scholarly journals Low Incidence of Grade II-IV Acute GVHD Following Tacrolimus and q8h Mycophenolate Mofetil (MMF) Prophylaxis in Pediatric and Young Adult Recipients of Allogeneic Stem Cell Transplantion (AlloSCT)

2015 ◽  
Vol 21 (2) ◽  
pp. S369-S370
Author(s):  
Olga Militano ◽  
M Fevzi Ozkaynak ◽  
Daniel Mitchell ◽  
Karen Wolownik ◽  
Sandra Fabricatore ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mycophenolate Mofetil ◽  
Young Adult ◽  
Acute Gvhd ◽  
Grade Ii ◽  
Low Incidence

Improved Immune Reconstitution Following Pre-Emptive CD8-Depleted Donor Lymphocyte Infusions (DLIs) after Haploidentical Stem Cell Transplantation (SCT) Using a Reduced-Intensity Conditioning (RIC) Regimen.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2908-2908
Author(s):  
Paolo Corradini ◽  
Anna Raganato ◽  
Matteo Carrabba ◽  
Lorenza Gandola ◽  
Claudia Lombardo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Total Dose ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Hematological Malignancies ◽  
Acute Gvhd ◽  
Immune Recovery ◽  
Grade Ii ◽  
The Impact

Abstract Allogeneic stem cell transplantation (SCT) from an haploidentical family donor has been reported as a viable option in acute leukemias when matched donors are unavailable. However, the extensive T-cell depletion (TCD), required to prevent graft-versus-host disease (GVHD), is associated to delayed immune recovery and high transplant-related mortality. In an ongoing phase I–II trial for patients (pts) with advanced hematological malignancies, we combined a RIC regimen, including thiotepa (10 mg/kg), fludarabine (120 mg/ms), cyclophosphamide (60 mg/kg) and TBI (2 Gy), with pre-emptive administration of CD8-depleted DLIs (starting from 1x104 up to 1x105 cells/kg). Ex-vivo and in-vivo TCD were carried out by CD34+ cell selection using the CliniMACS device and alemtuzumab (30 mg day −2), respectively. The aim of the study was to investigate in a dose finding study the safety and the impact on immune-reconstitution of CD8-depleted DLIs. Six-teen pts with hematological malignancies (n=14 NHL/HD, n=1 ALL, n=1 AML) were included, median age was 35 years (range, 15–65), 10 (63%) were chemorefractory, and 68% and 75% had failed a previous auto or at least 3 CT lines, respectively. Pts received a median of 10.6 x106/Kg CD34+ and 1x104/kg CD3+. All pts engrafted with full donor chimerism from day +30. At a median follow-up of 9 months, 12 pts were alive and 4 died (n=1 infection, n=3 disease). The estimated OS at 2 years was 58%; 7 of 16 (44%) relapsed at median time of 100 days after SCT. CD8-depletion of 14 donor lymphocyte aphereses was performed with a new depletion protocol (Clinimacs CD8-Microbeads) that reduces the content of CD8+ cells by at least 3 logs. The median CD3+, CD4+, CD56+/CD3+, CD20+ cell recovery were 62% (range, 35–91%), 88% (63–128%), 51% (8–78%), 76% (33–128%), respectively. Before DLIs, only 1 of 16 pts (6%) developed de novo acute GVHD (grade II). A total of 22 CD8-depleted DLIs were administered to 9 of 16 pts without any engraftment problem. The first cohort of pts (n=5) received a total dose of 3–6x104/kg CD8depleted DLIs starting at day +45 divided in 3 monthly infusions: none of them developed aGVHD. Given no toxicity, we escalated doses and the second cohort (n=4) received a total dose of 10–25x104/kg CD8-depleted DLIs divided in 3 monthly infusions: 3 pts had acute GVHD (grade II). Overall, the incidence of acute GVHD was higher (75% vs 0%, P<0.04) in pts receving larger numbers of donor cells. Interestingly, the median values of CD4+/ul and CD8+/ul were 98 (range, 8–612) and 150 (range, 15–988) at 4 months; 247 (range, 55–333) and 235 (range, 3–1000) at 5 months after SCT. The median value of CD19+/ul cells were 134 (range, 0–292) and 160 (range, 0–256) at 4 and 5 months, respectively. NK cells remained between the value of 394/ul and 569/ul in the first 6 months after SCT. Our results suggest that: (1) haploidentical SCT with RIC regimen is feasible with a high rate of engraftment and a low acute GVHD incidence; (2) pre-emptive CD8-depleted DLIs are feasible without GVHD until the total dose of 6 x104/kg; 3) higher doses can induce acute GVHD, but no grade III–IV was observed; 4) despite the limited number of pts, we observed a faster immune recovery and a relatively low mortality rate for infections.

