scholarly journals Photochemical treatment of donor lymphocytes inhibited their ability to facilitate donor engraftment or increase donor chimerism after nonmyeloablative conditioning or establishment of mixed chimerism

2002 ◽  
Vol 8 (11) ◽  
pp. 581-587
Author(s):  
Bryon D Johnson ◽  
Patricia A Taylor ◽  
Marja C Stankowski ◽  
Sohel Talib ◽  
John E Hearst ◽  
...  
Keyword(s):  
Mixed Chimerism ◽  
Donor Chimerism ◽  
Donor Lymphocytes

An Experimental Study on the Effects of Sensitized-Donor Lymphocytes Infusion after Non-Myeloablative Allo-Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5203-5203
Author(s):  
Bao-An Chen ◽  
Yan Zhang ◽  
Yan-Zhi Bi ◽  
Jia-Hua Ding ◽  
Gang Zhao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
T Lymphocytes ◽  
Stem Cell Transplantation ◽  
Peripheral Blood ◽  
Mixed Chimerism ◽  
Hematopoietic Stem ◽  
Donor Chimerism ◽  
Cd8 T Lymphocytes ◽  
Donor Lymphocytes

Abstract Objectives :To explore the effects and mechanisms of the recipients chimerism, the rate of graft-versus-host disease (GVHD) and the immune state by infusion of donor lymphocytes (DLI) which were sensitized by the skin of recipients after non-myeloablative allogeneic stem cell transplantation (NSCT). Methods :Female C57BL/6 mice (H-2b, B6) as recipients received total-body irradiation (TBI) of 5.5 Gy (60CoC-ray) on day 0 followed by allogeneic hematopoietic stem cells transplantation (allo-HSCT). The allo-grafts consisted of 2×107 peripheral hematopoietic stem cells from mobilized male BALB/C (H-2d) donor mice with recombinant human granulocyte colony-stimulating factor (rhG-CSF). Two days after allo-HSCT, the recipient mice were given cyclophosphamide (Cy) (200mg/kg) intraperitoneally. Afterwards these recipient mice were infused 2×106 sensitized or unsensitized-donor lymphocytes at the day of 28 after transplantation respectively. Recipients were observed clinical manifestation, phenotype, re-establishment of haematogenesis, histopathologic changes of internal organs suffered from GVHD and investigated donor chimerism by the semi-quantitate analyses of polymerase chain reaction (PCR). Immunologic reconstitution was evaluated through T-lymphocytes Subsets in peripheral blood detected by flow cytometer (FCM). Data was analyzed by SPSS 10.0 software and expressed as mean ± SD. Results: The mice receiving sensitized-donor lymphocytes infusion did not suffer from GVHD and the phenotypic character of the recipient mice (black color) converted to that of the donor mice (white color), and to full-donor chimerism. It was found that the ratio of CD4+/CD8+ T lymphocytes of them decreased at the earlier period and increased after half month, but which were also lower than that of the normal value. mixed lymphocyte reaction (MLR) showed the specific hyporesponsiveness to donor mice. While various grades of aGVHD were observed in that of the unsensitized-DLI group and the mixed-chimerism were maintained, though it increased a little, and the ratio of CD4+/CD8+ T lymphocytes increased at first, then decreased to the normal level half month later. The effects were more significant in the group of sensitized-DLI than that of unsensitized-DLI. The result of MLR also showed hyporesponsiveness, but it exceeded that of the sensitized-DLI recipients. The effects were more significant in the group of sensitized-DLI than that of unsensitized-DLI (P<0.05). Conclusions Mixed-chimerism can be achieved using a nonmyeloablative TBI and CTX-based conditioning regimen combination with infusion of peripheral blood stem cells mobilized by rhG-CSF in fully mouse histocompatibility-2 complex (H-2) mismatched recipients, and donor chimerism can be promoted by administration of DLI. Furthermore, sensitized DLI converted mixed to comlete donor chimerism without GVHD. The ratio of CD4+/CD8+ and the reactiveness of MLR showed super dependability with the chimerism and the incidence of GVHD.

