Postgrafting Immune Suppression Combined with Nonmyeloablative Conditioning for Transplantation of HLA-Identical Hematopoietic Cell Grafts: Results of a Phase I Study for Treatment of Immunodeficiency Disorders.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 327-327
Author(s):  
Lauri Burroughs ◽  
Rainer F. Storb ◽  
Wendy Leisenring ◽  
Michael Pulsipher ◽  
Michael R. Loken ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Gvhd ◽  
Severe Combined Immunodeficiency ◽  
Cd40 Ligand ◽  
Hematopoietic Cell ◽  
Myeloablative Conditioning ◽  
Immunodeficiency Disorder ◽  
Life Threatening ◽  
Conditioning Regimens ◽  
Related Mortality

Abstract Myeloablative conditioning regimens may cause significant life threatening transplant related toxicities in patients with immunodeficiency disorders, particularly in patients with co-morbid conditions. This current study was designed to determine whether an immunosuppressive nonmyeloablative regimen would safely enable stable donor engraftment of hematopoietic cells in patients with immunodeficiency disorders who were ineligible for myeloablative conditioning regimens because of life-threatening infections or organ dysfunction. Fourteen patients with severe combined immunodeficiency disorder (SCID; n=3), common variable immunodeficiency (CVID; n=1), T-cell immunodeficiency disorder (TCD; n=3), Wiskott-Aldrich syndrome (WAS; n=2), CD40 Ligand deficiency (CD40LD; n=2), immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX; n=1), X-linked agammaglobulinemia (XLA; n=1) and chronic granulomatous disease (CGD; n=1) received HLA-matched related (n=7) or unrelated (n=7) hematopoietic cell grafts from marrow (n = 8), peripheral blood stem cell (n = 5), or umbilical cord blood (n = 1). All patients were given postgrafting immunosuppression with MMF and CSP. Two patients had no pre-transplant conditioning, whereas host immunosuppression was provided by 200 cGy TBI alone (n=3) or in combination with 90 mg/m2 fludarabine (n=9) before hematopoietic cell transplantation (HCT). Mixed (n=5) or full (n=5) donor cell chimerism was established in 10 patients. Four patients required second HCT (n=3) or donor lymphocyte infusion (n=1) due to either T cell graft rejection (n=1), loss of the granulocyte graft (n=1), or low levels of T cell chimerism (n=2). Mortality by days 100 and 180 was 0%. The cumulative incidences of grade II–IV and III–IV acute graft versus host disease (GVHD) were 79% and 14%, respectively. The 1-year incidence of extensive chronic GHVD was 64%. Median follow up for the living recipients was 3 (range, 0.8–6.4) years. The 2 year overall survival, event free survival and transplant related mortality were 68%, 60%, and 16%, respectively. In 7 of the 10 patients with stable donor engraftment correction of immune dysfunction was documented. Specifically, the 4 patients with SCID (n=3) and CVID (n=1) had normal T cell numbers and function following HCT. One patient with WAS had correction of T cell function and platelet numbers after HCT; however subsequently died of B cell non-EBV lymphoma. In addition, 1 patient with CD40LD showed increases in functional CD40 ligand expressing T-cells and response to a neoantigen. Finally, 1 patient with CGD exhibited a normal neutrophil oxidative burst following HCT. Three patients (TCD n=2, CD40LD n=1) were not evaluable for disease response due to continued immunosuppression for chronic GVHD. These results indicate that postgrafting immunosuppression plus nonmyeloablative HCT markedly reduces early HCT related mortality among high-risk patients with immunodeficiency disorders.

