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.

Converting Mixed Chimerism to Full Donor Chimerism in Recipients of Campath-Containing Reduced Intensity Transplants Reduces the Relapse Risk and Results in Significantly Improved Survival Compared to Those with Persistent Full Donor Chimerism.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2026-2026
Author(s):  
Bronwen E. Shaw ◽  
Jenny L. Byrne ◽  
Emma Das-Gupta ◽  
Ian Carter ◽  
Nigel H. Russell
Keyword(s):  
Residual Disease ◽  
Complete Response ◽  
Disease Relapse ◽  
Post Transplant ◽  
Donor Chimerism ◽  
Group A ◽  
Group B ◽  
The Impact ◽  
Group D ◽  
Reduced Intensity

Abstract Donor leucocyte infusions (DLI) are frequently required following reduced intensity conditioned (RIC) allografts to convert mixed donor chimerism (MC) to full donor chimerism (FDC). The rationale is to prevent tolerance developing and therefore to maximise the graft versus tumour (GvT) responses. However, the impact that the chimeric state has on disease relapse and transplant outcome remains controversial. To address this we analysed the impact of the complete (global) chimerism pattern in 125 recipients of RIC transplants. The transplants were performed for a broad range of malignant haematological diseases. Conditioning regimens consisted of fludarabine, melphalan, campath (65), fludarabine, busulphan, campath (13), BEAM, campath +/− fludarabine (38) and other (9). The donors were HLA matched siblings (62, 50%), HLA mismatched siblings (6, 5%), matched unrelated (29, 23%) and mismatched unrelated (28, 22%). The median patient age was 52 and donor age was 42. The median follow up was 823 days (range 99–2674). Four patterns of chimerism were seen: A. always 100% donor chimerism (68, 54%), B. persisting MC post transplant including cases refractory to DLI (27, 22%) C. MC post transplant with subsequently development of FDC either spontaneously or post DLI (22, 18%), D. lost DC and had autologous reconstitution (8, 6%). A number of patients in both groups B and C had FDC early post transplant. In group A 18 (26%) patients received DLI for relapse or residual disease. A complete response was achieved in 6 (35%). In group B 10 (37%) patients had DLI: 4 for MC, 1 for residual disease, 2 for relapse and 3 for both MC and relapse; only partial responses were seen (20%). In group C DLI was given in 14 (64%) patients: 4 for MC, 5 for residual disease, 3 for relapse and 2 for both MC and relapse. A complete response was achieved in 12 (86%). The risk of relapse at 2 years was significantly associated with the pattern of chimerism (p=0.012) and was greatest for group D (75%). Patients in group C (DLI responders) had a relapse rate of 24% compared to 61% in group B (DLI non-responders). In group A it was 37%. This resulted in a significant survival advantage for patients in group C as compared to all other groups (p=0.009). Predicted overall survival at 2 years was 95% in group C, but 54% in group A, 57% in group B, and 58% in group D. We conclude that patients with MC who later achieve FDC have a lower incidence of disease relapse than those with persistent MC, supporting the use of DLI in this group. However the observation that the patients receiving DLI to achieve FDC have a superior outcome to those patients with persistent FDC (group A) suggests that this group may have benefited from a GvT effect against minimal residual disease. The use of pre-emptive DLI in this group (despite FDC) may reduce the risk of relapse and improve transplant outcome.

Results of a Prospective Clinical Trial of Pre-DLI Lymphoreduction Using Oral Fludarabine In Patients with Mixed Chimerism Post Allogeneic Transplant.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1299-1299
Author(s):  
Bronwen E. Shaw ◽  
Jenny Byrne ◽  
Emma Das-Gupta ◽  
Mark Ethell ◽  
Daniel Figueroa ◽  
...  
Keyword(s):  
Single Dose ◽  
T Cell ◽  
Lymphocyte Count ◽  
Response Rates ◽  
Mixed Chimerism ◽  
Disease Relapse ◽  
Time Points ◽  
Post Transplant ◽  
Donor Chimerism ◽  
Reduced Intensity