Coexistence of Two Functioning T-Cell Repertoires in Healthy Ex-Thalassemics Bearing a Persistent Mixed Chimerism Years After Bone Marrow Transplantation

Blood ◽  
1999 ◽  
Vol 94 (10) ◽  
pp. 3432-3438 ◽  
Author(s):  
Manuela Battaglia ◽  
Marco Andreani ◽  
Marisa Manna ◽  
Sonia Nesci ◽  
Paola Tonucci ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Mixed Chimerism ◽  
Functional Studies ◽  
Repertoire Analysis ◽  
Donor Cells ◽  
Donor Lymphocytes

Bone marrow transplantation (BMT) from an HLA-identical donor is an established therapy to cure homozygous β-thalassemia. Approximately 10% of thalassemic patients developed a persistent mixed chimerism (PMC) after BMT characterized by stable coexistence of host and donor cells in all hematopoietic compartments. Interestingly, in the erythrocytic lineage, close to normal levels of hemoglobin can be observed in the absence of complete donor engraftment. In the lymphocytic lineage, the striking feature is the coexistence of immune cells. This implies a state of tolerance or anergy, raising the issue of immunocompetence of the host. To understand the state of the T cells in PMC, repertoire analysis and functional studies were performed on cells from 3 ex-thalassemics. Repertoire analysis showed a profound skewing. This was due to an expansion of some T cells and not to a collapse of the repertoire, because phytohemagglutinin stimulation showed the presence of a complex repertoire. The immunocompetence of the chimeric immune systems was further established by showing responses to alloantigens and recall antigens in vitro. Both host and donor lymphocytes were observed in the cultures. These data suggest that the expanded T cells play a role in specific tolerance while allowing a normal immune status in these patients.

Use of Pre-Emptive Donor Lymphocyte Infusions To Achieve Durable Remission Following Alemtuzumab Based Reduced Intensity Conditioning (RIC) Transplantation for AML or MDS.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1124-1124
Author(s):  
ZiYi Lim ◽  
Laurence Pearce ◽  
Wendy Ingram ◽  
Rafael Duarte ◽  
Stephen Devereux ◽  
...  
Keyword(s):  
T Cell ◽  
Advanced Disease ◽  
Disease Stage ◽  
Mixed Chimerism ◽  
Donor Chimerism ◽  
Significant Difference ◽  
Cell Source ◽  
Recipient Age ◽  
The Impact

Abstract Use of alemtuzumab in RIC HSCT reduces the incidence of graft rejection and graft vs host disease(GvHD). However, there can be a delay in full T-cell donor engraftment. As a dominant donor T-cell chimerism may be important to achieve a strong graft vs leukaemia effect(GvL), we examined the impact of pre-emptive DLI (pDLI) on patients with falling donor chimerism. 76 patients with AML or MDS were treated with RIC HSCT (fludarabine 150mg/m2, busulphan 8mg/kg, alemtuzumab 100mg). Complete sublineage chimerism data up to day +100 was available on all patients. The underlying diagnoses were AML n=27, MDS n=49. 33 patients had early disease vs 44 advanced disease (advanced disease as defined by AML >CR1, MDS RAEB or AML with multilineage dysplasia). The median recipient age was 51.6 years (range:19–72), with median follow-up of 526 days (range:137–1256). There were 30 sibling and 50 VUD allografts. Stem cell source was 61 PBSC vs 15 BM. 62 patients were fully HLA matched and 14 patients were HLA mismatched. CD15 engraftment occurred rapidly with 95% of patients achieving full donor chimerism(FDC) at day 30 and 96% at day 100. In contrast, CD3 engraftment was significantly delayed, with only 50% of patients FDC at day 30, 47% at day 100. Incremental doses of pDLI were considered for patients with falling donor chimerism (<50% donor) after day 100. Patients had immunosuppresion withdrawn, and had to have no GvHD. 20 patients received a total of 55 doses of pDLI. 10/20 had advanced disease, and 6/20 had unfavourable cytogenetics. Median donor CD3 chimerism at time of pDLI was 31.5%(range:7–59). The median CD3 dose of pDLI was 8.4x106/kg, with the first dose given at a median of day +176 (range:104–494). The median interval between pDLI was 8 weeks(range:4–22). 15 patients had FDC restored at median of 130 days following first doses of pDLI (range:36–523). 8/20 developed acute Gd II-IV GvHD following pDLI, with 2 patients dying of GvHD related complications. 2 patients relapsed with AML following treatment: with 1 death, and 1 patient currently undergoing treatment. 2 patients had not reached FDC at follow-up. A further 9 patients received DLI for cytogenetic or morphological relapse. Time to first dose of DLI was 257 days (range:76–837). The median CD3 dose was 1.67 x 107/kg. 3 patients were FDC and 6 patients MDC at time of relapse. All 3 patients with FDC failed to respond to DLI. Complete remission was seen in 3/6 patients with MDC. 4/9 patients developed acute Gd II-IV GvHD. 5/9 patients have died(all of underlying AML). The outcome of patients receiving pDLI was compared with patients with FDC(n=28), and stable mixed chimerism(defined as donor CD3 chimerism >70%) who did not receive DLI(n=18). There was no significant difference in recipient age, disease, disease stage, HLA type, cell source or cell dose between groups. However, there were more sibling donors in the group receiving pDLI(p=0.02). The 2 year DFS, OS and relapse rate was comparable between patients with FDC, stable chimerism and those receiving pDLI (59% vs 83% vs 67% p=0.22), (62% vs 88% vs 75% p=0.13), (12% vs 17% vs 15% p=0.74) respectively. In summary, pre-emptive DLI is effective in reversing falling donor chimerism, and can induce prolonged remission, even in a sub-group of patients with high risk disease. A dominant donor CD3 chimerism(>70%) may be sufficient to acheive an allo-immune effect in majority of patients.