Unmanipulated Haploidentical Bone Marrow Transplantation and Post-Transplant Cyclophosphamide for Hematologic Malignanices Following A Myeloablative Conditioning.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3034-3034
Author(s):  
Andrea P Bacigalupo ◽  
Anna Maria Raiola ◽  
Alida Dominietto ◽  
Maria Teresa Van Lint ◽  
Francesca Gualandi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Myeloablative Conditioning ◽  
Free Survival ◽  
Disease Free ◽  
Active Disease ◽  
Related Mortality

Abstract Abstract 3034 Despite a large number of unrelated donors (UD), not more than 30% of patients who have activated a donor search, undergo an allogeneic UD stem cell transplant. HLA haploidentical family members are being increasingly considered as an alternative donors, both using T cell depleted or T cell replete grafts. Post-transplant high dose cyclophosphamide (PT-CY), introduced by the Baltimore group, has shown very promising results following non myeloablative conditioning regimens. We are now reporting 50 patients with high risk hematologic malignancies, who received a myeloablative regimen, followed by unmanipulated haploidentical bone marrow transplant (hBMT) and PT-CY. The myeloablative conditioning consisted of thiotepa (10 mg/kg), busulfan (9,6 mg/m2̂), fludarabine (150 mg/m2̂)(n=35), or total body irradiation (9,9–12 Gy), fludarabine (120 mg/m2̂) (n=15). The median age was 42 years (18–66); 23 patients were in remission and 27 had active disease; 10 patients were receiving a second allograft. Graft versus host disease (GvHD) prophylaxis consisted in PT-CY on day+3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). The median nucleated cell dose was 3.6 ×108̂/kg (range: 1,4 – 7,7). The median time to neutrophil counts of >0.5×109/L was 18 days (range, 13–30 days) and to platelet counts of >20×109/L 23 days (range, 14 – 58 days), respectively. There was no correlation between infused number of nucleated cells and days of neutrophil engraftment. The cumulative incidence of engraftment was 90%for neutrophils and 86% for platelets. Three patients died before engraftment, and 2 patients had autologous recovery: 45 patients (90%) had full donor chimerism on day +30. The cumulative incidence of grade II-III acute GvHD was 12%, and of moderate chronic GvHD 10%. With a median follow up for surviving patients of 333 days (149–623), the cumulative incidence of transplant related mortality is 18%, and the rate of relapse 26%. The actuarial 22 months disease free survival is 68% for patients in remission and 37% for patients with active disease (p<0.001). Causes of death were pneumonia (n=3), haemorrhage (n=3), sepsis (n=3) and relapse (n=7). In conclusion, a myeloablative conditioning regimen followed by h-BMT with PT-CY, results in a low risk of acute and chronic GvHD and encouraging rates of transplant related mortality and disease free survival. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Conditioning Regimens for Hematopoietic Cell Transplantation in Primary Immunodeficiency

2019 ◽  
Vol 19 (11) ◽  
Author(s):  
S. H. Lum ◽  
M. Hoenig ◽  
A. R. Gennery ◽  
M. A. Slatter
Keyword(s):  
Cell Transplantation ◽  
Primary Immunodeficiency ◽  
Hematopoietic Cell Transplantation ◽  
Standard Of Care ◽  
Hematopoietic Cell ◽  
Myeloablative Conditioning ◽  
Stem Cell Source ◽  
Conditioning Regimens ◽  
Reduced Toxicity ◽  
Related Mortality

Abstract Purpose of Review Hematopoietic cell transplantation (HCT) is an established curative treatment for children with primary immunodeficiencies. This article reviews the latest developments in conditioning regimens for primary immunodeficiency (PID). It focuses on data regarding transplant outcomes according to newer reduced toxicity conditioning regimens used in HCT for PID. Recent Findings Conventional myeloablative conditioning regimens are associated with significant acute toxicities, transplant-related mortality, and late effects such as infertility. Reduced toxicity conditioning regimens have had significant positive impacts on HCT outcome, and there are now well-established strategies in children with PID. Treosulfan has emerged as a promising preparative agent. Use of a peripheral stem cell source has been shown to be associated with better donor chimerism in patients receiving reduced toxicity conditioning. Minimal conditioning regimens using monoclonal antibodies are in clinical trials with promising results thus far. Summary Reduced toxicity conditioning has emerged as standard of care for PID and has resulted in improved transplant survival for patients with significant comorbidities.

