High Prognostic Impact of Mixed Chimerism of Blood and Marrow In the First Year After Allogeneic Hematopoietic Stem Cell Transplantation: The Need to Rapidly Establish Complete Donor Chimerism.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3464-3464
Author(s):  
Ellen Meijer ◽  
Lucia Duinhouwer ◽  
Eric Braakman ◽  
Joke Boonstra ◽  
Inge de Greef ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Progression Free Survival ◽  
Disease Recurrence ◽  
Mixed Chimerism ◽  
P Value ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Post Transplant ◽  
Donor Chimerism

Abstract Abstract 3464 Introduction: Monitoring hematopoietic chimerism following allogeneic hematopoietic stem cell transplantation (alloSCT) after non-myeloablative (NMA) conditioning is commonly used to document engraftment. While mixed chimerism (MC) is frequently observed after NMA alloSCT, it occurs only rarely after myeloablative (MA) alloSCT. Persistent mixed chimerism is generally considered a risk factor for both relapse and rejection of the donor graft, irrespective of the type of conditioning regimen. However, it is still unknown to what extent mixed chimerism quantitatively predicts for relapse and whether patients at high risk for relapse can accurately be identified by assaying chimerism in either blood, marrow, and/or T cells. Therefore, we prospectively evaluated the establishment of complete and mixed chimerism in blood, marrow, and CD3+ selected T cells at 3, 6 and 12 months following alloSCT to investigate the predictive value of mixed chimerism in either subset for relapse. Methods: The study cohort included 152 recipients of an alloSCT, performed between October 2005 and December 2009 because of hematological malignancies (AML: n=61, ALL: n=25, NHL: n=18, Myeloma: n=15, CML: n=5, CLL: n=18, MDS: n=6, MPN: n=4). Median age was 50 years (range 17–67). Seventy-eight patients received a sibling donor transplant, 74 a transplant from a matched related donor. MA and NMA conditioning consisted of Cyclophosphamide/TBI 1200 cGy (n=45) and Fludarabine/TBI 200cGy (n=107), respectively. Chimerism tests were routinely performed in bone marrow (BM), peripheral blood (PB) and CD3 selected samples at 3, 6 and 12 months post transplant, using PCR and electrophoresis of variable number of tandem repeats or fluorescent in-situ hybridization by sex-chromosome specific probes. Complete (donor) chimerism (CC) was defined as >95% donor hematopoiesis, MC as ≤95% donor hematopoiesis. The cumulative incidence of disease recurrence/progression and progression free survival by chimerism status was evaluated as from 3, 6 and 12 months post transplant and adjusted for type of conditioning, donor type, patient/donor sexe and age. Results: MC appeared very rare after MA conditioning, but was more frequently observed after NMA alloSCT with incidences of BM-MC of 28, 22 and 9% at the 3, 6 and 12 month timepoints, respectively. MC in BM as well as PB samples at 6 and 12 months post transplant was highly predictive for disease recurrence/progression, both after univariate and multivariate analyses (BM: hazard ratio (HR) at 6 months: 3.52 (1.30-9.53 95% confidence interval (CI)), p-value 0.013; at 12 months: 5.42 (1.17-25.13 95%CI), p-value 0.031). The probability to develop a relapse increased to 40% in time if MC was detected at 6 months following transplantation, as compared to 15% in the CC group. MC detected at 12 months resulted in a relapse incidence of ≥50% (Figure 1). Moreover, MC at these timepoints also predicted for decreased progression free survival (BM: HR at 6 months: 2.35 (1.04-5.27 95%CI), p-value 0.039; at 12 months: 9.36 (2.94-29.92 95%CI), p-value 0.000). Chimerism results in CD3+ selected T cell fractions did not show a significant association with relapse/progression or progression free survival. Conclusion: These results show that patients with MC at 6 and 12 months post transplant in either BM or PB are at a 3 to 9 fold higher risk of disease recurrence/progression. T cell chimerism appeared not associated with relapse, which may be explained by a significant different and protracted pattern of kinetics after transplantation as compared to kinetics of PB and BM chimerism, thereby identifying different subgroups of patients. Collectively, this study highlights the need to rapidly establish complete donor chimerism both after MA and NMA alloSCT. The preferred medical intervention in patients with MC after NMA conditioning, however, remains to be established in a prospective study. Disclosures: No relevant conflicts of interest to declare.

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<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.