Comparison between Anti-Thymocyte Globulin and Alemtuzumab and the Possible Impact of KIR-Ligand Mismatch in Melphalan/Fludarabine Dose-Reduced Conditioning Followed by HLA-Matched and Mismatched Unrelated Stem Cell Transplantation in Patients with Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 980-980
Author(s):  
Nicolaus Kroeger ◽  
Brownen Shaw ◽  
Simona Iacobelli ◽  
Tatjana Zabelina ◽  
Karl Peggs ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Statistical Significance ◽  
High Dose ◽  
Grade Ii

Abstract We compared anti-thymocyte globulin (ATG-Fresenius median dose 60 mg/kg: n= 48) with alemtuzumab (Campath-1H 100mg: n=25) in 73 patients with multiple myeloma, who underwent dose-reduced conditioning with melphalan and fludarabine, followed by allogeneic stem cell transplantation from matched (n=63) or mismatched (n=10) unrelated donors. Patients of the ATG group had higher age (median 50 vs 47 years, p=0.05), more prior high-dose chemotherapies (p<0.001), while in the Campath group more bone marrow as stem cell source was used (p<0.001). No primary graft failure occurred in both groups. Patients receiving alemtuzumab had a significant faster engraftment of leukocyte (p=0.03) and of platelets (p=0.02) and a lower incidence of acute GvHD grade II-IV (24 vs 47%, p=0.05). However, after treatment with donor lymphocyte infusion due to persistent disease or mixed hematopoietic chimerism the difference of acute GvHD grade II-IV between alemtuzumab and ATG treated patients did not reach statistical significance (32 vs 47%, p=0.2). No difference in incidence of chronic GvHD was observed (25 vs 33%, p=0.6) More CMV seropositive patients in the alemtuzumab group experienced CMV reactivation (100% vs 47%, p=0.001). The cumulative incidence of treatment related mortality at 2 years for ATG and Campath was 29.3% (CI=17–50%) vs 28.5% (CI=15–54%), p=0.7. No significant difference could be observed in the estimated 2 years OS and PFS between ATG and Campath: 53% (CI:38–75) vs 45% (CI:28–73) and 29% (CI:16–54) and 36% (CI: 20–62), respectively. For PFS, in a multivariate analysis relapse to prior high-dose chemotherapy was the strongest negative factor: HR 2.9, p= 0.001. Including only those patients who did not experienced any relapse at time of allogeneic stem cell transplantation the Campath-group had a 2.5 fold higher risk of progression in comparison to the ATG group, but without reaching statistical significance (HR: 2.5, p=0.15). Ten out of 73 patients had KIR-ligand mismatch in GvH direction. While in patients without KIR-ligand mismatch the cumulative incidence of relapse at two years was 50%, none of the KIR-ligand mismatched patients relapsed so far (p=0.02). The immunosuppressive effect from Campath is stronger than ATG resulting in less acute GvHD, but requires more DLI procedures to control diseases and resulted in a trend to a lower PFS in chemosensitive patients. This preliminary data further implicated a major role of KIR-ligand mismatch transplantation in multiple myeloma

Killer Immunoglobulin-Like Receptor and NOD2/CARD15 Polymorphisms Independently Influence Survival after Allogeneic Hematopoietic Stem Cell Transplanation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2167-2167
Author(s):  
Sebastian Giebel ◽  
Aleksandra Holowecka-Goral ◽  
Izabela Nowak ◽  
Tomasz Czerw ◽  
Jerzy Wojnar ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Kir Genes ◽  
Increased Risk ◽  
Grade Ii ◽  
Card15 Gene ◽  
Grade Iii