Outcomes among Patients with Recurrent High-Risk Hematologic Malignancy after Nonmyeloablative Versus Myeloablative Allogeneic Hematopoietic Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 262-262
Author(s):  
Marco Mielcarek ◽  
Paul J. Martin ◽  
David G. Maloney ◽  
Rainer Storb ◽  
Brenda M. Sandmaier
Keyword(s):  
High Risk ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematologic Malignancy ◽  
Survival Rates ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Myeloablative Conditioning ◽  
Life Threatening ◽  
Conditioning Regimens

Recurrence of high risk hematologic malignancy after allogeneic hematopoietic cell transplantation (HCT) indicates the persistence of malignant cells that are resistant to the conditioning regimen given before HCT and the immunologic effects of donor cells after HCT. Early recurrence of high-risk hematologic malignancy after myeloablative conditioning is associated with a very poor prognosis. Given the minimal exposure to cytotoxic therapy during and the lower burden of regimen-related toxicity after nonmyeloablative preparative regimens, we hypothesized that relapse-directed interventions would be more effective for patients with high-risk malignancy after HCT with nonmyeloablative conditioning compared to myeloablative conditioning. We retrospectively analyzed outcomes among 195 patients treated for acute leukemia (AML, n=123; ALL, n=28), chronic myeloid leukemia beyond accelerated phase (n=21), or high-risk myelodysplastic syndromes (n=23) that recurred after HCT with myeloablative or nonmyeloablative conditioning between 1995 and 2004. Relapse-directed interventions included withdrawal of immunosuppression (WIS), chemotherapy, and donor lymphocyte infusion (DLI) used singly or in combination as allowed by clinical circumstances. Interventions were used for 68% and 87% of patients who had recurrence < 100 days after HCT with myeloablative or nonmyeloablative conditioning, respectively, and for 83% and 95% of those who had recurrence ≥ 100 days after HCT. The incidence rates of life-threatening GVHD and remission were 6% and 25% among patients with myeloablative conditioning, compared to 19% and 26% among those with nonmyeloablative conditioning (Table 1). The incidence of remission was higher among patients who had recurrence ≥ 100 days after HCT as compared to < 100 days after HCT (p = 0.04). Contrary to our hypothesis, interventions were not more effective among patients with nonmyeloablative conditioning compared to myeloablative conditioning, as measured by remission rates (Table 1) or survival. The 2-year survival rates among patients with recurrence < 100 days after HCT were 4% and 0% among patients who had myeloablative and nonmyeloablative conditioning regimens, respectively. The corresponding 2-year survival rates among patients with recurrence ≥ 100 days after HCT were 12% and 5%. In summary, with either myeloablative or nonmyeloablative conditioning regimens, limited clinical benefit is gained from the interventions typically used for management of early recurrent high-risk hematologic malignancy after HCT. Thus, innovative and more effective strategies are needed for treatment of recurrent high-risk malignancy after allogeneic HCT. Interventions and outcomes among patients treated for recurrent high-risk hematologic malignancy after allogeneic HCT Total WIS Chemo DLI GVHD* CR *GVHD, life-threatening graft-versus-host disease; CR, complete remission. **Recurrence was detected at 100–200 days from HCT in 9 cases and >200 days in 11 cases. Myeloablative conditioning Recurrence < Day 100, n (%) 87 78 51 11 6 16 (90) (59) (13) (7) (18) Recurrence ≥ Day 100–200, n (%) 65 50 55 13 3 21 (77) (85) (20) (5) (32) Non-myeloablative conditioning Recurrence < Day 100, n (%) 23 18 13 5 5 5 (78) (57) (22) (22) (22) Recurrence ≥ Day 100, n (%)** 20 13 15 2 3 6 (65) (75) (10) (15) (30)

scholarly journals Allogeneic hematopoietic cell transplantation for XIAP deficiency: an international survey reveals poor outcomes

Blood ◽  
2013 ◽  
Vol 121 (6) ◽  
pp. 877-883 ◽  
Author(s):  
Rebecca A. Marsh ◽  
Kanchan Rao ◽  
Prakash Satwani ◽  
Kai Lehmberg ◽  
Ingo Müller ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
High Mortality ◽  
Hematopoietic Cell Transplantation ◽  
Mortality Rates ◽  
Hematopoietic Cell ◽  
International Survey ◽  
Myeloablative Conditioning ◽  
Key Points ◽  
Conditioning Regimens ◽  
Poor Outcomes

Key Points High mortality rates are observed in patients with XIAP deficiency treated with myeloablative conditioning regimens for hematopoietic cell transplantation.