Low Pre-DLI Lymphocytes Counts Are Predictive of Good Disease Responses in Patients with Mixed Chimerism Following Campath-Containing Reduced Intensity Transplants.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 261-261
Author(s):  
Bronwen E. Shaw ◽  
Jenny L. Byrne ◽  
Emma Das-Gupta ◽  
Ian Carter ◽  
Nigel H. Russell
Keyword(s):  
Lymphocyte Count ◽  
Residual Disease ◽  
Suppressor Cells ◽  
Mixed Chimerism ◽  
Post Transplant ◽  
Donor Chimerism ◽  
Significant Difference ◽  
Group B ◽  
The Impact ◽  
Reduced Intensity

Abstract Following reduced intensity conditioned (RIC) transplants, donor leukocyte infusions (DLI) are frequently used either to convert mixed chimerism (MC) to full donor chimerism (FDC) or for residual or relapsed disease. Unfortunately, DLI are not universally successful and few factors are known (e. g disease type and level of pre-DLI chimerism) which predict for good responses. We analysed the impact of the chimerism pattern in 125 recipients of (CAMPATH containing) RIC transplants for malignant diseases. Of these, 68 (55%) had FDC (group A), 49 (39%) developed MC and 8 (6%) lost DC and had autologous reconstitution (group D). The patients who developed MC could be further subdivided into those with persisting MC post transplant (27, 55%; group B: non-responders) and MC post transplant with subsequently development of FDC (22, 45%; group C: responders). These two groups were analysed further. The median patient age was 55 (range: 19–71). The donors were siblings (22) or unrelated (27). The diseases were as follows: AML/MDS 14, CML 4, Myeloma, 4, lymphoma/CLL 26, MF 1. Stem cell source was PBSC (38) and bone marrow (11). Conditioning consisted of fludarabine, melphalan and campath (fmc) in 24 patients; fludarabine, busulphan and campath (fbc) in 5; BEAM, campath +/− fludarabine in 18 and FLAG in 2. There were no significant differences in any of these features between groups B and C. 25/49 patients received DLI. This was for disease relapse in10 patients, residual disease in 6 and MC alone in 8 (Unknown in 1). A complete disease response (CDR) was seen in 9/14 (64%) evaluable cases. There was a highly significant difference in CDR between the two groups (group B: 0/4, group C: 9/10, p=0.005). The reason for the difference in response rate was investigated. Median time to DLI was 196 days (range: 57–2123), not significantly different between the groups (p=0.561). The indication for and total number of DLI, the underlying disease and the degree of pre-DLI donor chimerism were not significantly different. In addition there was no significant difference in the incidence of post DLI GvHD (p=0.137), although this was 10/13, 77% in those who responded and 2/5, 40% in those who did not. Conversely, there was a significant difference in the pre-DLI lymphocyte counts (p=0.036). The median count was 2.24 × 109/l. In group B 3/11 (27%) were below this while 10/14 (71%) in group C were below this. The pre-DLI lymphocyte count was not significantly correlated with the time post transplant at which DLI was given, the type of donor, the indication for DLI or the disease, conditioning or post transplant immunosuppression regimen. The predicted overall survival at 2 years was significantly better in group C than in group B (95% versus 57%, p=0.002). This was largely due to the higher relapse risk in group B (77%) compared to group C (32%) (p=0.043). In conclusion, in patients with MC, the development of FDC was significantly associated with a superior OS. In those receiving DLI, the factor most significantly predictive for a ‘responsive’ (C) versus ‘non-responsive’ (B) pattern was the presence of a low pre-DLI lymphocyte count, suggesting that a lack of ‘space’ for expansion or increased suppressor cells in the lymphoid compartment mediate DLI resistance. We postulate that DLI ‘non-responders’ (those with higher lymphocyte counts) may be converted to ‘responders’ by the addition of pre-DLI lymphoreduction, thus reducing relapse and improving outcome.