Abstract Background: Activating and inhibitory killer immunoglobulin-like receptors (KIRs) regulate function of NK cells and a subset of T cells. KIR genotype, in particular the content of activating KIR genes is highly polymorphic. NOD2/CARD15 protein is broadly expressed in APCs and lymphocytes. Single nucleotide polymorphisms (SNPs) of this gene have been reported to impair the pathogen elimination and trigger pathologic immunologic reactions like GvHD. The goal of this prospective study was to evaluate the impact of donor’s and recipient’s KIR and NOD2/CARD15 genotypes on outcome after allogeneic hematopoietic stem cell transplantation (alloHSCT). Pateints and methods: One-hundred-two consecutive patients with hematological malignancies, aged 32(18–58)y, treated with alloHSCT from HLA-matched related (n=34) or matched unrelated donor (MUD) (n=68) were included. The conditioning regimen was myeloablative, GVHD prophylaxis consisted of CsA, Mtx, and, in case of MUD-HSCT, pre-transplant ATG. Donors and recipients were tested for 11 KIR genes as well as SNP8,12,13 of the NOD2/CARD15 gene. In addition, immune reconstitution including KIR expression on T cells, was analyzed on days +28, +56, +100, +180, and +360. Results: Overall survival (OS) rate at 2y was significantly lower in alloHSCT with at least one activating KIR mismatch compared to transplants with full compatibility (62% vs. 86%, p=0.01). In particular, the presence of at least one activating KIR in the donor with its absence in the recipient (D+R−) was associated with decreased probability of OS (60% vs. 78%, p=0.01) and DFS (58% vs. 82%, p=0.005), as well as increased incidence of non-relapse mortality (NRM) (27% vs. 7%). KIR2DS1 and KIR3DS1 D+R− mismatches resulted in increased risk of grade II–IV acute GvHD, whereas KIR2DS3 and KIR2DS2 D+R− mismatches were associated with increased risk of chronic GvHD. The presence of at least one activating KIR D+R− mismatch was associated with increased CD8+/CD4+ T cell ratio up to day +100. In all cases of incompatibility regarding KIR2DS1, KIR2DS2 and KIR3DS1, T cells with expression of respective receptors could be detected up to 360 days after alloHSCT. The presence of SNP8 of the NOD2/CARD15 gene in the recipient was associated with decreased probability of OS (20% vs. 70%, p=0.005) and DFS (20% vs. 70%, p=0.01) as well as increased incidence of NRM (60% vs. 17%) and grade III–IV acute GvHD (67% vs. 8%). In a multivariate analysis including KIR and NOD2/CARD15 polymorphisms together with other potential risk factors, increasing number of D+R− activating KIR mismatches as a linear variable appeared to independently influence OS (HR: 1.3, p=0.02), DFS (HR: 1.3, p=0.008), NRM (HR: 1.4, p=0.02), grade II–IV acute GvHD (HR: 1.4, p=0.001), and chronic GvHD (HR: 1.2; p=0.02). Recipient SNP8 of NOD2/CARD15 was predictive for OS (HR: 5.5, p=0.003), DFS (HR: 4.4, p=0.008), NRM (HR: 5.9, p=0.006), grade III–IV acute GvHD (HR: 6.1, p=0.02), and chronic GvHD (HR: 3.7; p=0.03). Conclusions: Both activating KIR D+R− mismatches and recipient SNP8 of NOD2/CARD15 appear to enhance alloreactivity and independently influence survival after alloHSCT. Evaluation of these polymorphisms may contribute to better donor selection and optimization of the alloHCT procedure.

A Donor-Derived Tongue Squamous Cell Carcinoma After Allogeneic Peripheral Blood Stem Cell Transplantation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4510-4510
Author(s):  
Yongxian Hu ◽  
Yi Luo ◽  
Yamin Tan ◽  
Jimin Shi ◽  
Jie Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Squamous Cell Carcinoma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cyclosporine A ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
Solid Malignancies ◽  
Grade Ii