Prevention of Graft-Versus-Host Disease (GVHD) with Tacrolimus after Allogeneic Grafting for Hematological Malignancies Following Sub-Myeloablative Conditioning.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5321-5321
Author(s):  
Joseph Fay ◽  
Giovanna Saracino ◽  
Edward Agura ◽  
Brian Berryman ◽  
Luis Pineiro ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cumulative Incidence ◽  
Hematological Malignancies ◽  
Chronic Gvhd ◽  
Progression Free Survival ◽  
P Value ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Post Transplant

Abstract Severe acute or chronic GVHD following allogeneic hematopoietic stem cell transplantation therapy (HSCT) has a deleterious effect on the successful treatment of hematological malignancies. We have retrospectively studied mycophenolate mofetil (MMF) and tacrolimus (FK) or cyclosporine (CSA) following allogeneic HCST in the prevention of GVDH and the induction of immune tolerance in 93 patients with hematological malignancies using non-myeolablative pre-transplant conditioning. In the current study, there were 35 patients with leukemia, 36 patients with lymphoma, 12 patients with myelodysplastic syndrome or a myeloproliferative disorder and 10 patients with multiple myeloma. There were 63 women and the median age was 42 (15–75) years. Twenty patients had relapsed after previous autologous or allogeneic HSCT and 45 patients were older than 59 years. The remaining patients had co-morbid medical conditions that precluded the use of chemotherapy/radiotherapy dose-intensive pre-conditioning. Conditioning prior to allogeneic HSCT (94 blood stem cell grafts and 1 marrow graft) was fludarabine (90 mg/m2 in three daily doses) and TBI (200cGy) in 86 patients, fludarabine (120 mg/m2 in 4 daily doses) and cyclophosphamide (50mg/kg) in 5 patients, and TBI (200 cGy) only in 4 patients. Forty-three patients received sibling and 50 unrelated grafts. Median follow-up post transplant is 3.0 (0.2–6.1) years. Five (5.3%) patients did not experience sustained hematological chimerism post-transplant. MMF and FK were administered to 33 recipients and MMF and CSA to 60 recipients. The dose and schedule of MMF, CSA and FK have been published (Laport et al. Blood, 2006 and Fay et al. Blood, 1996.) There was no difference in the degree of HLA mismatching between the two groups of patients. Cumulative incidences were used to estimate the incidence of acute and chronic GVHD, all deaths and disease progressions not related to GVHD being considered as the competing events. The Gray test was used to compare cumulative incidences between groups. The unadjusted cumulative incidence of grade III–IV acute GVHD that required oral or systemic corticosteroid therapy, was 54% (95% CI, 40%–68%) in evaluable patients who received CSA in contrast to 38% (95% CI, 18%–58%) in patients who received FK (p-value=0.25). Furthermore, the unadjusted cumulative incidence of extensive chronic GVHD at 1 year was 45% (95% CI, 32%–58%) for CSA versus 34% (95% CI, 14%–54%) for FK (p-value=0.48). Progression-free survival between patients who received FK or CSA at the time of the analysis of this study is similar (p-value=0.6191). The progression-free survival at 1 year was 43% (95% confidence interval [CI], 24%–62%) for CSA versus 43% (95% CI, 31%–55%) for FK. Analyses of the overall morbidity and the incidence of infectious complications between the 2 groups are ongoing. FK combined with MMF may be superior to CSA and MMF in the prevention of GVHD post sub-myeloablative allogeneic HSCT therapy for hematological malignancies and FK may result in improvement of treatment outcome. We believe further study is warranted.

Post-Transplant Cyclophosphamide and Sirolimus Are Synergistic in Preventing Rejection and Inducing Stable Mixed Chimerism Independently of Regulatory T Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3540-3540 ◽  
Author(s):  
Courtney Fitzhugh ◽  
Matthew M. Hsieh ◽  
Oswald Phang ◽  
Camille Madison ◽  
Leo Luznik ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Regulatory T Cells ◽  
Synergistic Effect ◽  
Bone Marrow Cells ◽  
Mixed Chimerism ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Donor Chimerism ◽  
Marrow Cells