Abstract Abstract 1299 Donor leukocyte infusions (DLI) are frequently used following reduced intensity conditioned (RIC) transplants to convert mixed donor chimerism (MC) to full donor chimerism (FDC). In part, due to the significant correlation, which several studies have shown between persisting MC and an increased risk of disease relapse. There are few factors which have been consistently shown to predict for responsiveness. We recently reported response rates (conversion to FDC) of approximately 50% in patients with MC. Patients with a high peripheral blood lymphocyte count pre-DLI were significantly less likely to respond than patients with a low lymphocyte count (33% compared to 89%) (Shaw BE et al, BBMT 2007;13(5):550-9). Based on these and other data we hypothesised that the use of a lymphoreducing agent pre-DLI in those with a high lymphocyte count would enhance DLI responsiveness and hence improve clinical outcomes. We instituted a prospective pilot trial (CCR2942) to investigate this hypothesis. Inclusion criteria were: 1. mixed chimerism in whole blood (< 95% donor), 2. previous reduced intensity transplant for a haematological malignancy or failure to respond to a previous dose of DLI and 3. a lymphocyte count of >1.0 × 109/l. Patients consenting to the trial received three doses of oral fludarabine as an outpatient at 25mg/m2 on day -7, -6 and -5. DLI was given on day 0. The starting dose of DLI for patients with MC alone was 5 × 105 CD3/kg (unrelated donor) or 1 × 106 CD3/kg (sibling donor). Higher doses were used in those with evidence of both disease and MC. Samples were collected at various time points for Ki67 and T cell subset analysis. To date, 15 patients have been entered onto the trial and 13 have reached the study end point (day 90 chimerism) (1 early death due to leukaemia relapse, 1 currently too early for assessment). Each received a single dose of DLI. The disease categories were: AML (8), ALL (1), MDS (2), T-PLL (1), HD (1), DLBCL (1) and MCL (1). Only 2 patients had co-existing evidence of disease (morphological relapse of AML, 2% positive by immunophenotyping in T-PLL). The mean age was 51 years (range: 22–66), 9 males and 6 females. 11 HLA-matched sibling donors and 4 10/10 allele matched unrelated donors. The majority of patients (11) had conditioning with fludarabine, melphalan and alemtuzumab, with cyclosporine post transplant. The median time to DLI post-transplant was 7.2 months (range: 3–11). The median percentage of donor chimerism pre-DLI was 85% (range: 18–93). The median lymphocyte count pre-DLI was 1.3 (range: 1.0–2.7). Of the 13 eligible patients, 9 (69%) have responded to a single dose of DLI (CR=8 (>95%), PR=1 (chimerism 94% donor at study end)). Three patients developed GvHD – grade 1 (liver), grade III (liver/GI), grade IV (liver/skin). GVHD resolved completely in all cases and all patients achieved FDC. 3 patients reactivated a virus (CMV, 2 × EBV), although not all required treatment. The chimerism level pre-transplant was associated with response, with those below the median having a trend towards a worse response rate (p=0.052, Fishers exact test). As only 2 patients had measurable disease at study entry, this parameter was not statistically assessed, however the patient with a frank relapse of AML progressed rapidly despite DLI, suggesting that this strategy may not be sufficiently aggressive in that setting. We analysed the patterns in T cell subsets (CD8, CD4 and Tregs). There was a significant decrease in the absolute numbers of CD8 and CD4 cells between day -7 and day 0, while the absolute number of Tregs was not significantly changed. Interestingly, we found significantly higher absolute counts at all time points in both CD8 and Treg subsets in the DLI responders, compared to non-responders (unpaired t-test, mean: 13.66 vs 0.03, p<0.0001 and mean: 0.018 vs 0.008, p<0.004 respectively). There were no significant differences in CD4 counts. In conclusion, in patients with MC, the use of pre-DLI lymphoreduction results in good response rates, superior to a historical cohort. The incidence of GVHD and adverse events is low. Preliminary finding suggest that both CD8 and Treg subsets may play a role in responsiveness. For patients with very low levels of donor chimerism or frank disease relapse an increased intensity of pre-DLI chemotherapy is likely to be necessary. Larger patient numbers and randomised studies are required to investigate the efficacy of this approach further. Disclosures: No relevant conflicts of interest to declare.

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 &gt;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 (&lt;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 &gt;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(&gt;70%) may be sufficient to acheive an allo-immune effect in majority of patients.