Abstract Abstract 4510 Recently the increasing number of cases of solid malignancies developed in recipients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has attracted more attention while less donor-derived solid malignancies after allo-HSCT have been found. We describe here a case of donor-derived tongue squamous cell carcinoma (SCC) in a young adult patient who had undergone allogeneic peripheral stem cell transplantation for acute leukemia 2 years ago. The female patient had a history of acute lymphoblastic leukemia (ALL-L2) at 20 years of age in July 2004 and received a successful busulfan and cyclophosphamide (BU/CY2) myeloablative allografting (allogeneic peripheral blood stem cells) from a HLA-matched unrelated male donor in August 2006. Acute graft versus host disease (GVHD) prophylaxis consisted of cyclosporine A 2.5 mg/kg/day, methotrexate 10 mg on day 1,3,6, and mycophenolate mofetil 0.5 g/day. However, on day 12 the patient developed skin grade II acute GVHD. Subsequently, she complicated with intestinal grade II acute GVHD characterized by recurrent diarrhea on day 49. 2 mg/kg/day of methylprednisolone and 4 mg/kg/day of cyclosporine A were given. 7 days later acute GVHD was controlled gradually. After that, grade II chronic GVHD with skin rash and oral mucositis accompanied by leukoplakia occurred after 5 months post engraftment. Prolonged immunosuppressive agents containing prednisolone and cyclosporine A were administered. In April 2008 (20 months post engraftment), the patient presented with symptoms of pain in the tongue which worsened in the following 2 months. A firm mass was seen in the tongue which was highly suspicious for malignancy. The histology of the puncture biopsy showed a well-differentiated SCC. The neoplastic cells were pleomorphic and prominent nucleoli. Cell nests and keratinous pearls could be seen clearly. Then she was treated with mass excision in addition to supraomohyoid neck dissection immediately. At the same time peripheral blood STR analysis showed full donor's chimerism, and bone marrow aspiration as well as minimal residual disease with FACS indicated complete remission of the primary disease. The patient is now under follow-up with no recurrence or metastasis. Further investigation of the tissue specimens by fluorescent in situ hybridization (FISH) (X,Y probes) combined with double-SP immunohistochemical staining (CD45, Pan-cytokerin) revealed the presence of one Y chromosome-specific signal and one × signal within most of the neoplastic cells which was identified as pan-cytokerin (+), CD45(-) cells and this suggested that donor-derived stem cells might transform into malignancies in the recipient by several potential mechanisms (Hu YX et al, Onkologie 2010). Till now about 13 cases developing donor-derived solid malignancies including oral SCC (Janin A et al, Blood 2009; Tomihara K et al, Head Neck 2009), colonic adenoma (Cogle CR et al, Stem cells 2007), breast adenoma (Golfinopoulos V et al, Breast Cancer Res Treat 2009), gastric adenoma (Arai Y et al, AM J Transplant 2006), larynx squamous cell carcinoma (Avital I et al, Stem cells 2007), Kaposi's sarcoma (Avital I et al, Stem cells 2007), lung adenoma (Avital I et al, Stem cells 2007) and glioblastoma multiforme (Avital I et al, Stem cells 2007) have been reported post-HSCT. The presence of donor-derived solid malignancies suggests that human bone marrow-derived stem cells have a role in the carcinogenesis of solid organ cancer especially in the organ with inflammation. But which kind of bone marrow derived stem cells transformed into solid malignancies and its mechanisms need further investigation. Disclosures: No relevant conflicts of interest to declare.

Clinical Factors Predicting the Response of Acute Graft-Versus-Host Disease to Corticosteroid Therapy.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3046-3046
Author(s):  
Makoto Murata ◽  
Hideki Nakasone ◽  
Junya Kanda ◽  
Takahiko Nakane ◽  
Tatsuo Furukawa ◽  
...  
Keyword(s):  
Stem Cell ◽  
Corticosteroid Therapy ◽  
Acute Gvhd ◽  
Systemic Corticosteroid ◽  
Japanese Patients ◽  
Clinical Factors ◽  
Cell Sources ◽  
Grade Ii ◽  
Probability Of Improvement ◽  
Systemic Corticosteroid Therapy