Abstract Abstract 3540 Poster Board III-477 A strategy that can induce stable mixed chimerism across human leukocyte antigen (HLA) barriers would be beneficial in extending the application of hematopoietic stem cell transplantation (HSCT) to patients with severe sickle cell disease (SCD) who are in need of this potentially curative procedure. Indeed, we have recently demonstrated the feasibility of an HLA-matched sibling protocol employing low dose total body irradiation (TBI, 300cGy), the lymphocyte depleting agent alemtuzumab, and sirolimus to reverse the phenotype with minimal side effects. Due to the lack of HLA-matched siblings in the majority of patients, our goal is to develop a safe haploidentical regimen. In this work, we focused on determining optimal postgrafting immunosuppression and examined sirolimus and post-transplant cyclophosphamide (PT-cy), agents known to induce transplantation tolerance. To determine the optimal sequence for combining these drugs and whether this combination is synergistic in promoting stable donor chimerism despite the antiproliferative effects of sirolimus, we used a mismatched murine model with BalbC donors and C57Bl6 recipients. Twenty-five to 40 recipient mice received 200cGy TBI and PT-cy (200mg/kg intraperitoneally (IP) 2 days post transplant) with or without sirolimus (3mg/kg IP) for 14 to 30 days starting 1 day before or 4, 6, or 10 days post transplant. We found that in contrast to sirolimus or PT-cy alone, the combination of PT-cy and a limited course of sirolimus resulted in stable mixed chimerism: all mice that received PT-cy and sirolimus starting between 1 day before and 6 days after transplant attained donor chimerism levels ranging from 15-35%. Further, a 14 day course of sirolimus was sufficient to maintain stable mixed chimerism in our model (See Figures 1 and 2). To examine whether this synergistic effect is mediated by regulatory T cells, we administered anti-CD25 monoclonal antibody (CD25 mAb), an agent known to transiently deplete these cells in vivo. Fifteen mice received 200cGy TBI, sirolimus, PT-Cy, and either no CD25 mab, CD25 mab (1mg IP) on 7 and 3 days before and 1 day after transplant, or CD25 mab starting 14 days after transplant. CD25 mab was given biweekly for 5 weeks to mice in both groups. Donor engraftment levels did not differ in the three groups, with donor chimerism levels ranging from 30-40%. Our data show that the anti-proliferative effects of sirolimus do not inhibit the efficacy of the cytotoxic agent cyclophosphamide. Rather, our data demonstrate that the combination of PT-cy and a limited course of sirolimus synergistically promote mixed bone marrow chimerism in a complete mismatched setting. Further, the synergistic effect of this drug combination appears to be mediated independently from CD25+ regulatory T cell expression. In light of our previous success using sirolimus in an HLA-matched HSCT protocol, these findings lay the groundwork for developing PT-cy and sirolimus as a novel, safe, and effective means of promoting stable mixed chimerism in the haploidentical setting and thus greatly enhancing our ability to successfully apply this approach to patients with severe SCD. Figure 1 PT-cy and sirolimus are synergistic. 25 to 40 C57BI6 mice received 200cGy TBI, 22-25 × 106 bone marrow cells from BalbC mice, and PT-cy (Cy) 200mg/kg IP 2 days post transplant with or without sirolimus (Sir) 3mg/kg IP for 30 days starting from 1 day before to 4 days after transplant. Figure 1. PT-cy and sirolimus are synergistic. 25 to 40 C57BI6 mice received 200cGy TBI, 22-25 × 106 bone marrow cells from BalbC mice, and PT-cy (Cy) 200mg/kg IP 2 days post transplant with or without sirolimus (Sir) 3mg/kg IP for 30 days starting from 1 day before to 4 days after transplant. Figure 2 Fourteen days of sirolimus is sufficient to maintain stable mixed chimerism. 25 to 40 C57BI6 mice received 200cGy TBI, 22-25 × 106 bone marrow cells from BalbC mice, and PT-cy (Cy) 200mg/kg IP 2 days post transplant with or without sirolimus (Sir) 3mg/kg IP for 14 days starting from 1 day before to 10 days after transplant. Figure 2. Fourteen days of sirolimus is sufficient to maintain stable mixed chimerism. 25 to 40 C57BI6 mice received 200cGy TBI, 22-25 × 106 bone marrow cells from BalbC mice, and PT-cy (Cy) 200mg/kg IP 2 days post transplant with or without sirolimus (Sir) 3mg/kg IP for 14 days starting from 1 day before to 10 days after transplant. Disclosures: No relevant conflicts of interest to declare.