Dendritic Cells Recovery and Chimerism after Reduced Intensity Hematopoietic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5341-5341
Author(s):  
Reza Tabrizi ◽  
Francis Belloc ◽  
Xavier Lafarge ◽  
Virginie Perreau ◽  
Krimo Bouabdallah ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Stem Cell ◽  
Conditioning Regimen ◽  
Mixed Chimerism ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Sibling Donor ◽  
Donor Chimerism ◽  
Reduced Intensity

Abstract The circulating dendritic cells (DC) are known to have an immunoregulatory role after allogeneic HSC transplantation, and recipient DC have been shown to be important in the development of GVHD in animal model. We studied the DC chimerism of 21 patients (pts) transplanted with reduced intensity conditioning regimen between January 2004 and August 2005. The blood was sampled at days -1, 15, 28 and 56 after transplantation. A series of 17 control normal bloods were also analyzed. DC were identified as ILT3-expressing cells negative for CD14. These cells were sorted by flow cytometry and chimerism was analyzed by PCR of Short Tandem Repeat motifs. Preliminary experiments showed that at least 500 sorted cells were necessary to perform chimerism analysis. Eight females and 13 males (median of age: 54 yrs; 25–61) were enrolled in the study. Diagnoses were 6 AML, 2 sAML, 1 MDS, 3 ALL, 6 MM, 2 NHL and 1 CML. Fifteen pts had high-risk disease. As conditioning regimen, all but 3 pts received cumulative dose of ATG (Thymoglobulin, Genzyme, Lyon, France) (2.5 mg/kg for sibling and 7.5 mg/kg for MUD), in addition to Busulfan 8 mg/kg and Fludarabine 150mg/m2. Eight pts received stem cells from a 10/10 MUD, 2 pts from 9/10 MUD, and 11 pts from sibling donor. For all but one patient, the stem cell source was blood. CsA alone was used for 11 pts, CsA with methotrexate for 8 pts and CsA with MMF for 2 pts. In the absence of aGVHD, the immunosuppressive therapy was tapered within 4 weeks (after day 28 in sibling donor and after day 90 for MUD). The kinetics of the absolute number of DC showed significantly lower count of circulating DC than in control samples at day -1, and a rapid increase, reaching normal values at day 15 post-transplant while the other leukocytes remained at a low value. To determine the origin of post-transplant blood DC, chimerism was analyzed on sorted DC. From 20 pts DC chimerism at day 15 was of full donor origin for 8 pts, mixed in 10 pts. Two pts had no detectable DC. At day 28 from 18 pts, only 4 pts had mixed chimerism. Of these 4 pts, 3 presented at day 56 a full donor chimerism and one patient died from relapse. For T cells at day 15, only one/17 pt had full donor chimerism, and one had no detectable circulating T cells. At day 28, 7/20 pts had full donor chimerism and one without detectable T cells. Only 2/17 had still mixed chimerism at 3 months. Six out of 21 pts relapsed and 3 died from relapse. Among these 6 pts, all but one reached full donor T cells, 3 had a full donor DC at day 28. Six pts from 21 had grade ≥ 2 aGVHD and 3 died from aGVHD. 7/17 evaluable pts had cGVHD. We didn’t found any correlation between DC chimerism and engraftment or relapse. At day 15, the median percentage of recipient DC was lower in pts who developed cGVHD (P&lt;0.017) while it was higher in those with aGVHD (but p not significant). In conclusion, this study demonstrates that the circulating DC pool is rapidly reconstituted from both donor and recipient origins. Thereafter at day 28, donor engraftment of DC became predominant. The median of recipient DC was significantly higher in pts without cGVHD. An analysis on a larger series would be useful to determine if the chimerism in DC could be predictive for cGVHD.

Absolute Lymphocyte Count Recovery Predicts Post Transplant Outcomes in Peripheral Blood Haploidentical Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4698-4698
Author(s):  
Jason Thomas Romancik ◽  
Michael Slade ◽  
John F DiPersio ◽  
Peter Westervelt ◽  
Kathryn Trinkaus ◽  
...  
Keyword(s):  
Lymphocyte Count ◽  
Immune Reconstitution ◽  
Acute Gvhd ◽  
Absolute Lymphocyte Count ◽  
Demographic Characteristics ◽  
Post Transplant ◽  
Significant Difference ◽  
The Impact ◽  
Time Point

