Impact of T-Cell Chimerism on Clinical Outcome in 117 Patients Who Underwent Allogeneic Stem Cell Transplantation with a Busulfan-Containing Reduced-Intensity Conditioning Regimen.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2009-2009
Author(s):  
Bungo Saito ◽  
Takahiro Fukuda ◽  
Hiroki Yokoyama ◽  
Saiko Kurosawa ◽  
Toshihiro Takahashi ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Increased Risk ◽  
Wide Range ◽  
The Mean ◽  
Reduced Intensity

Abstract Background: Within the concept of reduced-intensity stem cell transplantation (RIST), there is a wide range of differences in regimens utilized, in terms of toxicities and antileukemia effects, and only a little information is available on the clinical impact of chimerism status in patients conditioned with a busulfan-containing regimen. To examine this point, we reviewed the pattern of lineage-specific chimerism to correlate with subsequent clinical outcomes. Patients and Methods: We retrospectively reviewed the data of 117 patients (median age, 52 years: range, 29–68) who had various hematological malignancies and underwent busulfan-containing RIST with related blood stem cells (n=81), related marrow (n=4) or unrelated marrow (n=32), between January 2000 and December 2006. The conditioning regimen consisted of busulfan (8 mg/kg) and fludarabine (180 mg/m2, n=64) or cladribine (0.66 mg/kg, n=53), with or without 2–4 Gy TBI (n=26) or anti-thymocyte globulin (5–10 mg/kg: n=31). Prophylaxis for GVHD consisted of cyclosporin or tacrolimus, with or without methotrexate. Chimerism was evaluated with peripheral blood samples taken on days 30, 60 and 90 after transplantation by PCR-based amplification of polymorphic short tandem repeat regions. Results: The median follow-up of surviving patients was 857 days (50–2535). Percent donor-chimerism was significantly higher in granulocytes than T-cell fraction throughout the entire course, and the mean values were, respectively, 96% vs 83%, 98% vs 89% and 98% vs 91% at days 30, 60 and 90 after RIST. At day 30, the numbers of patients with T-cell chimerism >90%, 60–90% and <60% were 67 (58%), 32 (27%) and 18 (15%), respectively. The mean percentage of donor T-cell chimerism on day 30 was 18% (0–63%) in 5 patients who experienced graft failure (GF), which was significantly lower than that (86%; 15–100%) in the rest of the patients (p<0.01). No correlation was found between the kinetics of T-cell chimerism and the occurrence of acute or chronic GVHD. A multivariate analysis showed that low donor T-cell chimerism of <60% at day 30 was significantly associated with an increased risk of treatment failure (TF) at day 100, which included GF, progressive disease, relapse and non-relapse mortality (HR: 3.3 [95% CI, 1.4–7.8] p<0.01), but not with 1-year TF. The stem cell source and the addition of TBI or ATG were not associated with the degree of T-cell chimerism, overall survival (OS) or TF. In a Cox proportional hazard model, low donor T-cell chimerism of <60% at day 30 was associated with poor OS (HR: 2.2 [95% CI, 1.1–4.4] p=0.02) (Figure) and TF (HR: 2.0 [95% CI, 1.1–3.8] p=0.02). Conclusion: We found that 42% of the patients retained mixed donor T-cell chimerism (≤90% donor), whereas 92% achieved complete chimerism in granulocyte fraction. Low donor T-cell chimerism of <60% at day 30 may predict a poor outcome, and a prospective study to examine the value of early intervention based on chimerism data is warranted. Figure Figure

Durable Engraftment with Minimal Toxicities after Allogeneic Hematopoietic Stem Cell Transplantation with a Reduced-Intensity Regimen Incorporating Fludarabine and 8 mg/kg Busulfan.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5246-5246
Author(s):  
Naoyuki Uchida ◽  
Takahiro Fukuda ◽  
Atsushi Wake ◽  
Sung-Won Kim ◽  
Kazuhiro Masuoka ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Disease Progression ◽  
Cell Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Reduced Intensity

Abstract Background: The optimal regimen for allogeneic stem cell transplantation with a reduced-intensity conditioning regimen (RIST) needs to be established. Therefore, we retrospectively reviewed data of 84 patients who underwent RIST using 180 mg/sqm fludarabine and 8 mg/kg busulfan (Flu/Bu8). All patients received mobilized blood stem cells from a related donor between Nov. 2000 and Jun. 2005. Patients and Methods: The median age of the patients was 53 years (range, 25–65). The diagnosis included 42 AML/MDS, 34 lymphoma and 8 others. Sixty-nine patients (82%) had high-risk diseases, including 56 (81%) in non-remission status before RIST. All were serologically 6/6 matched pairs, except for one who had a 5/6 match. For GVHD prophylaxis, 61 used cyclosporine A (CSP) alone, 21 used CSP + methotrexate (MTX), and 2 used some other compounds. Results: The engraftment kinetics were remarkable since all of the patients successfully engrafted at a median of 11 days (5–24 days), with no late graft rejection. Toxicities of grade 2 or 3 according to CTCAE v.3 were observed at minimal frequencies, i.e. 38 mucosal, 35 hepatic, 13 GI tract, 12 renal, 2 cardiac, 1 pulmonary, 19 febrile neutropenia, and 9 documented infections, and there were no grade 4 toxicities. The administration of MTX increased the incidence and severity of stomatitis (P=0.05). The cumulative incidences of grade II–IV and III–IV acute GVHD were, respectively, 50% and 29%, and 76% experienced chronic GVHD. Seventy-three patients (87%), including 38 of the 56 patients who were not in CR at the time of transplant, achieved partial or complete remission. The median follow-up of surviving patients was 1349 days (34–1981 days), and the day-100 mortality was 11% (disease progression 6% and non-relapse mortality [NRM] 5%). The 5-year overall and progression-free survival rates were 36% and 30%, respectively. Among 46 total deaths, 27 were from disease progression and 19 were from NRM primarily related to GVHD. The patients in remission at transplant showed better overall survival than those who were not in remission (85 % vs 34 % at 5 years post-transplant, respectively, P<0.05). The 5-year overall survival was 85 % for those in remission at transplant and 34 % for the remaining patients (P<0.05). Multivariate analyses showed that age older than 52 years and non-CR status at transplant were associated with an increased risk for mortality after RIST. Conclusions: Our study showed that RIST with this Flu/Bu8 regimen is feasible with durable engraftment and low early mortality. The clinical response rate is adequate for those who stayed in remission at transplantation, but otherwise a novel approach to prevent disease progression should be developed.

