakar, Wolfgang Bethge, Rainer StorbAbstract:Objectives: Low donor chimerism after hematopoietic cell transplantation (HCT) is associated with increased risk of post transplant relapse. Our group has shown that donor lymphocyte infusion (DLI) was ineffective for converting 90% elicited GVT effects (Blood 2004;103:790). To facilitate effectiveness of DLI for patients (pts) with low or declining donor CD3chimerism, a prospective multicenter trial assessing the safety and efficacy of addingPentostatin was developed. Patients and Methods: Pts at risk for rejection after HCTs, defined as low ( 5%) donor CD3 chimerism and with stable/in remission disease, were included. Pts were excluded if they had evidence of relapse/progression, ongoing grades II-IV acute (a)GVHD, or extensive chronic (ec)GVHD. Between 2003 and 2014, 36 pts were treated on the study; 35 pts received a total of 41 DLIs following a dose of Pentostatin, and 1 pt received Pentostatin only. Diagnoses included AML (n=13), NHL (n=4), CLL (n=7), CML (n=2), MDS (n=6), MPD (n=2), MM (n=1), NHL and MDS (n=1). Pts received nonmyeloablative (n= 35) or ablative (n=1) conditioning, followed by PBSCs from HLA-matched related (n=17) or unrelated (n=17) donors, or 1-allele mismatched unrelated donor (n=2). Median age at HCT was 58 (34-72) years. DLI was given at a median of 96 (54-339) days after HCT. A dose of Pentostatin was given 2 days before infusing 1x107 CD3 cells/kg (n=26), 2x107 CD3 cells/kg (n=1), or 3x107 CD3 cells/kg (n=14). Per protocol, prophylactic immunosuppression (IS) with cyclosporine and MMF was given after DLI to the last 6 pts on study. Results: Median donor CD3chimerism beforePentostatin/DLI was 28 (5-47)%. Efficacy, defined by increases in donor CD3chimerism>10% maintained to day 56 post-DLI, was seen in 16 pts (44.4%) with a median CD3 donorchimerism of 64 (48-100)%. There was a trend for better efficacy among the 21 pts who received first treatment within 100 days after transplant (57%) compared to the 15 pts who received first treatment more than 100 days after HCT (27%) (p=0.07). Six pts received 2nd treatment ofPentostatin/DLI; among them 1 responded. Fifteen pts (12 responders) developedaGVHD after DLI [grade I (n=2), II (n=9), III (n=3), IV (n=1)] at a median of 10 (0-83) days after DLI. One pt developed skinGVHD, grade II, afterPentostatin administration and DLI was aborted. Of the 16 pts who developedaGVHD afterPentostatin/DLI, 3 had a prior history of GVHD after transplant. Thirteen pts developedcGVHD, ofwhom 10 developedecGVHD at a median of 112 (13-347) days after DLI. One pt developedecGVHD with no prioraGVHD. Among the 6 pts who received prophylaxis IS after DLI 1 pt developedaGVHD grade II, and none developedcGVHD. However, only 2 of those 6 pts responded. Seventeen pts developed grade 4cytopenia after DLI; 9 pts developed both neutropenia and thrombocytopenia, 4 pts developed neutropenia, and 4 pts developed thrombocytopenia. Among the 13 patients who developed grade 4 neutropenia, 9 (69%) were non-responders. Median time between DLI and lowest ANC count was 22 (2-100) days, and neutropenia lasted for median of 7 (1-52) days. Twelve pts received platelet transfusions started at median of 33 (1-98) days after DLI. Nineteen pts relapsed at a median of 91 (26-777) days after DLI. Among the 20 non-responders 12 relapsed (60%), compared to 7 of 16 responders (44%) (HR 0.64 (0.3-1.6), p=0.35). Ten of the 17 pts (59%) who developedcytopenia relapsed, 6 ofwhom (60%) were non-responders. Median number of significant infections was 2 (0-10) per pt. Twenty-eight pts died at a median of 522 (67-2028) days after DLI. Causes of death were relapse (n=21), respiratory failure/infections (n=4), grade IV GVHD (n=2), or other causes (n=1). Five of the 16 responders (31%) are alive, all in CR. Six of the 20 non-responders (30%) are alive, only 3 in CR (Figure 1). Summary:Pentostatin/DLI increased donor CD3chimerism in pts after HCT if was given within 100 days after transplant, and it was well tolerated. Response was associated with GVHD. Delayed treatment after HCT and prophylactic IS after DLI were associated with decreased efficacy. There was a trend for higher relapse rate among the non-responders and pts who developed cytopenia, but the differences were not statistically significant. Disclosures Pulsipher:Novartis: Consultancy, Other: Advisory Board, Steering Committee for Phase II Study; Jazz Pharmaceutical: Consultancy, Other: Advisory Board; Chimerix: Consultancy, Other: Advisory Board ; Medac: Other: Travel support for a study group.