Outcome of Patients Developing GVHD after DLI for CML Relapse from HLA-Identical Sibling or VUD HSCT.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1817-1817
Author(s):  
Yves Chalandon ◽  
Christoph Schmid ◽  
Kimmo Porkka ◽  
Alvaro Urbano-Ispizua ◽  
Bernd Hertenstein ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Chronic Gvhd ◽  
Median Number ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Initial Cell ◽  
Cell Dose ◽  
Stem Cell Source ◽  
Related Mortality

Abstract Using data submitted to the EBMT registry, we analyzed outcome on 344 patients (pts) who had received donor lymphocyte infusions (DLI) for relapse after allogeneic hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) in 31 centers. 113/344 pts (33%) developed acute graft-versus-host disease (aGVHD) a median of 50 days post DLI (max grade: I=42, II=30, III=31, IV=6)(60% grade II–IV). Organs involved (%): skin (88), liver (42), gut (30). Median age was 38 (4–59), 58% pts were male, 62 transplants were HLA-identical sibling and 51 unrelated. 74 were T-cell depleted, 92 transplanted in CP1, 21 beyond CP1. Relapse was molecular in 19 pts, cytogenetic in 31, hematological in 49, accelerated or blastic in 12. Median initial cell dose was 107CD3+ cells/kg (0.01–32), median number of DLI was 1 (1–10). aGvHD was treated with prednisone in 92% of pts, CSA in 52 %, ATG and monoclonal antibodies in 2% and other in 19%. aGVHD resolved in 53% of the pts within a median of 63 d (7–546). 82/344 pts (24%) had chronic GVHD (cGVHD)(30 limited, 50 extensive, 2 not specified), of those 46 (56%) following aGVHD post DLI. Organs involved (%): skin (75), liver (35), lungs (13), mouth (43), eyes (22) and gut (5). Median age was 35 (6–58), 51% were male, stem cell source was PB in 15% and marrow in 85%, 43 underwent HLA-identical sibling HSCT and 39 unrelated donor HSCT. Forty-three were T-cell depleted, 66 transplanted in CP1, 16 beyond CP1. Relapse was molecular in 21 pts, cytogenetic in 29, hematological in 22, accelerated or blastic in 7. Median initial cell dose was 107 CD3+ cells/kg (0.05–40), median number of DLI was 1 (1–7). 61 pts are alive with a median follow-up of 50 mth. Treatment was with steroids in 83% of pts, CSA in 58 %, MMF in 20%, thalidomide in 15%, photopheresis in 15%, PUVA in 10% and other in 17%. cGVHD resolved in 39% of the pts within a median of 354 d (44–1588). The estimated 5-y OS post-DLI was significantly lower in pts who developed aGVHD post-DLI, 61 ± 10% vs 74 ± 7% in the one that did not, p=0.007 and also a tendency to have a lower 5-y EFS, 58 ± 10% vs 65 ± 7%, p=0.19. Median duration of response to DLI in aGVHD pts was 4 y. aGVHD post-DLI did not influence the relapse rate (5 ± 5% vs 6 ± 5% in the absence of aGVHD). 5-y DLI related mortality was significantly higher in aGVHD pts, 31 ± 8% vs 4 ± 4%, p<0.00001. On the other hand, pts that developed cGVHD post-DLI had a tendency to have a better 5-y OS and EFS, 74 ± 11% and 71 ± 11% respectively vs 69 ± 6% and 62 ± 7% in those that did not, p=0.32 and 0.09. This was related to a tendency to lower incidence of relapse, 2 ± 3% in pts with cGVHD vs 9 ± 6% without, p=0.2. DLI related mortality was not different, 11 ± 8% vs 10 ± 5%, p=0.77. aGVHD post-DLI for CML relapse is mainly of advanced stage and negatively influence OS and EFS with a higher DLI related mortality. cGVHD post-DLI is mainly extensive, but pts with cGHVD tend to have better outcome with better 5-y OS, EFS and less relapse than those without, although this was not statistically significant.

