scholarly journals Long-Term Tolerance to Kidney Allografts After Induced Rejection of Donor Hematopoietic Chimerism in a Preclinical Canine Model.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2991-2991
Author(s):  
David Mathes ◽  
Scott Stoll Graves ◽  
George E. Georges ◽  
Christian Kuhr ◽  
Jeff Chang ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Organ Transplant ◽  
Canine Model ◽  
Hematopoietic Cell ◽  
Mixed Chimerism ◽  
Solid Organ ◽  
Kidney Graft ◽  
Marrow Graft

Abstract Abstract 2991 Allogeneic hematopoietic cell transplantation provides a reliable method for inducing tolerance towards solid organ grafts. However, this procedure can result in graft-versus-host disease (GVHD) thereby limiting its application. Here we test the hypothesis that mixed chimerism can be intentionally reverted to host hematopoiesis without rejection of a kidney graft. Recipient dogs were given 2 Gy total body irradiation (TBI) before and a short course of immunosuppression after marrow infusion from dog leukocyte antigen-identical littermates. All dogs achieved stable mixed chimerism. After a mean of 20 weeks, one cohort of dogs received kidney transplants from their respective marrow donors. Subsequently, recipients were reconditioned with 2 Gy TBI and given autologous granulocyte-colony stimulating factor-mobilized leukocytes (recipient leukocyte infusion) that had been collected before marrow transplant. Dogs receiving a second TBI and recipient leukocyte infusion without a kidney transplant rejected their donor hematopoietic graft within 3 weeks. Dogs that received kidney grafts, followed by a second TBI and recipient leukocyte infusion, rejected their marrow graft without rejecting their transplanted kidneys for periods greater than one year. Mixed chimerism may be clinically reverted to 100% recipient without rejection of a kidney allograft. This model has potential applications in understanding the mechanism of split tolerance. This finding may have application towards minimizing the risk of GVHD in solid organ transplant patients given hematopoietic cell transplantation from HLA-identical donors. Disclosures: No relevant conflicts of interest to declare.

Establishment of Trichimerism in the Dog Leukocyte Antigen (DLA)-Identical Canine Hematopoietic Transplant Model.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3193-3193
Author(s):  
Scott S. Graves ◽  
William Hogan ◽  
George E. Georges ◽  
Christian Kuhr ◽  
Razvan Diaconescu ◽  
...  
Keyword(s):  
Cord Blood ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Cord Blood Transplantation ◽  
Variable Number Tandem Repeat ◽  
Hematopoietic Cell ◽  
Solid Organ ◽  
Kidney Graft ◽  
Blood Transplantation ◽  
Cell Counts