Abstract Abstract 3046 Systemic corticosteroid therapy is recommended as a first-line treatment for grade II or higher acute graft-versus-host disease (GVHD). Several clinical factors have been reported to be predictive of response to corticosteroid therapy in retrospective studies in which most or all patients received bone marrow transplantation. However, stem cell sources for allogeneic hematopoietic cell transplantation (HCT) dramatically changed with the frequent use of peripheral blood stem cells (PBSCs) and umbilical cord blood (UCB), and no study has compared the response rates of corticosteroid therapy among these stem cell sources. A retrospective study to identify clinical factors affecting the response of grade II-IV acute GVHD to systemic corticosteroid therapy was performed using the national registry data for Japanese patients who received first allogeneic HCT with bone marrow (BM) (n=2004), PBSCs (n=685), and UCB (n=863). Data were analyzed by STATA ver.12 statistical software. This study was approved by the ethical committees of the Nagoya University School of Medicine. Acute GVHD improved in 2259 (63.6%) of the 3552 patients. On multivariate logistic regression analysis, various factors were identified to predict corticosteroid response (Table 1). Interestingly, UCB was significantly associated with a higher probability of improvement, whereas HLA-matched unrelated BM and HLA-mismatched stem cell sources other than UCB were significantly associated with a lower probability of improvement; HLA-matched related PBSC was not significantly different from HLA-matched related BM. The cumulative incidence of non-relapse mortality (NRM) was significantly higher in patients without than with improvement of acute GVHD with corticosteroid therapy (P < 0.0001). On competing risk regression analysis, patients without improvement with corticosteroid therapy were more likely to have NRM than those with improvement [HR, 2.50; 95% CI, 2.18–2.88]. Other factors associated with significantly worse NRM included age 16–49 y and ≥ 50 y (vs. < 16 y), grade III and IV acute GVHD (vs. grade II), and liver involvement of acute GVHD (vs. no involvement). Overall survival (OS) was significantly lower in patients without improvement with corticosteroid therapy than in patients with improvement (29.5% vs. 42.5% at 15y after transplantation) (P < 0.0001). After adjustment by patient age, disease, grade of acute GVHD, and liver involvement of acute GVHD, OS was significantly lower in patients without than in patients with improvement with corticosteroid therapy [HR, 1.63; 95% CI, 1.46–1.81]. The present study demonstrated, for the first time, a higher probability of improvement in grade II-IV acute GVHD with systemic corticosteroid therapy in patients after UCB transplantation than in those after BM and PBSC transplantation. This finding should be considered in the design of future clinical trials of acute GVHD treatment. The response rate to corticosteroid therapy in Japanese patients (63.6%) was comparable to that in Caucasian patients (50–60%) and, when it is ineffective, Japanese patients also show high NRM and low OS. Thus, another important message of this study is that the establishment of a second-line treatment for corticosteroid-refractory acute GVHD is required for not only Caucasian patients but also for Japanese patients. A prospective study to validate the present findings is warranted. Table 1. Factors predicting the response of grade II-IV acute GVHD to systemic corticosteroid therapy Factor Relative risk* (95% CI) P Patient age (y)     <16 1     16–49 1.54 (1.22–1.94) <0.001     ≥50 1.16 (0.91–1.47) 0.239 Stem cell source     HLA-matched related BM 1     HLA-matched related PBSC 0.81 (0.60–1.10) 0.185     HLA-matched unrelated BM 0.59 (0.45–0.78) <0.001     UCB 1.37 (1.01–1.85) <0.041     HLA-mismatched related BM 0.39 (0.26–0.60) <0.001     HLA-mismatched related PBSC 0.43 (0.28–0.64) <0.001     HLA-mismatched unrelated BM 0.60 (0.45–0.81) <0.01 Onset of acute GVHD     ≤day14 1     > day14 1.21 (1.02–1.44) 0.033 Grade of acute GVHD     II 1     III 0.48 (0.39–0.58) <0.001     IV 0.07 (0.05–0.10) <0.001 Liver acute GVHD     No 1     Yes 0.55 (0.45–0.67) <0.001 Gut acute GVHD     No 1     Yes 0.71 (0.59–0.85) <0.001 * Values > 1.0 indicate higher probability of improvement; values < 1.0 indicate lower probability. Disclosures: No relevant conflicts of interest to declare.

Absolute Lymphocyte Count Recovery after Allogeneic Hematopoietic Stem Cell Transplantation Predicts Clinical Outcome

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2499-2499
Author(s):  
Haesook T Kim ◽  
Philippe Armand ◽  
David Frederick ◽  
Emily Andler ◽  
Corey S Cutler ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Progression Free Survival ◽  
Absolute Lymphocyte Count ◽  
Threshold Value ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Grade Ii ◽  
Conditioning Intensity