Myeloablative Conditioning Followed by T-Cell Depletion Is Associated with Low Treatment Related Mortality.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5221-5221
Author(s):  
Nicolas Novitzky ◽  
Valda Thomas ◽  
Cecile du Toit ◽  
Andrew McDonald
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Disease Recurrence ◽  
Haematological Malignancies ◽  
Reduced Intensity Conditioning ◽  
Myeloablative Conditioning ◽  
Gvhd Prophylaxis ◽  
Reduced Intensity ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Introduction: Classically the conditioning for transplantation in haematological malignancies has been with myeloablative doses of radiation or chemotherapy, and was followed by variable immunosuppression for the prevention of GvHD. This strategy has been associated with substantial transplant related mortality from regimen toxicity and GvHD, which were most pronounced in older patients. Reduced intensity conditioning programs that are mainly immunosuppressive allow engraftment and predisposed to donor chimerism and appear to have lower TRM, but seem associated to higher rates of GvHD and disease recurrence. To better apportion conditioning strategies for patients undergoing allogeneic stem cell transplantation, we studied the outcome of 81 patients who received similar GvHD prophylaxis with T-cell depletion and immunosuppression, after myeloablative conditioning. Patients & methods: Patients with haematological malignancies, in remission or still responsive to chemotherapy who had an HLA identical sibling were offered T-cell depleted stem cell grafts. Conditioning was with ablative doses of either chemotherapy or total body radiotherapy. Stem cells were mobilised into the blood (PBPC) with G-CSF (5–10ug/kg × 5) and grafts were harvested by large volume (30 litres) apheresis. GvHD prophylaxis was by ex vivo depletion of lymphocytes from the graft with CAMPATH-1 H antibodies followed by therapeutic doses of cyclosporin until day 90. End points were TRM, disease recurrence rate and overall survival time. Results: 90 consecutive patients with median age of 45 (17–62) years were studied. The diagnosis included acute leukaemia (ALL in 7) in CR in 38, myeloproliferative disorders in 16, lymphoproliferative diseases in 26 and multiple myeloma in 10. Post transplantation, patients with CML received, in addition, escalating doses of lymphocytes at 6 months (maximum 1 × 107/kg CD3) or imatinib for 12 months. Median CD34+ cell number was 2.7 (1–12.3) and the median dose of campath-1H was 10 (range 7.5–45) mg. Median time to engraftment was 11 days. Overall, 20 (22%) individuals died while treatment related mortality occurred in 17% (n= 15; VOD 3, infections in 8, pneumonitis in 1, EBV lymphoma in 1 and GvHD in 2). GvHD (> grade1) occurred in 7 patients, was controlled with further immunosuppression but lead to death from infections in 6. Disease recurrence was seen in 12, but 7 with CML or myeloma responded to DLI. At a median follow up of 688 days, 77 survive; 75% in unsustained remission. Conclusions: Myeloablative conditioning is well tolerated in patients receiving T-cell depleted grafts, and treatment related mortality of <20% can be expected consistently with this strategy. This information is useful to more precisely select patients who would benefit most from reduced intensity conditioning schedules.

Proportions of T-Cell CD8+ Subsets Lacking CD28 Expression at Day 30 after Myeloablative Allogeneic Stem Cell Transplantation Are Predictive for Relapse and Chronic GVHD.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2979-2979
Author(s):  
Ibrahim Yakoub-Agha ◽  
Pasquine Saule ◽  
Leonardo Magro ◽  
Pascale Cracco ◽  
Valerie Coiteux ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Gvhd ◽  
Immunosuppressive Treatment ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Mixed Chimerism ◽  
Effector Memory ◽  
Myeloablative Conditioning ◽  
Risk Of Relapse