Abstract Background: Hematopoietic cell transplantation (HCT) is the only curative therapy for many patients with hematologic malignancies. In matched related donor (MRD) and matched unrelated donor (MUD) transplants, absolute lymphocyte count (ALC) recovery has been used as a surrogate marker for immune reconstitution, and a faster rate of ALC recovery is associated with improved overall survival (OS), relapse-free survival (RFS), and transplant-related mortality (TRM). Higher ALC counts have also been associated with higher rates of graft-versus-host disease (GVHD). For patients that do not have an HLA-matched donor available, haploidentical transplant (haplo-HCT) is now a viable option. Less is known about the impact of ALC recovery on outcome in the setting of haploidentical transplant with post-transplant cyclophosphamide (PTCy). Methods: In this study we retrospectively evaluated all patients who underwent haplo-HCT with post-transplant cyclophosphamide (PTCy) at our institution between June 2009 and January 2016. ALC and total white blood cell (WBC) count at days 30, 100, 180, and 365 post-transplant were collected along with demographics, treatment details, and outcome measures (OS, RFS, NRM, acute GVHD, and severe chronic GHVD). Since ALC is a component of total WBC used to assess for immune reconstitution, we performed additional analysis to assess if a high ALC relative to total WBC Ð or conversely, a low ALC relative to total WBC Ð had an effect on outcomes. At each time point, patients were divided into subgroups based on percentile of total WBC. Individual survival curves were generated for each subgroup for comparison. Cox proportional hazard models were used to measure the association between ALC and each outcome. The proportional hazards assumptions and functional assessment of ALC values were carried out using the K-S test and simulated martingale residuals. ALC was analyzed on a log scale to improve the fit of these models. Results: Of 141 evaluable patients, 128 survived to day 30 and were included in analysis. Clinical characteristics are summarized in table 1. At day 30, 100, 180 and 365 there were128, 99, 78 and 48 patients were alive, respectively. A high ALC at day 180 following transplant was associated with improved OS (mean ALC 915, HR 0.61, 95% CI 0.39-0.953; p = 0.030) and RFS (mean ALC 912, HR 0.593, 95% CI 0.422-0.834, p = 0.003). Furthermore, a higher ALC at day 100 was found to be associated with improved TRM (mean ALC 528, HR 0.54, 95% CI 0.35-0.84, p = 0.006). ALC was not associated with acute GVHD at any of the four time points. Severe chronic GVHD only occurred in 4 patients and therefore was not modeled. While a high ALC remained a significant predictor of improved OS, RFS, and TRM, there was no statistically significant difference between subgroups adjusted for percentile of WBC at each time point. Conclusions: ALC recovery is associated with improved OS, RFS, and TRM. Our results suggest that ALC is a useful prognostic marker for patients undergoing haploidentical HCT with post-transplant cyclophosphamide. Further studies examining immune reconstitution in this setting are planned, including the recovery of various T cell and NK cell subsets and their potential impact on outcomes after haplo-HCT using PTCy. Table 1 Clinical and demographic characteristics of patients undergoing haplo-HCT with PTCy. Table 1. Clinical and demographic characteristics of patients undergoing haplo-HCT with PTCy. Figure 1 Months to outcome or last follow-up by ALC, adjusted for percentile of total WBC. Figure 1. Months to outcome or last follow-up by ALC, adjusted for percentile of total WBC. Disclosures No relevant conflicts of interest to declare.

Donor Lymphocyte Infusion Is an Effective Management of Increasing Mixed Chimerism, and High Risk Disease with Minimal Side Effects.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3672-3672
Author(s):  
Geothy Kochethu ◽  
Leena Karnik ◽  
Ginny Turner ◽  
Mike Griffiths ◽  
Mark Velangi ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Residual Disease ◽  
Donor Lymphocyte Infusion ◽  
Mixed Chimerism ◽  
Malignant Diseases ◽  
Post Transplant ◽  
Cell Dose ◽  
The Impact ◽  
Cmv Reactivation