A Significant Early Detection Of Poor Outcome In Acute Myeloid Leukemia Patients Having a Minimal Residual Disease Using Multiparameter Flow Cytomerty Combined To Mixed Chimerism At Three Months After Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4639-4639
Author(s):  
Florence Beckerich ◽  
Mohamad Sobh ◽  
Stephane Morisset ◽  
Adriana Plesa ◽  
Valerie Dubois ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Disease Recurrence ◽  
Mixed Chimerism ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Minimal Residual ◽  
Acute Myeloid

Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative strategy for acute myeloid leukemia (AML) patients in complete remission (CR) presenting poor prognostic factors or with relapsed/refractory disease. However, the risk for disease recurrence following allo-HSCT remains significant and associated with poor outcomes. After transplantation, the early detection of minimal residual disease (MRD) using immunophenotyping combined to chimerism documentation before morphological relapse may allow for immediate interventions and can lead to better results. Immunophenotyping using Multiparameter Flow Cytometry (MFC) and chimerism documentation by PCR have been widely used to track disease recurrence, although a validated consensus on the use of these techniques in the post-allo-HSCT follow-up has not been established yet. The aim of our study was to evaluate the impact of positive MRD by MFC associated to chimerism documentation at 3 months after allo-HSCT on patients overall and progression-free survival (OS, PFS). Patients and Methods We evaluated 137 AML patients who received allo-HSCT in a single center between January 2005 and October 2012 at our department and for whom a 3 months MRD evaluation and chimerism documentation has been performed using MFC, and PCR analysis. There were 71 (52%) males and 66 females with a median age of 47 years (range: 19-66), 77% had de novo AML, 20% had secondary AML and 3% had biphenotypic AML. According to cytogenetics, 40% were normal, 51% were unfavorable (9% classified as failure). According to molecular markers, 9% were favorable, 31% intermediate, 44% unfavourable and 16% had no molecular markers. At allo-HSCT, 46% of patients were in first complete remission (CR1), 25% were in CR 2 and 29% had active disease; 40% received a full intensity conditioning and 60% got reduced intensity one. As cell source, 35% were bone marrow, 53% peripheral blood and 12% cord blood cells. Donors were related in 53% of the cases (45% were 10/10 HLA matched) and unrelated in 47% of cases (20% were 10/10 HLA matched). MFC was performed using BM samples with a sensitivity of 0.01%. Chimerism analysis was performed on marrow and/or blood samples using polymerase chain reaction (PCR) based on informative polymorphic short tandem repeat with an accuracy of ± 5%, a mixed chimerismwas defined by having 5% or more of recipient cells. Results After transplantation, all patients engrafted, the cumulative incidence of acute GVHD at 3 months was 19.9% (95% CI: 16.2-20.6) while the cumulative incidence of chronic GVHD reached 26.7% (95% CI: 22.9-30.5) at 1 year. After a median follow-up of 16 months (range: 3-77), the median OS was 66 months (65-NR) with a 3 years probability of 64% (95% CI: 56-73), the median PFS was 32 months (13-NR) with a 3 years probability of 50% (95% CI: 37-58) while the transplant related mortality rate reached 13.6% (95% CI: 10-16) at 2 years. The 3 months chimerism evaluation (n=137) showed a mixed chimerism in 12 (9%) patients, while the MFC (n= 62) detected 15 patients with leukemic cells. Sixty eight patients showed morphological relapse after a median time of 4.8 months (1-34.7); the correlation study between MRD positivity, mixed chimerism detection and morphological relapse showed a higher correlation for both chimerism and MFC (correlation=0.69, p<0.001) than if we consider chimerism or MFC alone. Multivariate analysis showed a significant worse OS for patients with 3 months positive MFC [1 year OS of 20% vs. 80%, HR= 4 (95% CI: 1.4-11.7), p=0.01] and patients with mixed chimerism [1 year OS of 21% vs. 70%, HR= 4 (95%CI: 1.3-12.1), p=0.01]; these results were still valid even after stratification on disease status at transplantation. These results applied also in terms of PFS for positive MFC [1 year PFS of 13% vs. 76%, HR= 3.6, p=0.02], and mixed chimerism[1 year PFS of 0% vs. 70%, HR= 7, p=0.001], Figure 1. Conclusion The 3 months MRD evaluation using MFC combined to chimerism documentation seems to be an independent prognostic factor on overall and progression-free survival for AML patients undergoing allo-HSCT. The standardisationof this evaluation may lead to the identification of patients with high relapse risk suggesting the need of early therapeutic intervention. Disclosures: No relevant conflicts of interest to declare.