Abstract The curative potential of allo-SCT for malignancies derives from the progressive reconstitution of the immune system and the development of effective anti-tumor immunity, but GVHD and disease relapse remain considerable obstacles to improvement in overall outcomes. Because in recipients target antigens are persisting, donor-derived T-cell responses may be expected to lead to the accumulation of a sizable proportion of differentiated T-cells, as happens following infection with persisting pathogens. A few cross-sectional studies have pointed to the preponderance of certain memory T-cell subsets associated with chronic GVHD (cGVHD), but the subset identified differed between studies. Inasmuch as qualitative T-cell recovery takes months to years to complete and there is substantial variability in time to development of GVHD or relapse, serial analysis might be more suitable to unveil early changes in T-cell subset composition attributable to transplantation-related events. From October 2003 on, 55 pts who underwent an allo-SCT after myeloablative conditioning were monitored prospectively in terms of clinical post-graft complications, including graft rejection, infections, GVHD and relapse. Blood samples were obtained on days 30±2, 60±3, 90±5, 180±10 and 365±15 post-transplant. Naive (CD45RA+CCR7+), central memory (TCM, CD45RAnegCCR7+), effector memory (TEM, CD45RAnegCCR7neg), and terminally differentiated effector (TTD, CD45RA+CCR7neg) were enumerated within the CD4+ and CD8+ pools, and the percentage of cells coexpressing CD28 was calculated within each eight subsets. The degree of donor-derived T-cell chimerism was assessed by real time PCR (sensitivity ≤ 1%). Median follow-up was 733 d (404–1251). Dynamics of CD4+ and CD8+ naive, TCM, TEM, and TTD were similar between the pts who developed cGVHD (n=15) and those who did not and between pts who relapsed and those who did not. However, costaining to detect CD28 demonstrated contrasting differences between cGVHD and relapse. At day 30, pts who subsequently relapsed (n=17) had elevated percentages of cells keeping CD28 expression within CD8+ T-cell subsets (TCM, p=.001; TCM, p=.021; and TTD, p=.007). Conversely, pts who subsequently developed cGVHD (n=15; only one relapsed) had diminished percentages of CD28+ cells within the two CD8+CCR7+ subsets at day 30 (p=.002 and p=.034, respectively). Loss of CD28 expression is known to be a hallmark of CMV infection but multivariate analysis ruled out, however, a confounding effect of CMV. Adjusted hazard ratios were 0.10 (95% CI, 0.01-0.76; p=.026) and 5.56 (95% CI, 1.16-25.00; p=.032) with CD28neg cells 16.7% of all CD8+ TCM at day 30 for relapse and cGVHD, respectively. Furthermore, pts with relapse had more often mixed chimerism at day 30 while those with cGVHD had more often full-donor chimerism (p=.042 and p=.023, respectively). CONCLUSION: This prospective study is the first to associate an early contrasting change in CD8+CD28neg T-cells with the risk of relapse and cGVHD after a myeloablative conditioning. Determination at day 30 of the proportions of CD8+ T-cell subsets expressing CD28 and of the level of T-cell chimerism could assist in predicting risk of relapse and cGVHD and help build an algorithm for the management of immunosuppressive treatment.

Successful Rescue of Childhood Acute Leukemia In Non-Remission by Non-T-Cell Depleted HLA-Haploidentical Hematopoietic Cell Transplantation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4582-4582
Author(s):  
Shogo Kobayashi ◽  
Atsushi Kikuta ◽  
Masaki Ito ◽  
Hideki Sano ◽  
Kazuhiro Mochizuki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Complete Remission ◽  
Acute Leukemia ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Myelogenous Leukemia ◽  
Haploidentical Hematopoietic Cell Transplantation