Abstract To determine the impact of absolute lymphocyte count (ALC) recovery on clinical outcome after allogeneic hematopoietic stem cell transplantation (HSCT) and to determine the threshold value of ALC, we conducted a retrospective study of 1109 adult patients who underwent a first allogeneic HSCT from 2003 through 2009, excluding patients who died or relapsed before D30. The median age was 51 years (range: 18-74) with 52% undergoing reduced intensity HSCT and 48% myeloablative intensity HSCT with T-replete PBSC (93.7%) or marrow (6.4%) grafts; 41% receiving HLA-matched related donors, 51% HLA-matched unrelated donors, and 8.5% HLA-mismatched transplantation. The median follow-up time was 6 years (range: 2.5 – 9.8 years). To determine the threshold value, we randomly split the entire cohort into a training set and a validation set in a 1:1 ratio stratified by conditioning intensity, and then applied a restricted cubic spline (RCS) smoothing method to obtain relative hazard estimates of the relationship between ALC at 1 month and log hazard of progression-free survival. Based on this approach, ALC was categorized as low (≤0.2x 109 cells/L) or normal (>0.2x109 cells/L). For patients with low ALC at 1, 2, or 3 months after HSCT, excluding relapse or death prior to each time point to rule out the direct influence of relapse on the ALC, the overall survival (OS) (p≤0.0001) and progression-free survival (PFS) (p≤0.0002) were significantly lower and non-relapse mortality (p≤0.002) was significantly higher compared to patients with ALC >0.2x109 cells/L at each timepoint, but there was no difference in relapse. Since patients with newly low ALC at 2 or 3 months post HSCT had equally poor outcome as those whose ALC was low at 1 month post HSCT, we combined patients who had low ALC at 1, 2 or 3 months post HSCT and compared their outcome to that of patients who had ALC>0.2x109 cells/L at 1, 2, and 3 months after HSCT. The 5-year OS for patients with low ALC was 28% vs 46% for patients without low ALC (p<0.0001); the corresponding 5-year PFS were 21% vs 39%, p<0.0001 and NRM 40% vs 18%, p<0.0001 (Figure A-C). This result was consistent when other prognostic factors, including occurrence of grade II-IV acute GVHD, were adjusted for in multivariable Cox models stratified by conditioning intensity: HR for OS was 1.52 , p≤0.0001; for PFS, 1.42, p=0.0008; and for NRM, 2.4 p<0.0001 for patients with low ALC within 3 months of HSCT. Low ALC was not significantly associated with relapse (HR 1.01, p=0.92) in the multivariable model. Low ALC early after HSCT is an independent risk factor for increased NRM and poor survival independent of grade II-IV acute GVHD. ALC assessment early after HSCT may be useful to identify high-risk patient cohorts that may benefit from additional therapeutic interventions. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Donor-Derived CIK Cell Infusion As Consolidative Therapy after Non-Myeloablative Allogeneic Transplant in Patients with Myeloid Neoplasms

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3232-3232
Author(s):  
Rupa Narayan ◽  
Jonathan Benjamin ◽  
Ginna Laport ◽  
Lu Tian ◽  
Keri Tate ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Intention To Treat ◽  
Cik Cells ◽  
Myeloid Neoplasms ◽  
Grade Ii ◽  
Low Incidence ◽  
One Year ◽  
Grade Iii

Abstract Introduction: Non-myeloablative conditioning combining total lymphoid irradiation (TLI) with rabbit anti-thymocyte globulin (ATG) has been shown to have a low incidence of non-relapse mortality (NRM) for patients with myeloid neoplasms (Benjamin Biol Blood Marrow Transplant 2014). As with other reduced intensity conditioning regimens, relapse remains the primary cause of treatment failure following allo-HCT using TLI-ATG conditioning. Cytokine induced killer (CIK) cells derived from peripheral blood culture with interferon (IFN)-γ, interleukin (IL)-2, and anti-CD3, have demonstrated anti-tumor effects in vitro, and have been safely administered in a phase I/II study of patients with post-transplant relapse with low incidence of acute GVHD (Laport Biol of Blood and Marrow Transplantation 2011). In an effort to promote conversion to full donor chimerism and reduce the risk of relapse following TLI/ATG conditioning for patients with myeloid neoplasms, we evaluated the addition of donor derived cytokine induced killer (CIK) cells post-HCT. Methods: Here we report interim results for 37 patients enrolled to date in an unplanned analysis. Day+90 full donor chimerism (FDC) was the primary endpoint. Secondary endpoints include overall survival and incidence of acute GVHD. Median age is 64 years (range 37-74) with primary disease of de novo MDS (19, 51.3%), secondary AML (6, 16.2%), MPN (2, 5.4%), and therapy (t-) related myeloid neoplasm (10, 27%; including 4, t-MDS; 4, t-AML; 2, t-MDS/MPN overlap). Of patients with MDS or MDS/MPN overlap, 54% had intermediate-2 IPSS risk classification. Fifteen (40.5%) patients had a morphological complete remission at the time of HCT. Twenty-three (62%) donors were unrelated. Results: Median CD34+ dose was 7.2e6/kg (range 2.3-17e6/kg). Ten patients (27%) did not receive CIK cells; causes included CD34+ cell dose below the threshold for culture inoculation (n=4), acute graft versus host disease (n=2), fever with concern for active infection at the time of scheduled infusion (n=1), or logistical reasons (n=3, including lack of donor consent for CIK infusion, transplant delay, and reagent unavailability). Of the 27 patients receiving CIK cells, 23 received the target dose of 1e8/kg CD3+ CIK product, at a median time of 26 days (range 24-31) post peripheral blood stem cell (PBSC) infusion. The median CD3+, CD3+CD56+, CD3+CD8+NKG2D+, CD8+CD45RO+ cell culture content was 97%, 13%, 51%, and 41%, respectively. Median followup time for living patients is 420 days. Day+90 FDC, defined by 95% or greater donor-type peripheral blood CD3+ cells, was 29%. The incidence of acute GVHD grade II-IV and grade III-IV in the total cohort is 21.6% and 5.4%, respectively. The incidence of chronic GVHD is 19%. Of the 27 patients receiving CIK product, the incidence of acute GVHD grade II-IV is 7.4% with no acute grade III or IV events to date and 22% chronic GVHD. On an intention to treat analysis of enrolled patients, one year NRM 10.5% (95% CI: 0.8%-22.1%) and one year cumulative incidence of relapse 46.3% (95% CI: 28.4%-64.1%) are not significantly different compared to our historical cohort (5.2%, 95%CI: 2.0%-8.4% and 53%, 95%CI: 45.9%-60.1%) respectively. The 1-year OS by intention to treat of 68.6% (95%CI: 54%-87%) is similar to our historical control, 60.8% (95%CI: 54.3%-68.2%, p=0.76). The 1-year OS in the 27 CIK recipients is 75% (95%CI: 59.3%-94.7%). Conclusion: CIK infusion was found to be safe and feasible. There was no increase in grade III-IV acute GVHD or chronic GVHD risk. There was a statistically non-significant trend towards increased one-year survival in our cohort. The potential benefit on overall survival remains to be further evaluated with additional patient enrollment and longer followup. However, given the favorable safety profile of CIK cells, future strategies to enhance efficacy such as repeat dosing or modification of CIK cells are worth potential exploration. Disclosures Benjamin: Amgen, Inc.: Employment, Equity Ownership. Rezvani:Pharmacyclics: Research Funding.