Everolimus and Cyclosporine in Combination with 2Gy TBI as Pre- and Posttransplant Immunosuppression in a Canine Transplantation Model.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4861-4861
Author(s):  
Sandra Lange ◽  
Susanne Rathsack ◽  
Rainer Wacke ◽  
Simone Altmann ◽  
Volker Weirich ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Trough Level ◽  
Mixed Chimerism ◽  
Comparable Efficacy ◽  
Hematopoietic Stem ◽  
Donor Chimerism ◽  
Normal Limits ◽  
Group 2 ◽  
Median Maximum ◽  
Group 1

Abstract BACKGROUND: Everolimus (RAD) is a potent immunosuppressant used for the prevention of acute allograft rejection in renal and cardiac transplantation. RAD in combination with cyclosporine A (CSA) demonstrates comparable efficacy to mycophenolate mofetil (MMF) and azathioprine, respectively, whereas it has a more feasible side effect profile. Studies that investigate RAD in hematopoietic stem cell transplantation (HSCT) are lacking. The aim of the present study was to evaluate the efficacy and safety of RAD in combination with CSA in a nonmyeloablative HSCT model. METHODS: Dogs were given conditioning with 2Gy total body irradiation (TBI) before allogeneic HSCT (d0). Dog leukocyte antigen-identical littermate marrow was infused i.v. at a median of 3.6x10E8 TNC/kg. Three dogs received unmodified marrow (group 1) whereas three other dogs were given sensitized marrow from a donor that had rejected the graft of a prior HSCT from the sibling that served as recipient in the current experiments (group 2). All dogs received an immunosuppression consisting of 15mg/kg CSA BID PO (days -1 to 35) and 0.25mg BID PO (days 0 to 27) initially. Pharmacokinetics of RAD and CSA at day 5 were used for doses adaptation to reach targeted trough level of 3 8ng/ml for RAD and C0 and C2 level of 300 500ng/ml and 1500 2000ng/ml for CSA, respectively. Hematotoxicity, blood lipids, and creatinine were monitored. RESULTS: All dogs engrafted following HSCT and first hematopoietic mixed chimerism was detectable by day 7. Dogs in group 1 engrafted with a median maximum granulocyte chimerism of 82% (54–95%) at day 28. Median maximum PBMC chimerism was 52% (26–62%) at day 34. One dog rejected the graft after 10 weeks, 1 dog died from infection at week 9 but was a mixed hematopoietic chimera at the time of death (28% granulocytes, 36% PBMC), and 1 dog continues to be mixed chimeric through week 27 (0% granulocytes, 16% PBMC). Two of the 3 dogs in group 2 developed full donor chimerism among granulocytes and PBMC and remain stable full hematopoietic chimeras through weeks 15 an 26. The other dog rejected the graft after 10 weeks. Median RAD trough level at day 5 was 7.2ng/ml (2.3–12.0ng/ml). Synergism between RAD and CSA caused enhancement in CSA C0, C2, and AUC values by 112, 106 and 45%, respectively, compared to CSA levels in CSA/MMF treated dogs. CSA dose reduction was initiated in 3/6 dogs based on pharmacokinetics. Within all dogs a transient decrease in platelet and leukocyte counts with median nadirs of 0x10E9/l (0–21x10E9/l) at day 11 and 1.6x10E9/l (0.7–3.2x10E9/l) at day 8 was observed. Creatinine, cholesterol, triglyceride levels remained within normal limits. CONCLUSION: Immunosuppression with RAD/CSA as pre- and posttransplant conditioning is feasible in the canine HSCT model. RAD was well tolerated and allowed dose reduction of CSA. Using RAD and pre-sensitized bone marrow, full donor chimerism was achievable. Therefore, our data indicate that the combination of RAD/CSA might be used as alternative for CSA/MMF in the 2Gy nonmyeloablative HSCT setting.