High Levels of Interleukin-12 Are Associated with Reduced Incidence of Relapse and Death without Increasing Acute Graft-Versus-Host Disease (AGVHD) after Allogeneic Stem Cell Transplantation (SCT).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 295-295
Author(s):  
Vijay Reddy ◽  
Andrew G. Winer ◽  
Erika Eksioglu ◽  
Jeffery Levine ◽  
Herwig-Ulf Meier-Kriesche ◽  
...  
Keyword(s):  
Stem Cell ◽  
Disease Risk ◽  
Significant Risk ◽  
Interleukin 12 ◽  
P Value ◽  
Group Level ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Post Transplant ◽  
Medium Group

Abstract We recently found that a low number of circulating dendritic cells (DC) is predictive of increased relapse, acute GVHD, and poor survival following allogeneic SCT (Reddy V et al, Blood2004;103(11):4330–5). Interleukin-12 (IL-12) is an immunostimulatory cytokine involved in the activation of naïve T cells by DC (Rissoan et al. Science1999;283(5405):1183–6). We hypothesized that patients with high levels of circulating IL-12 in the post transplant period have improved relapse free survival. We studied 134 patients, 120 of whom were evaluable and transplanted during the period of July 1999 to April 2004. Seventy-two patients had transplants from related and 48 from unrelated donors, for predominantly high risk (88%) hematologic malignancies. Median follow up was 1158 days (range 70–1792). Blood samples were collected as baseline prior to conditioning, on day 0 prior to stem cell infusion and during the first week (day 4 and/or 7) after transplant. Plasma IL-12 levels were measured by ELISA. To determine the independent effect of post-transplant IL-12 levels and clinical outcomes, a cluster analysis was performed on the logarithmically transformed mean IL-12 concentration at days 4 and 7 post-transplant. The analysis generated a low, medium and high IL-12 group. Forty-six patients had low levels of IL-12 (median=2 pg/ml, range 0–6.5), 49 patients had medium (median=20.5 pg/ml, range 7–75.5) and 25 patients had high levels (median=181 pg/ml, range 84–623). There was a significant association between IL-12 level and onset of relapse. Using a multivariate Cox model with the low group level as reference, the high IL-12 group level had an adjusted hazard ratio (HR) of 0.27 (95% C.I. 0.09–0.79) and the medium group level a HR of 0.65 (95% C.I. 0.31–1.36). Incidence of relapse at 500 days by Kaplan-Meier analysis by IL-12 group were 23.0% (high group), 40.3% (medium group), and 48.8% (low group). Covariates in the multivariate models were gender match, disease risk, graft source, patient age, donor relation. There was a significant relationship between IL-12 levels and composite death and relapse, the high IL-12 group had a HR of 0.37 (95%C.I.=0.17–0.80) and the medium group a HR of 0.85 (95%.C.I. 0.50–1.45). There was no association between IL-12 levels and risk of AGVHD (p-value=0.51). In addition to IL-12, disease risk was a significant risk factor for the composite endpoint of relapse or death (HR=5.4, p-value=0.0052). The model generated for the outcome of relapse only did not have any additional significant risk factors. In conclusion, high post-transplant levels of IL-12 are associated with less relapse and improved relapse free survival after transplantation. This data suggests that IL-12 administration should be considered as a possible component in studies addressing treatment of relapse after transplantation. Figure Figure

Total Body Irradiation, Etoposide, Cyclophosphamide and Autologous Peripheral Blood Stem Cell Transplantation Followed by Randomization to Therapy with Interleukin-2 Versus Observation for Patients with Non-Hodgkin’s Lymphoma: Results of a Phase III Randomized Trial by the Southwest Oncology Group (SWOG 9438).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 326-326 ◽  
Author(s):  
John A. Thompson ◽  
Richard I. Fisher ◽  
Michael L. LeBlanc ◽  
Joseph M. Unger ◽  
Stephen J. Forman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Peripheral Blood Stem Cell ◽  
Interleukin 2 ◽  
Progression Free Survival ◽  
High Grade ◽  
Survival Estimate ◽  
Free Survival ◽  
Post Transplant ◽  
Total Body