scholarly journals High pre-transplant TREC levels indicate good prognosis after hematopoietic stem cell transplantation

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 1458
Author(s):  
Adriano de Moraes Arantes ◽  
Kharen Kawemura ◽  
Adriana Seber ◽  
José Salvador Rodrigues de Oliveira ◽  
Maria Gerbase-DeLima ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Bacterial Infection ◽  
Peripheral Blood ◽  
Lower Incidence ◽  
Cytomegalovirus Infection ◽  
Acute Gvhd ◽  
Hematopoietic Stem ◽  
Thymic Function ◽  
Grade Ii

BackgroundThymus-dependent T-cell reconstitution plays a role in immune recovery after stem cell transplantation (HSCT). High pre-HCST thymic function has been associated with higher survival, lower incidence of acute and chronic graft versus host disease (GVHD) and lower incidence of infections. The aim of this study was to analyze the relationship between pre-HSCT peripheral blood levels of T-cell receptor excision circles (TREC) and post-HSCT clinical events in recipients of HLA-identical hematopoietic stem cell transplants.MethodDelta deletion signal joint TRECs (sjTRECs) formed by the dREC-yJa rearrangement were quantified by real time PCR in peripheral blood lymphocytes of 62 HSCT recipients.ResultsUnivariate analysis revealed an association between low TREC levels and a higher incidence of grade II-IV acute GVHD (p=0.026), bacterial infection (p=0.005) and cytomegalovirus infection (p=0.033), whereas high TREC levels were associated with higher overall survival (p=0.028). In the multivariate analysis, low pre-HSCT TREC levels remained independently associated with lower survival (p=0.032; RR 2.6), occurrence of grade II-IV acute GVHD (p=0.031; RR: 2.5), bacterial infection (p=0.006, RR: 6.6) and cytomegalovirus infection (p=0.039; RR:2.8).ConclusionOur results corroborate the concept that pre-HSCT recipient´s thymic function is an important predictor of risk for acute grade II-IV GVHD and infection.

scholarly journals The Combination of Cyclosporine and Mycophenolate Mofetil Is Less Effective Than Cyclosporine and Methotrexate in the Prevention of Acute Graft-Versus Host Disease after Allogeneic Stem Cell Transplantation from Unrelated Donors

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1942-1942
Author(s):  
Ronit Yerushalmi ◽  
Noga Shem-Tov ◽  
Ivetta Danylesko ◽  
Arnon Nagler ◽  
Avichai Shimoni
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Advanced Disease ◽  
The Other ◽  
Unrelated Donor ◽  
Graft Versus Host ◽  
Intention To Treat ◽  
Unrelated Donors ◽  
Grade Ii ◽  
High Comorbidity