Abstract Abstract 4582 Refractory acute leukemia who do not achieve second or subsequent complete remission (CR) have an extremely poor prognosis. Non-T-cell depleted (TCD) HLA-haploidentical hematopoietic cell transplantation (haplo-HCT) is a form of adoptive cellular therapy that has a high degree of efficacy in hematologic malignancies. The major problems of non-TCD haplo-HCT are severe graft-versus-host disease (GVHD), graft failure (GF) and high-risk of early death. We conducted non-TCD haplo-HCT for children with acute leukemia in non-remission as a novel therapeutic strategy. Five consecutive children under 15 (0-13) years old with hematological malignancies underwent non-TCD haplo-HCT from family donors between November 2002 and July 2010 at Fukushima Medical University Hospital. All patients were in non-remission at transplantation. One donor was mother and the other 4 donors were fathers of the patients. One patient was in 3 loci, and 4 patients were mismatched 4 loci of the allele level for HLA-A, -B, -C and -DRB1. The blast count in the marrow before transplantation was 80%, 75%, 34%, 10% and 96%, respectively. There were two acute myelogenous leukemia and three acute lymphoblastic leukemia. There were two refractory diseases to chemotherapy and three relapses after HSCT. All of them received myeloablative conditioning (2 Busulfan based, 3 TBI based). Type of graft were bone marrow in one and peripheral blood stem cell in 4. Total of 9.9 ×108/kg of nucleated bone marrow cells were infused in the patient received BMT. The median number of TNC and CD34+ cell doses were 11 (8-21.4)×108/kg and 7.9 (6.5-8.8)×106/kg in PBSCT, respectively. GVHD prophylaxis were combination of tacrolimus, methotrexate was given in one patient, combination of tacrolimus, methotrexate and prednisolone in one, combination of tacrolimus, methotrexate, prednisolone, and antihuman thymocyte immunoglobulin (ATG) in 3. All patients achieved primary engraftment at median of 13 days (11 -15) and achieved complete remission. Five patients developed acute GVHD, with grade 1 in two patients, grade 2 in two patients, grade 3 in one patient. Chronic GVHD occurred in 2 of 4 evaluable patients. Infectious complications including 2 CMV reactivation, 1 CMV-IP, 1 invasive aspergillosis, 1 candida sepsis were observed. One patient died from CMV-IP in remission, remaining 4 patients survived disease-free + 4, + 9, + 10 and + 94 months after non-TCD haplo-HCT, respectively. These preliminary results suggested that non-TCD haplo-HCT is effective strategy in children with refractory leukemia. Disclosures: No relevant conflicts of interest to declare.

AK2 Regulates Hematopoietic Cell Survival, Proliferation and Differentiation Along the T-Cell and Neutrophil Lineages

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1315-1315
Author(s):  
Emmanuelle M. Six ◽  
Chantal Lagresle-Peyrou ◽  
Corinne Demerens-de Chappedelaine ◽  
Justine Trimouillas ◽  
Frédéric Rieux-Laucat ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
Conflicts Of Interest ◽  
Adenine Nucleotides ◽  
Severe Combined Immunodeficiency ◽  
T Cell Differentiation ◽  
Hematopoietic Cell ◽  
Hl60 Cell ◽  
Efficient Energy Transfer ◽  
Knock Down

Abstract Abstract 1315 AK2 deficiency is responsible for Reticular Dysgenesis (RD), a rare form of human Severe Combined Immunodeficiency which is characterized by the absence of blood neutrophils and T lymphocytes. AK2 which is located in the mitochondria interspace, plays an important role in energy metabolism and in efficient energy transfer through conversion of ADP into ATP and AMP and regulation of cellular adenine nucleotides homeostasis. We modelled the RD pathology using a lentiviral-mediated RNA interference strategy to knock-down AK2 expression. Human CD34+ progenitors invalidated for AK2 are deeply affected in their proliferative ability during the process of T-cell differentiation. Between 3 to 7 days after initiation of T-cell differentiation on the OP9-Delta1 stroma, we observed an increased cell apoptosis through disruption of the mitochondrial membrane potential, associated with a 2-fold decreased in the percentage of proliferative cells. In the presence of shAK2, the apparition of CD7+ T-cell precursors was profoundly reduced - as compared to the shControl - showing that the process of differentiation itself was affected. We also demonstrated that AK2 knock-down inhibits neutrophil differentiation using both G-CSF-mediated differentiation of CD34+ progenitors and ATRA-mediated differentiation of the HL60 cell line. In the HL60 system, we showed that the survival defect induced by the shAK2 could be rescued by expression of the anti-apoptotic protein Bcl-2, while this latter was not sufficient to restore a normal differentiation process. These data suggest a novel mechanism in which AK2 regulates not only the process of differentiation but also survival and proliferation of hematopoietic cell lineages. Disclosures: No relevant conflicts of interest to declare.