Abstract The increasing use of donor lymphocyte infusion (DLI) in both non-malignant and malignant diseases has demonstrated its potential use in cases with either increasing mixed chimerism (i-MC) or minimal residual disease (MRD) post transplant. Little data is available on the efficacy of this therapy in children. We performed a retrospective analysis of 31 consecutive patients who received DLI at Birmingham Children’s Hospital from 1998–2006. 18 patients (58%) had malignant illnesses (5 ALL, 6 AML, 1CML, 4JMML, 1 Hodgkin’s disease, 1 MDS). 13 patients (42%) had non-malignant conditions (3 aplastic anaemia, 1 glycogen storage disorder, 2 FHLH, 2 osteopetrosis, 5 thalassemia major). There were 19 haploidentical (61%) (6 fully matched), 8 unrelated (26%) and 4 sibling (13%) transplants. 15 (48%) were female and 16 (52%) were male. Mean age was 5 years (range 2 months to 16 years). Radiotherapy and non-radiotherapy based myeloablative conditioning regimes were used. 27/31 (87%) grafts were T cell depleted by CD34 selection and were given a T-cell dose between 1×104–105/kg CD3 cells. The mean CD34 cell dose for the haploidentical transplants was 14× 106/kg (range3.63–36.6× 106/kg) and for the allografts was 5.75 ×106/kg (range 1–15 ×106/kg). 19 (61%) patients were at risk of CMV reactivation. The main indications for DLI in the malignant cohort werepost-transplant or extramedullary relapse andidentification of locally-determined pre-transplant high risk features.17/31 (55%) patients satisfied these criteria, of which 11(65%) are alive and 5 (35%) dead. After prompt withdrawal of cyclosporin, upto seven escalating doses of DLI were given to this group till they show signs of GVHD. One to 2 doses of fludarabine 25mg/m2 were given to 7 patients for further immunosuppression, irrespective of their conditioning, prior to their second or subsequent DLI. 14/31 (45%) patients with i-MC, were treated with graded increments of DLI ranging from 5× ×103/kg–1×108/kg, delivered in 1–7 infusions, majority receiving 2 or 3. 10/14 (71%) had complete donor chimerism post DLI. Though 4 (29%) patients failed to show improvement in their chimerism, 2/4 had non malignant diseases and have stable mixed chimerism and 2/4 who had JMML had full autologous reconstitution with normal haemopoiesis. In the whole cohort, 87% had Grade 1–2 skin GVHD or no GVHD. Only 4/31 (13%) patients had severe morbidity due to Grade 3–4 GVHD and all responded to conventional treatment. There were no cases with CMV reactivation. One patient had graft aplasia from which he recovered after temporary cessation of DLI. There were 7 deaths. 6 patients died from relapsed disease. 1 patient given DLI for i-MC, died of streptococcal pneumonia due to non-compliance with penicillin V. Our experience in this age group demonstrates two main pointsDLI can be delivered safely in the setting of high risk malignant disease post transplant but further work is needed to define efficacy.The correction of i-MC with DLI can be achieved with minimal morbidity and mortality. In addition, the use of fludarabine enhances the impact of DLI but carries a theoretical risk of precipitating severe GVHD. No child died as a result of GVHD and to date 24/31 (77%) of the group survive disease free.

TCRbeta Gene Rearrangements for Detection and Monitoring of Minimal Residual Disease after Allogenic Stem-Cell Transplantation in Patients with Advanced Mycosis Fungoides and Sézary Syndrome.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2340-2340
Author(s):  
Laura Corti ◽  
Giorgia Saporiti ◽  
Elisa Fermo ◽  
Emilio Berti ◽  
Luigia Venegoni ◽  
...  
Keyword(s):  
Stem Cell ◽  
Residual Disease ◽  
Patient Specific ◽  
Gene Rearrangements ◽  
Post Transplant ◽  
Donor Chimerism ◽  
Skin Biopsies ◽  
Pcr Assays ◽  
Minimal Residual ◽  
Reduced Intensity