Long Term Outcomes of Hematopoietic Stem Cell Transplantation in Patients with Severe Phenotype Hurler Syndrome: an International Multi-Center Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1958-1958
Author(s):  
Mieke Aldenhoven ◽  
Maria Escolar ◽  
Robert Wynn ◽  
Ed Wraith ◽  
Anne O'Meara ◽  
...  
Keyword(s):  
Mixed Chimerism ◽  
Hurler Syndrome ◽  
Long Term Outcomes ◽  
Term Outcome ◽  
Hematopoietic Stem ◽  
Long Term Outcome ◽  
Donor Chimerism ◽  
Normal Enzyme

Abstract Abstract 1958 Background: Hurler syndrome (HS), the most severe phenotype in the spectrum of Mucopolysaccharidosis type I, is caused by a deficiency of the lysosomal enzyme alpha-L-iduronidase. HS is clinically characterized by a progressive and ultimately fatal multi-system deterioration with involvement of the central nervous system. At present, hematopoietic stem cell transplantation (HSCT) is the only treatment that prevents disease progression in the central nervous system and is therefore considered the treatment of choice in HS. Long-term follow-up of outcomes of HSCT for HS are sparse and risk factors for favorable long-term outcomes are still largely unknown. Therefore, an international multicenter study was initiated to describe the long-term outcomes of successfully transplanted HS patients. Methods: HS-patients transplanted between 1980 and 2007 within the leading transplantation centers in Europe and the United States were include in this study. Patient, donor, and transplantation-related variables which may influence long-term outcome were analyzed. Patients who were ‘alive and engrafted (donor-chimerism >10%)’ with a follow up of at least three years after HSCT were included. The functional outcomes assessed for the various organ systems - orthopedic, cardiac, ophthalmologic, respiratory and audiologic - were analyzed using multivariate Cox proportional hazards and logistic regression models. Results: 197 Hurler patients were included from 8 different transplant centers. This is estimated to be about 70–80% of the successfully transplanted HS patients worldwide during that time period. These patients had a median age of 16 (2–80) months at HSCT with a median follow up of 88 (36–258) months after successful HSCT. Seventy-nine % of the patients received a graft from an unaffected (non-carrier) donor. Seventy-two % of the patients achieved full (>95%)-donor-chimerism and 28% mixed-chimerism. After HSCT, normal enzyme-levels (EL; according to the local reference range) were found in 75% of the patients while 25% had EL below lower limit of normal; either due to mixed-chimerism or carrier-donorship). Multivariate analyses (table 1) showed having a “normal EL” after HSCT and younger (below the median age of 16mths) “age at transplantation” were associated with less serious orthopedic complications requiring surgical interventions; e.g. cord compression, genu-valgum surgery, carpal tunnel surgery. Genotype (double non-sense vs. any other genotype) was associated with a lower probability of requiring hip dysplasia surgery as well as with the occurrence of retinopathy. For other endpoints; e.g progression valve insufficiency, progression corneal clouding and development of retinopathy and the need for hearing aids having a normal EL as well as age at HSCT (<16mths) were predictors for better outcome. Furthermore, growth at the age of 60mths was influenced by EL (−1.93 SDS vs. −1,09 SDS; p=0.042). Conclusion: The long-term outcome of clinical manifestations in HS-patients after successful HSCT is promising although residual disease burden remains. Predictors, favorably influencing the long-term outcomes are suggested to be 1) enzyme level (normal vs. below LLN) after HSCT, 2) genotype and 3) age at HSCT. Achieving normal enzyme levels at an early age might significantly impact the prognosis of Hurler syndrome patients. Newborn screening (resulting in early HSCT), the use of non-carrier donors and achieving full-donor chimerism may be crucial in optimizing long-term outcomes. Disclosures: No relevant conflicts of interest to declare.

Adoptive immunotherapy in canine mixed chimeras after nonmyeloablative hematopoietic cell transplantation

Blood ◽  
2000 ◽  
Vol 95 (10) ◽  
pp. 3262-3269
Author(s):  
George E. Georges ◽  
Rainer Storb ◽  
Jennifer D. Thompson ◽  
Cong Yu ◽  
Ted Gooley ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Adoptive Immunotherapy ◽  
Hematopoietic Cell Transplantation ◽  
Skin Grafting ◽  
Mixed Chimerism ◽  
Hematopoietic Stem ◽  
Donor Chimerism ◽  
Mixed Chimeras