Abstract Although hematopoietic cell transplantation is generally accomplished utilizing a single donor and recipient pair, multiple donors have been used to mediate engraftment, particularly in the case of low donor cell counts as in umbilical cord blood transplantation. The general engraftment outcome of HLA nonidentical cord blood transplantation is the predominance of one of the units over the other. Here we pose the question whether in the canine hematopoietic cell transplantation model, can we establish multiple donor chimerism using two DLA-identical donors and a single recipient. We identified 8 triplets of DLA-identical littermates by matching highly polymorphic microsatellite markers within DLA class I and class II regions and confirmed by DLA-DRB1 gene sequencing. The marrow recipients received 2 Gy total body irradiation followed by intravenous infusions of marrow cells from both donors 1 and 2. The median number of donor cells injected was 4.1 (range = 2.0–7.0) X 108 cells/kg. Post grafting immunosuppression consisted of cyclosporine (CSP) and mycophenolate mofetil (MMF) given for 35 and 28 days, respectively. The median time to hematological recovery (blood counts equivalent to pre-HCT levels) was 38 (range = 30–42) days. The degrees of chimerism were determined using variable number tandem repeat-polymerase chain reaction (VNTR-PCR) methods. As shown in the Table, sustained trichimerism occurred in 4 out of 8 dogs with engraftment for a period grater than 26 weeks. For G631, both donor grafts were rejected shortly following discontinuation of CSP and MMF. Dog G513 developed graft versus host disease (GvHD) which was successfully treated with a short course of CSP. Five dogs received kidney allografts from one of the respective HCT donors 6 months after HCT to assess donor specific immune tolerance. Chimerism Analysis of Dogs Receiving Marrow from Two Donors Duration of Engraftment in Weeks (% Chimerism) Recipient Donor 1 Donor 2 Recipient GVHD Accept Donor 1 Kidney Graft (wks) ND = not determined; [R] = rejection G158 >43 (5%) 37 (0%) [R] >43 (95%) No Yes (20) G193 >44 (72%) 16 (0%) [R] >44 (28%) No Yes (10) G362 >47 (28%) >47 (55%) >47 (17%) No Yes (16) G513 >47 (53%) >47 (22%) >47 (25%) Yes Yes (16) G551 >32 (35%) >32 (20%) >32 (45%) No ND G631 8 (10%) [R] 8 (12%) [R] 8 (>88%) No ND G643 >30 (28%) >30 (40%) >30 (23%) No Yes (4) G664 >26 (50%) 6 (2%) [R?] >26 (48%) No ND Kidney allografts were found to be essentially free of inflammation when assessed histologically on biopsy. Dog G643, was tested for immune function by a mixed leukocyte reaction and found to be competent against DLA nonidentical stimulator cells but nonresponsive against either of the donor stimulator cells. In summary, following nonmyeloablative conditioning, simultaneous administration of marrow stem cells from two DLA-identical littermates can result in trichimerism. Furthermore, immunological tolerance to multiple hematopoietic cell donors can include a solid organ graft from one of the marrow donors.

scholarly journals Stable long-term mixed chimerism achieved in a canine model of allogeneic in utero hematopoietic cell transplantation

Blood ◽  
2014 ◽  
Vol 124 (12) ◽  
pp. 1987-1995 ◽  
Author(s):  
Jesse D. Vrecenak ◽  
Erik G. Pearson ◽  
Matthew T. Santore ◽  
Carlyn A. Todorow ◽  
Haiying Li ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Hematopoietic Cell Transplantation ◽  
Canine Model ◽  
Hematopoietic Cell ◽  
Mixed Chimerism ◽  
Graft Versus Host ◽  
Key Points ◽  
Clinically Significant

Key Points Optimization of IUHCT in a preclinical canine model yields stable long-term donor engraftment. Clinically significant levels of chimerism can be achieved without conditioning, immunosuppression, or graft-versus-host disease.

The Effect of In Vivo T-Cell Depletion with Alemtuzumab on Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3014-3014
Author(s):  
Julio Delgado ◽  
Srinivas Pillai ◽  
Reuben Benjamin ◽  
Dolores Caballero ◽  
Rodrigo Martino ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Lymphocytic Leukemia ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Mixed Chimerism ◽  
Allogeneic Hct ◽  
Reduced Intensity