Abstract Advanced tumor-stage mycosis fungoides (MF) and Sézary syndrome (SS) are cutaneous T-cell lymphomas (CTCL) characterized by very poor prognosis. Allogeneic haematopoietic stem cell transplantation (allo-SCT) represents an experimental treatment which has been shown to be very effective in achieving long lasting complete remission, possibly leading to cure in selected patients. However, high transplant-related mortality (TRM) limit its feasibility in the vast majority of patients with CTCL. Reduced-intensity conditioning regimens have been demonstrated to decrease TRM, allowing gradual establishment of full donor chimerism and possible graft-versus-lymphoma effect. In this setting, evaluation of minimal residual disease (MRD) is particularly useful to guide post-transplant strategies such as donor lymphocyte infusion (DLI). Detection of TCRgamma-chain gene rearrangements, owing to the relatively limited complexity of its genetic elements, is routinely used to detect MRD in T-cell malignancies. Nonetheless, due to the extensive combinatorial repertoire and the large hypervariable regions, TCRbeta represents the best target for MRD monitoring, allowing more sensitive detection of patient-specific rearrangements. With this study, we aimed to identify patient-specific TCRbeta rearrangements to monitor MRD in patients enrolled in a clinical phase II trial of reduced intensity allo-SCT for advanced stage refractory MF/SS. Skin biopsy and peripheral blood samples at diagnosis and at different time points after transplant were obtained from 6 out of 9 evaluable patients, all having achieved clinical complete remission (still enduring in 5). The BIOMED-2 multiplex TCRbeta PCR heteroduplex assay (InVivoScribe Technologies, USA) was used for identification of monoclonal TCRbeta rearrangements, clonal PCR products were directly sequenced in both directions using the complete set of V or J primers, and V, D, J segments identified using the ImMunoGeneTics database (http://imgt.cines.fr). Then, clonespecific PCR assays were performed on samples collected from every single patient and specificity tested by parallel amplification of normal polyclonal DNA samples. In all patients a monoclonal TCRbeta rearrangement has been sequenced allowing to obtain clone-specific primers for PCR assays. In 2 patients we identified the presence of a MRD at the early controls after transplant (+2 and +3 months, respectively) when both were polyclonal by standard TCRgamma rearrangement; clone-specific PCR assays for TCRbeta became negative afterwards, in concomitance with the achievement of full donor chimerism. In 3 patients polyclonality of TCRbeta was observed in all post-transplant controls. One developed chronic cutaneous GvHD and skin biopsies verified the absence of clone-specific T-lymphocytes. In another patient, all post-transplant assays performed by the standard TCRgamma-rearrangement were persistently positive, suggesting the presence of a non disease-specific monoclonality. The last of the 6 patients relapsed 52 months after transplant. Retrospective clone-specific analysis of TCRbeta rearrangements in DNA from skin biopsies unveiled the presence of molecular relapse already 24 months before, whereas standard TCRgamma assays became positive only after clinical relapse. Altogether, we observed good stability of monoclonal TCRbeta rearrangements over time. Our results suggest that the analysis of TCRbeta is more sensitive and more specific than the analysis of standard TCRgamma for detection of MRD in CTCLs, allowing earlier identification of relapses and adopatiention of pre-empatientive treatment such as DLI. With this method, we also demonstrated disappearance of MRD in concomitance with the achievement of full donor chimerism after allo-SCT. Finally, disease clone-specific TCRbeta rearrangement detection might be helpful in distinguishing cutaneous manifestations of acute GvHD from early relapse of MF. TCRbeta analyses of samples from the remaining 3 evaluable patients are ongoing and will be included in the final presentation.

scholarly journals COVID-19 in liver transplant candidates: pretransplant and post-transplant outcomes - an ELITA/ELTR multicentre cohort study

Gut ◽  
2021 ◽  
pp. gutjnl-2021-324879
Author(s):  
Luca Saverio Belli ◽  
Christophe Duvoux ◽  
Paolo Angelo Cortesi ◽  
Rita Facchetti ◽  
Speranta Iacob ◽  
...  
Keyword(s):  
Liver Disease ◽  
Respiratory Failure ◽  
Meld Score ◽  
Decompensated Cirrhosis ◽  
Cox Regression Analysis ◽  
Post Transplant ◽  
End Stage Liver Disease ◽  
Significant Difference ◽  
End Stage ◽  
The Impact

ObjectiveExplore the impact of COVID-19 on patients on the waiting list for liver transplantation (LT) and on their post-LT course.DesignData from consecutive adult LT candidates with COVID-19 were collected across Europe in a dedicated registry and were analysed.ResultsFrom 21 February to 20 November 2020, 136 adult cases with laboratory-confirmed SARS-CoV-2 infection from 33 centres in 11 European countries were collected, with 113 having COVID-19. Thirty-seven (37/113, 32.7%) patients died after a median of 18 (10–30) days, with respiratory failure being the major cause (33/37, 89.2%). The 60-day mortality risk did not significantly change between first (35.3%, 95% CI 23.9% to 50.0%) and second (26.0%, 95% CI 16.2% to 40.2%) waves. Multivariable Cox regression analysis showed Laboratory Model for End-stage Liver Disease (Lab-MELD) score of ≥15 (Model for End-stage Liver Disease (MELD) score 15–19, HR 5.46, 95% CI 1.81 to 16.50; MELD score≥20, HR 5.24, 95% CI 1.77 to 15.55) and dyspnoea on presentation (HR 3.89, 95% CI 2.02 to 7.51) being the two negative independent factors for mortality. Twenty-six patients underwent an LT after a median time of 78.5 (IQR 44–102) days, and 25 (96%) were alive after a median follow-up of 118 days (IQR 31–170).ConclusionsIncreased mortality in LT candidates with COVID-19 (32.7%), reaching 45% in those with decompensated cirrhosis (DC) and Lab-MELD score of ≥15, was observed, with no significant difference between first and second waves of the pandemic. Respiratory failure was the major cause of death. The dismal prognosis of patients with DC supports the adoption of strict preventative measures and the urgent testing of vaccination efficacy in this population. Prior SARS-CoV-2 symptomatic infection did not affect early post-transplant survival (96%).