Development of nontoxic and nonmyeloablative regimens for allogeneic hematopoietic stem-cell transplantation will decrease transplantation-related mortality caused by regimen-related toxic effects. In pursuit of this goal, a dog model of stable mixed hematopoietic chimerism was established in which leukocyte-antigen–identical litter mates are given sublethal total-body irradiation (2 Gy) before stem-cell transplantation and immunosuppression with mycophenolate mofetil and cyclosporine afterward. In the current study, we examined whether donor lymphocyte infusion (DLI) could be used as adoptive immunotherapy to convert mixed to complete donor chimerism. First, 8 mixed chimeras were given unmodified DLI between day 36 and day 414 after stem-cell transplantation. After a 10- to 47-week follow-up period, there were no significant changes in the percentage of donor engraftment. Next, we immunized the donor to the minor histocompatibility antigens (mHA) of the recipient by means of repeated skin grafting. Lymphocytes from the mHA-sensitized donor were infused between day 201 and day 651 after transplantation. All 8 recipients of mHA-sensitized DLI had conversion to greater than 98% donor chimerism within 2 to 12 weeks of the infusion. Complications from mHA-sensitized DLI included graft-versus-host disease in 2 dogs and marrow aplasia in 1. These results showed that the low-dose transplant regimen establishes immune tolerance, and mHA-sensitized DLI is required to break tolerance, thereby converting mixed to complete donor chimerism. We propose that mixed chimerism established after nonmyeloablative allogeneic stem-cell transplantation provides a platform for adoptive immunotherapy that has clinical potential in the treatment of patients with malignant diseases.

scholarly journals Impact of Donor Chimerism-Guided Immunomodulation after Allogeneic Stem Cell Transplant on the Outcome of Patients with AML and MDS

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2133-2133
Author(s):  
Juliane Steinmann ◽  
Sarah Lindner ◽  
Zuzana Jedlickova ◽  
Salem Ajib ◽  
Saskia C. Gueller ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Small Molecules ◽  
Research Funding ◽  
Mixed Chimerism ◽  
Cell Transplant ◽  
Donor Chimerism ◽  
Unrelated Donors ◽  
Travel Grant ◽  
The Impact

Abstract Introduction: After an allogeneic stem cell transplantation (SCT), analysis of donor chimerism (DC) is routinely used to monitor engraftment. In patients with myeloid malignancies, loss of a complete donor chimerism (CC) may indicate graft failure, but more often imminent leukemic relapse. Especially in patients without a valid marker for minimal residual disease (MRD), chimerism analysis may prompt reduction of immunosuppression or therapeutic interventions such as donor lymphocyte infusions (DLI) or hypomethylating agents (HMA). We retrospectively analyzed DC data and outcomes of 255 consecutive patients (pts) transplanted for an acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) at our center. Aims of our study were to evaluate the impact of (i) a falling DC, (ii) the first chimerism-guided intervention, and (iii) the application of DLI on survival and incidence of acute and chronic (a/c) GvHD. Patients and Methods: 255 pts that received a first SCT between 2005 and 2016 were monitored regularly (approx. every two weeks from day +14 to +100, then monthly) for DC using a validated, CE-labeled multiplex-STR PCR at a single laboratory (AgenDix GmbH, Dresden, Germany). CC was defined as ≥99% and mixed chimerism (MC) as <99% donor cells. Overall survival (OS), GVHD-free, relapse-free survival (GFRS) and the cumulative incidence (CI) of GVHD was analyzed for the whole cohort, OS and CI GVHD were analyzed for pts with MC and pts that received DLI with a prophylactic/preemptive (pDLI) vs. therapeutic (tDLI) indication. 245 pts (median age 53 years (range 19-73), 136 male) with AML (n=222) or MDS (n=23) achieved a CC within 60 days post SCT and were eligible for our analysis, 10 pts were excluded due to refractory disease (n=9) or early death (n=1). 101 out of 222 AML pts (45%) had intermediate (int)-2 or adverse cytogenetics according to ELN guidelines, and 10 out of 23 MDS pts (43%) had IPSS int-2 or high risk. 121 pts (49%) were transplanted in first complete remission (CR), 107 (44%) with active disease. For SCT, 96 pts (39%) had received myeloablative (MAC) and 149 (61%) reduced intensity conditioning regimens (RIC). Donors were HLA-matched siblings (MRD, n= 60) or unrelated donors (MUD, n=149), mismatched related (MMRD, n= 1) or unrelated donors (MMUD, n=27), or haploidentical family members (n=8). Results: A MC was detected in 95 pts (39%) at a median of 104 (range, 28-1764) days post SCT, of whom 18 pts (32%) had aGVHD G2-4. Pts with MC had received RIC significantly more often compared to pts with continued CC (69% vs 55%, p=0.046), the two groups did not differ regarding high risk cytogenetics/IPSS and remission status at SCT. MC prompted reduction of immunosuppressive therapy (IST, n=35), DLI (n=7), HMA (n=16), DLI+HMA (n=7), chemotherapy and/or 2ndSCT (n=7), small molecules (n=10) or best supportive care (BSC, n=13) as deemed appropriate by the treating physician. Median OS and GFRS were significantly better for pts with CC (OS not reached; GFRS 46 months (mths)) compared to pts with MC (OS 15.7 mths; Hazard ratio (HR) 0.25, 95%-CI 0.17-0.37, p<0.001, GFRS 3.7 mths; HR 0.39, 95%-CI 0.26-0.58, p<0.001, figures 1,2). 3-year survival was 75% for the CC group vs 31.7% for the MC group. For the 95 pts with MC, median OS was 27.4 and 35.8 mths following IST reduction or DLI+HMA, respectively, and 12, 8.8, 5.1 and 1.2 mths for pts treated with chemo/2ndHSCT, HMA, small molecules or BSC. Treatment of MC induced aGVHD G2-4 in only 2 additional pts (G3-4: n=1). CI of cGVHD requiring systemic IST was 27% at 1-year for all pts with MC compared to 13.9% for pts in the CC group. In the whole cohort, 46 pts (19%) received a median of 2 DLIs (median dose 0.5x106CD3+cells/kg). PDLIs were administered to 33 pts (72%) and tDLIs to 13 pts with relapsed disease (28%). The pDLI group had a 3-year survival of 82.9% and did not reach median OS, compared to 24.6% 3-year survival and 22 mths median OS in the tDLI group. Median GRFS was 91.4 vs 6.6 mths for the pDLI and tDLI group, respectively. No pt developed aGVHD G2-4 after DLI administration, 1 pt (8%) in the tDLI and 4 pts (12%) in the pDLI group developed cGVHD requiring systemic IST. Conclusion Occurrence of MC seems predictive of an inferior outcome, but early intervention such as careful reduction of IST if feasible or administration of DLI with or without HMA may effectively prolong OS and GRFS. Administration of pDLI after discontinuation of IST starting with low doses is safe and results in low rates of cGvHD. Disclosures Lang: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding. Toenges:Bayer: Research Funding. Schetelig:Sanofi: Consultancy, Research Funding; Roche: Honoraria; Abbvie: Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Serve:Bayer: Research Funding. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding. Bug:Astellas Pharma: Other: Travel Grant; Novartis Pharma: Honoraria, Research Funding; Neovii: Other: Travel Grant; Jazz Pharmaceuticals: Other: Travel Grant; Janssen: Other: Travel Grant; Celgene: Honoraria; Amgen: Honoraria.