Abstract Reduced-intensity allogeneic hematopoietic cell transplantation (HCT) is increasingly considered as a therapeutic option for young patients with advanced chronic lymphocytic leukemia (CLL). We report 59 consecutive CLL patients who underwent allogeneic HCT following fludarabine and melphalan conditioning at four different institutions. For graft-versus-host disease (GVHD) prophylaxis, 38 patients (Cohort 1) received alemtuzumab (20–100 mg) and cyclosporine; and 21 patients (Cohort 2) received cyclosporine plus methotrexate or mycophenolate. Donors were 47 HLA-matched siblings and 12 unrelated volunteers, 6 of whom were mismatched. Median age at transplant was 53 (range, 34–64) years and median number of previous chemotherapy regimens was 3 (1–6), with 39% of patients being refractory to fludarabine. Nine patients had previously failed an autologous HCT. Fluorescent in-situ hybridization and IgVH mutation status data were available in 33 (56%) and 31 (53%) patients, respectively, being unfavorable (17p- or 11q-) in 22 (67%) and unmutated in 24 (77%) of them. All but 1 patient engrafted, and the median interval to neutrophil recovery (> 0.5 × 109/l) was 14 (range, 10–36) days. Twenty patients (34%), mostly from Cohort 1, received escalated donor lymphocyte infusions due to mixed chimerism or disease relapse. The overall complete response rate among 53 patients with measurable disease at the time of transplantation was 70%, whereas 21% had stable disease. Grade II-IV acute GVHD was observed in 14 (37%) and 12 (57%) patients from Cohorts 1 and 2, respectively (P = 0.17). Extensive chronic GVHD was observed in 3 (8%) and 10 (48%) patients from Cohorts 1 and 2, respectively (P < 0.01). The incidence of cytomegalovirus reactivation was not significantly different between cohorts (67% vs 47%, P = 0.23). With a median follow-up of 36 (range, 3–99) months for survivors, 18 (30%) patients have died, 3 of progressive disease and 15 of transplant-related complications. The 3-year overall survival (OS), progression-free survival (PFS) and non-relapse mortality were 66% (95% CI 48–84%), 38% (20–56%) and 21% (8–34%), respectively, for Cohort 1 and 65% (44–86%), 54% (32–76%) and 29% (10–48%) for Cohort 2 (P = 0.66; P = 0.33; and P = 0.53). Despite low patient numbers, alemtuzumab seemed particularly effective for unrelated donor recipients, with a 3-year OS and PFS of 54% and 40% for Cohort 1; and 33% and 0% for Cohort 2 (P = 0.02 and P = 0.07). In conclusion, results with reduced-intensity allogeneic HCT are promising for these poor-prognosis patients. Furthermore, the alemtuzumab-based regimen was effective in reducing the chronic GVHD rate with no negative effect on NRM, PFS or OS.

Allogeneic Hematopoietic Cell Transplantation (allo-HCT) Can Induce Durable Remission in Heavily Pretreated Relapsed Hodgkin Lymphoma. (HL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1192-1192
Author(s):  
Robert Chen ◽  
Joycelynne Palmer ◽  
Leslie Popplewell ◽  
Jessica Shen ◽  
Eileen Smith ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
High Dose ◽  
Unrelated Donor ◽  
Heavily Pretreated

Abstract Abstract 1192 Poster Board I-214 Background: Even though Hodgkin lymphoma (HL) is a curable disease, about, 20-30% patients are either refractory to induction chemotherapy or relapse post treatment. High dose chemotherapy and autologous HCT has been shown to be an effective salvage therapy for patients with relapsed HL. However, relapse continues to occur after auto-HCT, especially in patients with chemoresistant or poor-risk features at relapse. The prognosis of these patients is poor with limited options of treatment. Although allo-HCT offers both cytoreduction and potential graft-versus-tumor effect, its use in relapsed HL has been limited by non-relapse mortality (NRM) and patient co-morbidities induced by numerous prior treatments. To examine the potential impact of allo-HCT on survival and disease outcomes, we performed retrospective analysis of allo-HCT in relapsed/refractory HL to determine if allo-HCT can induce long-term remission in heavily pretreated relapsed HL. Results: Between January 2003 and December 2008, 29 patients with relapsed HL underwent allo-HCT at City of Hope National Medical Center. The median age was 37 (range: 14-63). 20 (69%) patients were chemosensitive at time of allo-HCT. 17 (59%) patients had prior auto-HCT. 16 (55%) patients received matched siblings and 13 (45%) received unrelated donor cells. 20 (69%) patients had prior radiation treatments. The median number of prior regimens was 5 (range: 2-8). 23 (79%) patients underwent a non-myeloablative conditioning regimen while 6 (21%) patients had a myeloablative regimen. 14 (48%) patients received Tacrolimus/Sirolimus as graft versus host disease prophylaxis and 15 (52%) patients received a combination of Cellcept/CsA, Cellcept/CsA/MTX, Tacrolimus/MTX, or Tacrolimus/Sirolimus/MTX. With a median follow up of 31.9 months (range: 9.7-69.1) for surviving patients, the results show: Conclusion: Allogeneic hematopoietic cell transplantation in heavily pretreated relapsed Hodgkin's lymphoma is feasible, tolerable, and can induce durable clinical remissions. Disclosures: No relevant conflicts of interest to declare.