scholarly journals Anti-Mullerian Hormone (AMH) Level in Presence of Ovarian Endometrioma

2021 ◽  
pp. 71-85
Author(s):  
Nesma F. Radwan ◽  
Ahmed M. El Khyat ◽  
Adel E. El Gergawy ◽  
Hesham A. Salem
Keyword(s):  
Ovarian Reserve ◽  
Harmful Effect ◽  
University Hospital ◽  
Control Group ◽  
Rapid Decline ◽  
Statistical Significant Difference ◽  
Female Patients ◽  
Significant Difference ◽  
Group B ◽  
The Impact

Background: The effect of endometriomas itself on the ovarian responsiveness that relate to ovarian reserve had been reported with several inconsistent results. In one study evaluated women with unilateral endometriomas, ovaries with disease showed lower response to ovarian stimulation than contralateral healthy ovaries .However, recent study on infertile women with un-operated unilateral small endometriomas did not support difference in ovarian responsiveness. The aim was to evaluate the impact of presence of endometriomas on ovarian reserve as measured by circulating AMH. Methods: This retrospective study was carried out on 80 female patients in childbearing period attending outpatient clinic and/or inpatient department of obstetrics and gynecology at Tanat University Hospital and the study was conducted directly after approval in the period from Apri, 2019 till April 2020. Group (A): Study group: 60 female patients aged between 20 to 30 years old GROUP (B): Control group: 20 age matched female with healthy ovaries. Results: there is no statistical significant difference between groups as regard Menarche (years), Regularity and Amount of menstrual blood flow. There is statistical significant difference between groups as regard fixed tender Right Ventricular Failure. But there are no statistical significant differences between groups as regard nodule in rectovaginal septum, fixed tender adnexal masses, association with adenomyosis and infertility. There is highly statistical significant difference between case and control groups as regard AMH levels. there are highly statistical significant positive correlation between duration of endometriosis and each of presence of pelvic pain, cyst diameter and Visual Analogue Scale. Conclusions:    Women with endometrioma have significantly lower serum AMH levels and seem to experience a more rapid decline in serum AMH levels than age matched counterparts, suggesting a harmful effect of endometrioma per se on ovarian reserve.

scholarly journals Perbandingan Efek Pemberian Emulsi Kedelai dan Emulsi Tempe Terhadap Hitung Limfosit Total pada Tikus Putih yang Telah Diberi Prednison

2017 ◽  
Vol 5 (1) ◽  
pp. 56
Author(s):  
Rizka Bekti Nurcahyani ◽  
Imelda T Pardede ◽  
Huriatul Masdar
Keyword(s):  
Lymphocyte Count ◽  
Total Lymphocyte Count ◽  
Distilled Water ◽  
Adequate Nutrition ◽  
White Rats ◽  
Total Lymphocyte ◽  
Significant Difference ◽  
Group A ◽  
Group B

Adequate nutrition is one of important factors in immunodeficiency repairment. Soybean and tempeh contains proteins,zinc, ferrum, vitamins and isoflavon. Fermentation in tempeh makes it having better nutrients digestion and absorptionthan soybean. The objective of this study was to compare the effects of soy and tempeh emulsions on total lymphocytecount in rats treated with prednisone. The test was done on 24 male white rats divided into four groups. Group A wasgiven distilled water and group B, C and D had prednisone 2.5 mg/day for 6 days. After that, group A and B werecontinued having distilled water while groups C or D was fed with soy or tempeh emulsion 0.71 mL/day for 10 days,respectively. The results shown that soy and tempeh emulsion could increase total lymphocyte count significantly (p <0,05) but there was no significant difference of total lymphocyte count between soy and tempeh emulsion groups (p >0,05).

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