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reversal of low donor chimerism following hematopoietic cell transplantation using Pentostatin and donor lymphocyte infusion
Blood, 2016Co-Authors: Mary E.d. Flowers, Merav Bar, Thomas R Chauncey, Barry E Storer, Michael A Pulsipher, Monica S Thakar, Wolfgang BethgeAbstract:Abstract Objectives: Low donor chimerism after hematopoietic cell transplantation (HCT) is associated with increased risk of post transplant relapse. Our group has shown that donor lymphocyte infusion (DLI) was ineffective for converting 90% elicited GVT effects (Blood 2004;103:790). To facilitate effectiveness of DLI for patients (pts) with low or declining donor CD3chimerism, a prospective multicenter trial assessing the safety and efficacy of addingPentostatin was developed. Patients and Methods: Pts at risk for rejection after HCTs, defined as low ( 5%) donor CD3 chimerism and with stable/in remission disease, were included. Pts were excluded if they had evidence of relapse/progression, ongoing grades II-IV acute (a)GVHD, or extensive chronic (ec)GVHD. Between 2003 and 2014, 36 pts were treated on the study; 35 pts received a total of 41 DLIs following a dose of Pentostatin, and 1 pt received Pentostatin only. Diagnoses included AML (n=13), NHL (n=4), CLL (n=7), CML (n=2), MDS (n=6), MPD (n=2), MM (n=1), NHL and MDS (n=1). Pts received nonmyeloablative (n= 35) or ablative (n=1) conditioning, followed by PBSCs from HLA-matched related (n=17) or unrelated (n=17) donors, or 1-allele mismatched unrelated donor (n=2). Median age at HCT was 58 (34-72) years. DLI was given at a median of 96 (54-339) days after HCT. A dose of Pentostatin was given 2 days before infusing 1x107 CD3 cells/kg (n=26), 2x107 CD3 cells/kg (n=1), or 3x107 CD3 cells/kg (n=14). Per protocol, prophylactic immunosuppression (IS) with cyclosporine and MMF was given after DLI to the last 6 pts on study. Results: Median donor CD3chimerism beforePentostatin/DLI was 28 (5-47)%. Efficacy, defined by increases in donor CD3chimerism>10% maintained to day 56 post-DLI, was seen in 16 pts (44.4%) with a median CD3 donorchimerism of 64 (48-100)%. There was a trend for better efficacy among the 21 pts who received first treatment within 100 days after transplant (57%) compared to the 15 pts who received first treatment more than 100 days after HCT (27%) (p=0.07). Six pts received 2nd treatment ofPentostatin/DLI; among them 1 responded. Fifteen pts (12 responders) developedaGVHD after DLI [grade I (n=2), II (n=9), III (n=3), IV (n=1)] at a median of 10 (0-83) days after DLI. One pt developed skinGVHD, grade II, afterPentostatin administration and DLI was aborted. Of the 16 pts who developedaGVHD afterPentostatin/DLI, 3 had a prior history of GVHD after transplant. Thirteen pts developedcGVHD, ofwhom 10 developedecGVHD at a median of 112 (13-347) days after DLI. One pt developedecGVHD with no prioraGVHD. Among the 6 pts who received prophylaxis IS after DLI 1 pt developedaGVHD grade II, and none developedcGVHD. However, only 2 of those 6 pts responded. Seventeen pts developed grade 4cytopenia after DLI; 9 pts developed both neutropenia and thrombocytopenia, 4 pts developed neutropenia, and 4 pts developed thrombocytopenia. Among the 13 patients who developed grade 4 neutropenia, 9 (69%) were non-responders. Median time between DLI and lowest ANC count was 22 (2-100) days, and neutropenia lasted for median of 7 (1-52) days. Twelve pts received platelet transfusions started at median of 33 (1-98) days after DLI. Nineteen pts relapsed at a median of 91 (26-777) days after DLI. Among the 20 non-responders 12 relapsed (60%), compared to 7 of 16 responders (44%) (HR 0.64 (0.3-1.6), p=0.35). Ten of the 17 pts (59%) who developedcytopenia relapsed, 6 ofwhom (60%) were non-responders. Median number of significant infections was 2 (0-10) per pt. Twenty-eight pts died at a median of 522 (67-2028) days after DLI. Causes of death were relapse (n=21), respiratory failure/infections (n=4), grade IV GVHD (n=2), or other causes (n=1). Five of the 16 responders (31%) are alive, all in CR. Six of the 20 non-responders (30%) are alive, only 3 in CR (Figure 1). Summary:Pentostatin/DLI increased donor CD3chimerism in pts after HCT if was given within 100 days after transplant, and it was well tolerated. Response was associated with GVHD. Delayed treatment after HCT and prophylactic IS after DLI were associated with decreased efficacy. There was a trend for higher relapse rate among the non-responders and pts who developed cytopenia, but the differences were not statistically significant. Download : Download high-res image (61KB) Download : Download full-size image Disclosures Pulsipher: Novartis: Consultancy, Other: Advisory Board, Steering Committee for Phase II Study; Jazz Pharmaceutical: Consultancy, Other: Advisory Board; Chimerix: Consultancy, Other: Advisory Board ; Medac: Other: Travel support for a study group.