Abstract Allogeneic Stem cell transplantation (SCT) from unrelated donors is a potential curative approach for a variety of hematological malignancies. Acute graft-versus-host disease (GVHD) is a major treatment-related complication. Several regimens for GVHD prevention have been explored, but no regimen has shown superiority over the others. We performed this retrospective analysis to compare outcomes following two of the most frequently used regimens, the combination of cyclosporine A and a short course of methotrexate (MTX group) and the combination of cyclosporine A and mycophenolate mofetil (cellcept, CC group). The study included 472 patients (pts) given unrelated donor transplant over an 11 year period in a single institution. The median age was 55 years (range, 18-76). The diagnoses included acute leukemia/MDS (66%), lymphoproliferative diseases (including lymphoma and myeloma, 24%), chronic myeloproliferative disorders (including CML, 7%) and non-malignant disorders (3%). The status at SCT was early (28%), intermediate (24%) and advanced (47%) according to CIBMTR criteria. The conditioning regimen was myeloablative (MAC, 19%), reduced-intensity (RIC, 39%) and reduced-toxicity myeloablative (41%). All pts were given ATG during conditioning. 97% of all pts had PBSC as the stem cell source for SCT. 71% had a 10/10 HLA match and 29% had ≤9/10. 13% had a comorbidity index >2. In all, 314 pts were in the MTX group and 158 in the CC group. The CC group included older pts (median age 57 Vs. 52 years, respectively, P=0.002), a lower percentage had MAC (9% Vs. 24%, P=0.005), more pts had lymphoproliferative disease and less acute leukemia (P=0.02). More pts had advanced disease at SCT (63% Vs. 37%, P=0.001) and more had a high comorbidity score (18% Vs. 11%, P=0.05). Engraftment was faster after CC, day 11 vs 14, respectively (P=0.001). Acute GVHD grade II-IV occurred in 47% (95% CI, 40-56) vs 27% (22-33), P=0.001). Acute GVHD grade III-IV occurred in 28% (95% CI, 21-37) vs 12% (9-17), P=0.001). Multivariate analysis (MVA) identified HLA mismatch (HR, 2.5, P=0.001), RIC (HR 0.6, P=0.03) and the use of CC in GVHD prevention (HR 2.3, P=0.001) as risk factors for acute GVHD. Chronic GVHD was 30% (26-34) and was similar after CC and MTX. With a median follow-up of 52 months (range, 5-151) 175 pts are alive, 145 died of treatment related causes (NRM) and 152 of relapse. 5-year NRM was 44% (37-53) and 24% (20-30) after CC and MTX, respectively (P=0.001). The difference was due to excess death due to GVHD with similar non-GVHD related NRM. MVA identified age>55 years (HR 1.5, P=0.04), less than 10/10 matching (HR 2.3, P=0.001), advanced disease (HR 2.0, P=0.001), high comorbidity score (HR 1.8, P=0.02) and the use of CC (HR 1.6, P=0.02) as independent factors predicting NRM. However, the CC and MTX group were not balanced in terms of risk factors, with the CC group including pts with a higher risk for acute GVHD and NRM. To minimize this potential bias we analyzed these outcomes on the basis of the intention to treat. During the years 2008-2009, the leading GVHD prevention regimen for unrelated donor SCT in our institution included CC, 90 of 101 pts transplanted in this period had CC (90%). During the other years CC was used according to the attending physician discretion in 68 of 371 SCT (18%). The group transplanted in 2008-9 was well matched with the other periods in all pt characteristics. Acute GVHD grade II-IV occurred in 50% (41-61) in the years 2008-9 when CC was used predominantly and 30% (25-35) in the other periods (P=0.006). Acute GVHD grade III-IV occurred in 27% (CI, 19-39) vs 15% (11-19), respectively (P=0.008). NRM was 34% (26-44) vs 30%, respectively (p=0.58). GVHD related death was higher in 2008-9 but non-GVHD death was lower, resulting in similar NRM. Relapse mortality was similar after CC and MTX. Among all pts, CC was associated with a lower 5-year overall survival, 28% (21-35) and 41% (35-46), respectively (P=0.005). However, with the time period intention to treat analysis, OS was identical, 36% (P=0.81). In conclusion, cyclosporine and CC is associated with faster engraftment and possibly with less organ toxicity than cyclosporine and MTX. However, it is associated with inferior prevention of acute GVHD, more GVHD related death and possibly with increased NRM. Cyclosporine and MTX should remain the standard GVHD prevention regimen for unrelated donor SCT. *AN and AS equally contributed. Disclosures Nagler: Novaratis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding.

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