Nonmyeloablative allogeneic blood stem cell transplantation (NMBSCT) ± donor lymphocyte infusion (DLI) for chemorefractory advanced nasopharyngeal carcinoma (NPC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2549-2549
Author(s):  
H. C. Toh ◽  
E. H. Tan ◽  
C. H. Thng ◽  
S. P. Yap ◽  
K. M. Lee ◽  
...  
Keyword(s):  
Disease Control ◽  
Tumor Response ◽  
Chronic Gvhd ◽  
Fatal Case ◽  
Immunosuppressive Treatment ◽  
Graft Loss ◽  
Complete Removal ◽  
Disease Control Rate ◽  
Mixed Chimerism ◽  
Donor Chimerism

2549 Background: There is emerging clinical evidence for T cell immunotherapy in NPC. We report a NMBSCT regimen that induced mixed chimerism for DLI to potentially achieve a graft-versus-tumour effect (GVT) in NPC. Methods: 15 patients with advanced pretreated NPC were accrued to this prospective clinical trial. Our regimen comprised IV cyclophosphamide 50 mg/kg on day-5,-4,-3 and IV thymoglobuline on day-1, +1, +2 and +3 (n = 9) and then revised to IV thymoglobuline day-1, +1, +2, +3 (n = 6). Thymic radiation was given on day-1. G-CSF mobilized HLA-matched (n = 14) and 1-antigen-mismatched (n = 1) sibling PBSC were infused. DLI was initiated following taper of prophylactic cyclosporine (CyA). Results: Median age (n =15) was 49 yrs, median no. of metastatic organ sites was 3, mean no. of prior chemotherapy was 4 (range 2 - 8) and 14/15 had prior radiation. Median time to engraftment was 13 days and hospital stay was 17 days. Complete removal of prophylactic CyA was achieved for all patients at a median of day +28. DLI was given in 14 patients (median = 2, range 1 to 6). 4 patients were later re-started on GVHD immunosuppressive therapy. Two (13.3%) patients had acute GVHD (one Grade II and one fatal case who died on day+91). 3 patients developed chronic GVHD (20%), all controlled with short courses of standard immunosuppressive treatment. 11/15 died of PD, and 2/15 died from sepsis. 100-day TRM was 6.6%. 3/9 patients had donor graft loss. 6/6 patients on the revised protocol had stable and/or full donor chimerism. CMV antigenemia was 9/9 for the first regimen and 3/6 for the revised regimen (p = 0.044). Tumor response (RECIST) confirmed 40% PR, 33.3% SD and 40% PD, for a disease control rate of 73.3%. > day+100 anti-tumor response were observed in 5/15 patients (33.3%), implicating a GVT effect. 1 patient achieved a delayed PR on day+111 with stable donor chimerism of 19%. The longest surviving patient (36.5 mths) with multiple nodal, bone and lung metastasis achieved full donor chimerism and further tumor shrinkage at 8 mths post-NMBSCT. Conclusions: GVT is achievable with NMBSCT ± DLI in Stage IV NPC patients with a high disease control rate and acceptable GVHD. Early complete removal of prophylactic CyA was possible in all 15 patients. No significant financial relationships to disclose.