Treatment of Recurrent or Persistent AML/MDS After Allogeneic Hematopoietic Cell Transplantation with Azacitidine.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1288-1288
Author(s):  
Jennifer Vaughn ◽  
Barry Storer ◽  
Marco Mielcarek ◽  
Edus H. Warren ◽  
Paul J. Martin ◽  
...  
Keyword(s):  
High Risk ◽  
Cell Transplantation ◽  
Induction Chemotherapy ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Case Series ◽  
Hematopoietic Cell ◽  
High Dose ◽  
Persistent Disease ◽  
Relapsed Disease

Abstract Abstract 1288 Recurrence or persistence of disease after hematopoietic cell transplantation (HCT) remains a significant obstacle in the treatment of patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndromes (MDS). Standard therapies for relapsed disease include withdrawal of immunosuppression (WIS), donor lymphocyte infusion, induction chemotherapy, and in selected patients, a second HCT. Regardless of the intervention chosen, survival for post-transplant relapse has been dismal. Effective therapies without significant toxicity are needed. Azacitidine, a DNA demethylating agent, is the only non-HCT therapy shown to prolong survival in patients with MDS. It has also shown efficacy in patients with AML when used alone as induction or consolidation therapy or in combination with the anti CD-33 antibody gemtuzumab. Its use following HCT was inspired by the discovery of the drug's potential to enhance the graft-versus-leukemia effect through demethylation of the KIR regions on donor NK cells and by enhancing HLA-DR2 expression on leukemic blasts. It has also been shown to modulate T-cells post-engraftment and may result in lower rates of GVHD without impairing the GVL effect. Several small case series have been published evaluating azacitidine as therapy for treatment of relapse following HCT and have demonstrated improvement in disease status. None of these studies have examined azacitidine in the setting of persistent disease, which has become more relevant with the use of lower intensity conditioning regimens and the use of new methods to detect the presence of disease at extremely low levels. In this retrospective study, we determined the outcomes of patients treated with azacitidine (75 mg/m2/day for 7 days +/− gemtuzumab (3mg/m2) on day 9, every 4 weeks) for post-HCT recurrence or persistence of AML/MDS. Azacitidine treatment was initiated following HCT if there was evidence of recurrent or persistent disease (defined as any recurrent abnormal blasts detected by flow on peripheral blood or marrow or recurrent cytogenetic abnormalities). Seventeen (74%) of the patients had AML while 6 (26%) had MDS. FAB subtypes of the latter included RAEB (3), RA (1), CMML (1) and unclassified (1). Eighteen (78%) patients underwent conventional high dose conditioning, and 5 (22%) patients underwent nonmyeloablative conditioning prior to HCT. Eleven (48%) of patients had low risk cytogenetics, 3 (13%) had intermediate risk, and 9 (39%) had high risk cytogenetics. Seventeen (74%), 0 (0%) and 6 (26%) of patients were diagnosed with persistent or relapsed disease within 100, 100–200 and > 200 days following HCT. Patients began azacitidine 0–242 (median: 17) days from time of relapse and completed a median of 2 azacitidine cycles (range 1–8). Overall 6-month survival from the day of relapse was 57% and from start of azacitidine therapy was 48%. Among the 18 patients who started azacitidine within 2 months of documented relapse the 6-month survival was 50%. Blast count at time of relapse was not significantly associated with survival (> 1% vs ≤ 1%, HR=1.26, p=0.63), nor was survival after initial treatment with azacitidine affected by longer time intervals prior to first administration (> 28 days vs ≤ 28 days, HR=0.85, p=0.76). There were 12 patients who received gemtuzumab with azacitidine, and the addition of gemtuzumab made no difference in survival (HR with gemtuzumab = 0.81 (0.3-2.1), p=0.66). The 6-month survival with azacitidine is superior to that observed with induction chemotherapy (20%) or WIS (10%). Azacitidine therapy may be superior to standard therapies for recurrent/persistent disease following HCT and warrants further study. Disclosures: No relevant conflicts of interest to declare.

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