Abstract Purpose: To determine the effect of post-transplant immunotherapy with Interleukin-2 (IL-2) on the progression-free and overall survival of patients with non-Hodgkin’s lymphoma (NHL) after autologous stem cell transplantation and to assess the toxicity of post-transplant IL-2 therapy. Patients and Methods: Patients with previously treated low, intermediate, or high grade NHL (except Working Formulation Groups A and I) were treated with high-dose cyclophosphamide, etoposide, and total body irradiation (TBI) and an autologous peripheral blood stem cell transplant (PBSCT). Twenty-eight to 80 days after PBSCT, patients were randomized to treatment with IL-2 versus observation. Results: Between January 1995 and July 2004, three hundred ninety-four patients with low-grade (n=61) or intermediate-high grade NHL (n=315) were registered at one of 39 SWOG transplant centers. One hundred ninety patients did not proceed to randomization, because of patient refusal (44), grade V toxicity (30), disease progression (28), toxicity (28), or other reasons. Two hundred four patients were randomized to treatment with continuous infusion intravenous IL-2 (9 ×106 units/m2/day for four days followed five days later by 1.6 ×106 units/m2/day for 10 days) versus observation. The 4-year progression-free survival estimate for all eligible patients is 34%, and the 4-year overall survival estimate is 52%. There was no difference in progression-free survival (hazard ratio (HR) of IL-2 to observation = 0.90; p = 0.56) nor in overall survival (HR of IL-2 to observation = 0.88; p = 0.55). There were no deaths related to IL-2 treatment. Grade IV IL-2-related toxicities included hematologic (n=10), cardiovascular (4), renal/bladder (2), flu-like symptoms (1), lung (1), metabolic (1), and neurologic (1) and were reversible in all cases. Conclusions: These results confirm earlier SWOG findings that a regimen of cylophosphamide, etoposide and TBI followed by PBSCT can be administered to patients with relapsed or refractory NHL with acceptable toxicity and with encouraging progression-free and overall survival. Post-transplant therapy with IL-2 given at this dose and schedule of administration had no significant effect on post-transplant relapse, progression-free survival or overall survival.

Impact of Chimerism and Other Transplant Variables on Allogeneic Transplant Outcome after Reduced Intensity Conditioning (RIC) Regimens.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5258-5258
Author(s):  
Veronica Ortiz Corbella ◽  
Quoc-Hung Lê ◽  
Franck E. Nicolini ◽  
Anne Thiébaut ◽  
Xavier Thomas ◽  
...  
Keyword(s):  
Stem Cell ◽  
Myeloid Leukemia ◽  
Mixed Chimerism ◽  
Unrelated Donor ◽  
Linear Regression Method ◽  
Hematopoietic Stem ◽  
Transplant Outcome ◽  
Post Transplant ◽  
The Impact

Abstract RIC regimens followed by allogeneic hematopoietic stem cell transplantation (HSCT) were evaluated in patients with hematologic malignancies who were not candidates for conventional transplantation because of age or medical co-morbidities. In this kind of transplantation, the analysis of chimerism kinetics remains fundamental. The main aims of this study were to evaluate and compare the impact of pre- and post-transplant variables and chimerism on transplantation outcome. Chimerism status was evaluated in total blood (TB) and in purified CD3+ cells using quantitative PCR (STR/SNP) for all. We analysed donor type and kinetics chimerism of 52 patients (32 M - 20 F) who had undergone allogeneic HSCT after RIC for hematological malignancies. Median age was 40 years (range 25–67 years). Diagnosis were multiple myeloma: 16, acute myeloid leukemia: 13, myelodysplasia: 6, chronic lymphocytic leukemia: 5, Non Hodgkin’s lymphoma: 5, acute lymphoblastic leukemia: 1, chronic myeloid leukemia: 2 and primitive myelofibrosis: 4. Conditioning regimens were Fludarabine + Busulfan in 33 patients, Fludarabine + 2 Gys total body irradiation 15, Cyclophasphamide 3 (2 alone/one with Busulfan) and one other chemotherapy. Stem cell source was PB in all except one who received cord blood. Fourty-eight were identical sibling and 4 unrelated donor transplantations. At transplant, 17 patients were in CR, 21 PR and 14 in evolutive diseases. All patients except one engrafted. Twenty-five developed aGVHD ≥ Grade II (16 Grade III-IV). At the last follow-up 22 patients died (9 disease progression and 13 of transplant related mortality, 30 were alive (18 developed chronic graft vs Host disease (cGVHD) 12 extensive/6 limited cGHVD). Among 52 patients, only 49 had a long-term chimerism documentation of CD3 subpopulation (43 TB and CD3+ cells): 15 (14 TB) were full donor chimerism (FDC) throughout the follow-up, and 34 remained mixed chimerism (MC). Among these 34 (29 TB) MC patients at the latest follow-up, 7 (5 TB) remained in MC, 2 (5 TB) converted to recipient profile and 25 (19 TB) converted to donor profile. Univariate analysis demonstrated the close correlation between chimerism status evaluated on PB CD3+ cells only at any time post-transplant and the onset of aGVHD (p = 0.0391) but not cGVHD. Multivariate analysis according to linear regression method did not find any impact of the following variables on chimerism kinetics after RIC transplant: disease status before transplant, age, sex, type of RIC regimen, number of days of ATG, aGVHD (p ≥ 0.11). In conclusion, this study underlines the tight correlation that exists between chimerism status and kinetics on CD3+ PB subpopulations after RIC transplant and acute GVHD development that impacts on transplant outcome.