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extracorporeal photopheresis combined with Pentostatin in the conditioning regimen for canine hematopoietic cell transplantation does not prevent gvhd
Bone Marrow Transplantation, 2014Co-Authors: Wolfgang Bethge, Brenda M Sandmaier, Rainer Storb, Fabio R Kerbauy, Erlinda B Santos, Ted GooleyAbstract:Extracorporeal photopheresis (ECP) and the purine analog Pentostatin exert potent immunomodulatory effects. We evaluated the use of these treatment modalities to prevent GVHD in a canine model of unrelated dog leukocyte Ag-mismatched hematopoietic cell transplantation, after conditioning with 920 cGy TBI. We have shown previously in this model that 36/40 dogs given MTX alone as postgrafting immunosuppression engrafted and that 25 of 40 dogs had severe GVHD and median survival of 21 days. In the current study, nine dogs received conditioning with 920 cGy TBI and postgrafting MTX either with ECP on days -2 to -1 alone (n=5) or ECP on days -6 and -5 combined with two doses of Pentostatin (days -4 to -3) (n=4). Seven of nine dogs achieved engraftment. Six dogs developed severe acute GVHD (four in the group with ECP alone and two with Pentostatin and ECP). We failed to demonstrate a positive impact of ECP and Pentostatin for the prevention of GVHD compared with historical control dogs.
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extracorporeal photopheresis in addition to Pentostatin in conditioning for canine hematopoietic cell transplantation role in engraftment
Bone Marrow Transplantation, 2011Co-Authors: Wolfgang Bethge, Brenda M Sandmaier, Rainer Storb, Fabio R Kerbauy, Erlinda B Santos, Ted GooleyAbstract:Extracorporeal photopheresis in addition to Pentostatin in conditioning for canine hematopoietic cell transplantation: role in engraftment
Ted Gooley - One of the best experts on this subject based on the ideXlab platform.
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Extracorporeal Photopheresis in Addition to Pentostatin in Conditioning for Canine Hematopoietic Cell Transplantation: Role in Engraftment
2016Co-Authors: Wolfgang A. Bethge, Fabio R Kerbauy, Ted Gooley, Erlinda Santos, Brenda M. SAbstract:Extracorporeal photopheresis (ECP) and the purine analog Pentostatin exert potent immunomodulatory effects but have not been evaluated for their ability to enhance engraftment of hematopoietic stem cells. We evaluated in a canine model of dog leukocyte antigen (DLA)-identical hematopoietic cell transplantation (HCT) whether ECP in combination with Pentostatin could enhance engraftment using a nonmyeloablative regimen consisting of 100 cGy total body irradiation (TBI) and postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). We have shown previously that with 100 cGy TBI alone as conditioning, all of six dogs rejected their graft 2–12 weeks after HCT. With the addition of Pentostatin to 100 cGy TBI, 6 of 10 dogs rejected their graft. We now tested the additional use of ECP alone (n=2) or ECP plus 3–6 doses of Pentostatin (n=7) before 100 cGy TBI and HCT. Eight out of 9 dogs rejected their grafts within 6–11 weeks after HCT. Compared to data without ECP, we failed to demonstrate a positive impact of the use of either ECP or Pentostatin for prevention of rejection
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extracorporeal photopheresis combined with Pentostatin in the conditioning regimen for canine hematopoietic cell transplantation does not prevent gvhd
Bone Marrow Transplantation, 2014Co-Authors: Wolfgang Bethge, Brenda M Sandmaier, Rainer Storb, Fabio R Kerbauy, Erlinda B Santos, Ted GooleyAbstract:Extracorporeal photopheresis (ECP) and the purine analog Pentostatin exert potent immunomodulatory effects. We evaluated the use of these treatment modalities to prevent GVHD in a canine model of unrelated dog leukocyte Ag-mismatched hematopoietic cell transplantation, after conditioning with 920 cGy TBI. We have shown previously in this model that 36/40 dogs given MTX alone as postgrafting immunosuppression engrafted and that 25 of 40 dogs had severe GVHD and median survival of 21 days. In the current study, nine dogs received conditioning with 920 cGy TBI and postgrafting MTX either with ECP on days -2 to -1 alone (n=5) or ECP on days -6 and -5 combined with two doses of Pentostatin (days -4 to -3) (n=4). Seven of nine dogs achieved engraftment. Six dogs developed severe acute GVHD (four in the group with ECP alone and two with Pentostatin and ECP). We failed to demonstrate a positive impact of ECP and Pentostatin for the prevention of GVHD compared with historical control dogs.