NaïVe T Cell Depletion of PBSC Grafts Results in Very Low Rates of Chronic Gvhd and High Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 668-668
Author(s):  
Marie Bleakley ◽  
Ted A. Gooley ◽  
Barbara Hilzinger ◽  
Stanley R Riddell ◽  
Warren D Shlomchik
Keyword(s):  
T Cells ◽  
T Cell ◽  
Acute Leukemia ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
T Cell Subsets ◽  
Cell Depletion ◽  
Effector Memory ◽  
Phase Ii Trials ◽  
T Cell Depletion

Abstract Background Graft-versus-host disease (GVHD) frequently causes morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT) as a result of organ damage and infections. In HLA-identical HCT, GVHD results from recognition by donor T cells of minor histocompatibility (H) antigens on recipient tissues. Complete T cell depletion (TCD) of donor hematopoietic cell products is more effective than pharmacologic immunosuppression for preventing GVHD, but is complicated by delayed immune reconstitution and consequent life-threatening infections.Approaches to HCT which preferentially deplete the T cells that primarily cause GVHD and preserve pathogen-specific T cells may improve HCT outcomes. Mature CD3+ CD8+ and CD3+ CD4+ T cells can be classified into CD45RA+ CD62L+ naïve (TN) and CD45RO+ memory (TM) subsets, the latter of which includes effector memory (TEM) and central memory (TCM) cells. Murine studies in which allogeneic TCD bone marrow (BM) is transplanted with purified T cells from individual T cell subsets to irradiated minor H antigen disparate recipients have demonstrated that the most severe GVHD results from transplanting T cells of the TN subset. Purified TCM causes mild GVHD and TEM do not cause detectable GVHD and can transfer immunity to pathogens.In vitro studies have similarly demonstrated that human donor CD8+ T cells specific for recipient minor H antigens are found predominantly within the TN cell subset, suggesting selective TN cell depletion may alter the GVHD incidence and/or severity in human HCT. Methods and results We developed an effective process for engineering human peripheral blood stem cell (PBSC) grafts that depletes CD45RA+ TN cells and retains CD34+ stem cells and functional CD45RO+ TM cells specific for a broad range of opportunistic pathogens (Bleakley BBMT 2014). We are conducting clinical trials to evaluate the selective depletion of TN cells from HLA-matched allogeneic PBSC grafts for the prevention of GVHD in patients with acute leukemia, the first of which has been published (Bleakley JCI 2015, N=35). Seventy patients have now been treated on three consecutive phase II trials. The median age was 34 years (1-56 years), 56% of patients had a diagnosis of ALL, 46% had previously relapsed or had detectable disease (MRD or relapse) at the time of HCT, and 23% had unrelated donor (URD) grafts. Intensive myeloablative, TBI-containing (13.2Gy) conditioning was used for 63 patients, whilst 7 patients received a medium intensity 'midi' preparative regimen, including 4Gy of TBI. The TN-depletion procedure was successfully performed on URD PBSC products shipped overnight from donor centers throughout the US, as well as on MRD PBSC collected at our centers. Reliable engraftment with high-level donor chimerism was observed in recipients of 'midi' as well as intensive myeloablative conditioning. The 2-year estimates of overall survival, disease-free survival, survival free of relapse and chronic GVHD (CRFS) and survival free of relapse, grade II-IV acute GVHD, and chronic GVHD (GRFS) are 79%, 73%, 69% and 63% respectively. Median follow-up among survivors is 26 months. The frequency and severity of chronic GVHD is remarkably low (5%) compared to historical rates of 40-60% chronic GVHD in HLA-matched PBSC transplantation with conventional calcineurin inhibitor-based immunosuppression. Relapse and non-relapse mortality (NRM) are acceptably low at 19% and 8%, respectively. No NRM occurred in patients <40 years. Updated results will be presented. Conclusions The outcomes of recipients of TN-depleted PBSC grafts compare very favorably to published results of HCT for patients with acute leukemia. For example, the 69% incidence of CRFS at 2 years in TN-depleted recipients compares with reported 2-year GRFS rates of 37% and 17% in recipients of allogeneic PBSC from HLA-matched related donors with or without ATG (Kroger et al. NEJM 2016). Our results suggest that TN-depletion of PBSC grafts may reduce the risk of chronic GVHD without negatively impacting other important HCT outcomes. Disclosures Riddell: Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Cell Medica: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria.

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