Kinetics of Engraftment and Predictors of Outcome in Patients with Advanced Chronic Lymphocytic Leukaemia (CLL) After Treatment with Low Dose Total Body Irradiation (TBI) Followed by related or unrelated hematopoietic Stem Cell Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4532-4532
Author(s):  
Karin Hebenstreit ◽  
Simona Iacobelli ◽  
Ann-Kathrin Eisfeld ◽  
Christian Pfrepper ◽  
Thoralf Lange ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Transplantation ◽  
Progression Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Cell Donor ◽  
Donor Chimerism ◽  
The Impact ◽  
Kinetics Of

Abstract Abstract 4532 Introduction: In an unicenter analysis we investigated the impact of allogeneic hematopoietic cell transplantation (RIC-HCT) after reduced intensity conditioning on the kinetics of engraftment and predictor of outcome in 50 patients with advanced CLL. Patient and Methods: Patients in advanced stage CLL (n=50) received Fludarabine 30mg/m2 on day -4 to -2 and 2Gy TBI on day 0 followed by cyclosporine and MMF from unrelated (n=40) or related (n=10) donors between June 1999 and March 2010 at the University of Leipzig. The majority of patients (n= 35) were male, had Binet C (n=37, 74%) at RIC-HCT. The median age was 58 (range 44–69) years. Of 48 patients for whom cytogenetic analyses were available, 22 (46%) had unfavourable cytogenetics including del 17 or del 11q. Three (6%) patients had CR, 27 (54%) PR, 7 (14%) progressive disease, 12 (24%) stable disease and one (5%) relapse at RIC-HCT. Resistance to first line therapy was present in 25 (50%) patients, whereas 12 (24%) were resistant to Fludarabine. Richter’s transformation was found in six patients (12%). Chimerism was detected in bone marrow and peripheral blood on T-lymphocytes and B-lymphocyte subpopulation after sorting at monthly intervals in the posttransplant period and than in 6 months interval. Results: Hematological toxicities after RIC-HCT were moderate. The majority of patients (96%) engrafted with neutrophiles &gt;500/μ L median at day 22 after HCT. Six (12%) and 15 (30%) patients maintained absolute neutrophil counts (ANC) &gt;0,5 × 109/L and platelet counts &gt;50 × 109/L, respectively. T-cell donor chimerism increased to &gt;95% at day 56 and B-cell donor chimerism to 94% at day +360, respectively. B-CLL cells disappeared completely on day +360 (median 0%). Overall survival (OS) at 4 years was 51%, Non relapse related mortality (NRM) 30%, Progression-free survival 33% and progression/relapse 37%. The most common causes of NRM were GvHD (n= 7; 14%) and sepsis (n=3, 6%). Factors significantly associated with increased risk of relapse/progression were intermediate/advanced disease vs. CR/PR1 (p=0.022) and lymphocytes ≥ 5 × 109/L vs. &lt; 5 × 109/L (18% vs. 58%, p= 0.00) at 12 months in univariate analysis. Conclusion: Full donor T-cell chimerism was reached early after HCT, while B-cell reconstitution was observed only 1.5 years after RIC-HCT despite the absence of evident disease by 360 days after RIC-HCT. Best predictor for Progression-free survival (PFS) was CR or PR1. Disclosures: Pönisch: Mundipharma: Honoraria, Research Funding.

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