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extracorporeal photopheresis in addition to Pentostatin in conditioning for canine hematopoietic cell transplantation role in engraftment
Bone Marrow Transplantation, 2011Co-Authors: Wolfgang Bethge, Brenda M Sandmaier, Rainer Storb, Fabio R Kerbauy, Erlinda B Santos, Ted GooleyAbstract:Extracorporeal photopheresis in addition to Pentostatin in conditioning for canine hematopoietic cell transplantation: role in engraftment
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dla haploidentical stem cell allografts after anti cd44 therapy and nonmyeloablative conditioning the impact of donor lymphocyte infusion dli Pentostatin and graft composition on donor chimerism and rejection
Blood, 2005Co-Authors: Fabio R Kerbauy, Brenda M Sandmaier, Rainer Storb, Erlinda B Santos, Ted Gooley, Takahiro Fukuda, Hilary StempelAbstract:Background: We previously reported that engraftment across a dog leukocyte antigen (DLA) haplotype-mismatched barrier could be achieved after nonmyeloablative conditioning with 200 cGy total body irradiation (TBI) plus post-grafting mycophenolate mofetil (MMF) /cyclosporine (CSP) when anti-CD44 monoclonal antibody (MAb), S5, is added to the regimen. However, 50% of dogs rejected their grafts after discontinuation of MMF/CSP. Here, we studied the influence of donor lymphocyte infusion (DLI), Pentostatin, and graft composition in achievement of sustained full donor chimerism and prevention of rejection. Methods: Twenty-nine dogs were administered MAb S5 (0.2 mg/kg/day) from days -7 to -2, before 200 cGy TBI. Unmodified G-CSF-mobilized peripheral blood stem cells (PBSC) from DLA-haploidentical donors were infused followed by immunosuppression with MMF (5-10 mg/kg BID SQ) and CSP (15 mg/kg BID PO). Dogs in group 1 (n=8) were not given DLI and dogs in group 2 (n=5) were given 6 doses of Pentostatin (4 mg/m2/dose) before TBI and no DLI. Dogs in group 3 (n=10) and 4 (n=6) received escalating doses of DLI on days +35, +63, +92. In addition, dogs in group 4 received Pentostatin (4 mg/m2) 2 days prior to each infusion of DLI. Results: All dogs achieved initial engraftment between 1 to 2 weeks after transplant and survived 5 weeks or longer with mononuclear cell chimerism ranging from 2% to 98% (median 37%) on day +35. Higher cell subset levels in the PBSC graft were associated with stable donor engraftment: total nucleated cells (p=0.03), CD4+ (p=0.01), CD8+ (p=0.03) and CD14+ (p=0.009) cells. Also, there was a trend in the number of CD34+ (p=0.10) and CD3+(p=0.07) cells. Graft rejection was seen in 7 of 13 dogs without DLI (groups 1 and 2) and in 7 of 16 dogs that received DLI (groups 3 and 4). There was no statistically significant association between DLI and rejection (p=0.44). Six of 16 dogs who received DLI and 1 of 13 dogs with no DLI achieved full donor chimerism (p=0.18), yet there was no statistically significant association between the four groups (p=0.52). There was a trend for higher counts of CD4+ and CD8+ cells (p=0.08) and achievement of full donor chimerism. However, the use of Pentostatin before each DLI (group 4) did not impact achievement of full donor chimerism (p>0.95). Duration of mixed chimerism was associated with higher cell subset levels of infused PBSC; CD34+ (p=0.06), CD4+ (p=0.02), CD14+ (p=0.05), CD3+ (p=0.09), CD8+ (p=0.08). Conclusions: The use of DLI with or without prior infusion of Pentostatin after initial engraftment of DLA-haploidentical donor graft did not facilitate conversion to full donor chimerism, sustain mixed chimerism, or prevent graft rejection. However, the infusion of haploidentical donor PBSC graft with higher numbers of TNC, CD34+, CD3+, CD4+, CD8+ and CD14+ cells could prolong donor chimerism and prevent graft rejection.