Outcomes of Patients with Engraftment Syndrome (ES) Following Nonmyeloablative Hematopoietic Stem Cell Transplant (SCT) for Hematologic Malignancy(HM).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3661-3661 ◽  
Author(s):  
Erica Linden ◽  
Steven L. McAfee ◽  
Bimalangshu R. Dey ◽  
Karen Ballen ◽  
Susan Saidman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Weight Gain ◽  
Pulmonary Edema ◽  
Renal Dysfunction ◽  
Acute Gvhd ◽  
Hepatic Dysfunction ◽  
Mixed Chimerism ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Donor Chimerism

Abstract ES may accompany hematologic recovery following SCT and is characterized by fever and rash, in addition to one of the following clinical syndromes: noncardiogenic pulmonary edema, hepatic dysfunction, renal dysfunction, weight gain, or transient encephalopathy. A retrospective analysis was performed to evaluate the incidence of ES using a published clinical definition (Spitzer TR, Bone Marrow Transplant2001; 27:893–898), the use of corticosteroids in the peri-engraftment period, the relationship of ES to the development of GVHD, and the fate of the patient’s chimerism. Seventy-three patients with a HM (NHL, n=45; HD, n=9; AML, n=6; ALL, n=1; CLL, n=6; MDS, n=1; MM, n=4) who were treated with a nonmyeloablative conditioning regimen consisting of cyclophosphamide, antithymocyte globulin, thymic irradiation, cyclosporine, and hematopoietic SCT (bone marrow, n =57; peripheral blood stem cells, n =15) were analyzed. Chimerism was assessed weekly for the first 100 days, then q6 months by VNTR/STR analysis and/or flow cytometry. In the absence of full donor chimerism (FDC) or evidence of acute GVHD, donor leukocyte infusions (DLI) were given beginning 5 weeks post-transplant to convert mixed chimerism (MC) to FDC and thus maximize a graft-versus-tumor effect. Thirty-five (50%) patients met the clinical definition of ES, presenting with fever and rash (100% of ES patients), hepatic dysfunction (74.3%), fluid retention/weight gain (60%), noncardiogenic pulmonary edema (22.9%), renal dysfunction (22.9%), and transient encephalopathy (5.7%). Three (4.1%) patients never engrafted and thus were censored from the population. Median time to engraftment was 13 (range 9 to 18) days in ES patients and 14 (range 9 to 21) days in non-ES patients. The incidence of significant (≥ grade II) aGVHD was 45.7% in ES patients versus 22.9% in non-ES patients. The incidence of chronic GVHD was similar in both groups (63.6% in ES patients vs. 68.0% in non-ES patients). Loss of donor chimerism (LDC) was seen at a lower rate in ES patients (15.2%) vs. non-ES patients (36.4%). Conversely, full donor chimerism (FDC) was higher in ES patients (48.5%) versus non-ES patients (36.4%). Corticosteroids were administered based on clinical suspicion of ES. Thirty two (91.4%) of ES patients and nineteen (54.3%) of non-ES patients received steroids. Resolution of clinical abnormalities occurred in twenty seven (84.4%) of ES patients and eighteen (94.7%) of patients who did not fulfill the criteria for ES. In conclusion, patients with ES had a higher propensity to develop clinically significant acute GVHD, suggesting that ES may represent early GVHD. However, those who developed LDC and ES had indistinguishable clinical presentations of their ES. Thus, ES represents heterogeneous populations of patients with diverse immunologic alloreactivity (either GVH or HVG reactivity). The high incidence of ES (and of both GVHD and LDC) in this population of patients suggests that competing GVH and HVG alloreactivity following nonmyeloablative conditioning (and in all likelihood the occurrence of a “cytokine storm”) might be responsible for the clinical manifestations of this syndrome.

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