Sustained Engraftment Using Fludarabine, Melphalan and Thiotepa Conditioning for Haploidentical Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5081-5081 ◽  
Author(s):  
Stefan O. Ciurea ◽  
Suhail Qureshi ◽  
Gabriela Rondon ◽  
Susana Pesoa ◽  
Pedro Cano ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Platelet Recovery ◽  
Haploidentical Stem Cell Transplantation ◽  
Cd34 Cells ◽  
Reduced Intensity

Abstract BACKGROUND: Haploidentical stem cell transplantation (HaploSCT) using mega-doses of CD34 cells and a T-cell depleted allograft has generally been performed in advanced hematologic malignancies using a fractionated TBI-based conditioning regimen (CR) with very high toxicity. Here we evaluated the results of a reduced intensity chemotherapy-only conditioning regimen (RIC) with fludarabine (F), melphalan (M) and thiotepa (T) for HaploSCT. METHODS: 24 patients (pts) with advanced hematologic malignancies (18 with AML/MDS, 3 with ALL, 2 with CML and 1 with T-cell lymphoma underwent HaploSCT from related donors at MDACC between 10/2001 and 04/2007. The median age was 36 years. At the time of transplantation 15/24 pts (63%) had relapsed or primary refractory disease and 37% were in remission. Pts received a median of 10.8x10e6 CD34 cells. The median number of CD3 cells infused was 1x10e4/kg. The number of allele mismatch was 3/10 in 4 pts, 4/10 in 10 pts, 5/10 in 9 pts and 6/10 in 1 pt. HLA antibody (AB) specificity was determined using fluorescent beads coated with single antigens and detected in a Luminex platform. The CR consisted of M 140 mg/m2 on day −8, T 10 mg/m2 on day −7, F 160 mg/m2 over 4 days on days −6, −5, −4, −3, and 1.5 mg/kg of rabbit ATG a day x 4 on days −6, −5, −4, and −3 (FMT). No GVHD prophylaxis and no growth factors were administered. The pts were evaluated for engraftment and 100-day transplant-related mortality (TRM). RESULTS: 23 pts were evaluable for engraftment. 1 pt died on day 27 due to respiratory failure. 19/23 pts (83%) engrafted with hematopoietic recovery with donor-derived cells. 18 pts achieved a full donor chimerism while 1 had progressive leukemia. Neutrophil recovery to ANC >0.5 x 10e9/l occurred after a median of 13 days and platelet recovery to >20 x 10e9/l occurred after a median of 13.5 days. 4 pts failed to achieve primary engraftment, presumably due to rejection. No statistically significant correlation was found between graft failure (GF) and KIR-ligand mismatch (KIR-LM). In fact KIR-LM were more common in the group of pts who engrafted (7/19) than in pts with GF (1/4). After 09/2005 when anti HLA AB were started to be done, 3/14 pts had GF, 2 of which had donor directed AB. The regimen was relatively well tolerated; 4 pts experienced grade 4 nonhematologic, organ toxicities. Cumulative day 100 TRM was 25%. 19/24 pts (79%) were in CR after transplant with 6 surviving at the last follow-up (OS 25%). Only 1 pt developed aGVHD (4.1%) and 5 pts developed cGVHD (20.8%) with 3 experiencing extensive GVHD. 9 pts (37.5%) relapsed after a median of 71.5 days post transplant. The distribution of KIR-LM in the GVH direction was similar in pts with and without relapse (3/9 pts with relapse and 5/15 pts without relapse). Causes of death were disease relapse in 9 pts, infections in 3 pts, pulmonary failure/MOF in 4 pts and cGVHD in 1 pt. CONCLUSIONS: The reduced intensity FMT regimen was sufficiently immunosuppressive to support rapid engraftment after HaploSCT in 83% of pts with advanced hematologic malignancies. In this small series, KIR-LM in the HVG or GVH direction were not associated with graft rejection or malignancy relapse. The role of anti-HLA AB need further evaluation. The rate of toxicity and 100-day TRM appears lower as compared with published studies of TBI-based CR. The FMT RIC merits further evaluation in studies of HaploSCT.

Reduced intensity allogeneic stem cell transplantation in patients with myelodysplastic syndrome: Does the conditioning matter? A retrospective study of the SFGM-TC on 61 patients

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6547-6547
Author(s):  
L. Terriou ◽  
Z. Chir ◽  
H. Esperou ◽  
J. Boiron ◽  
N. Gratecos ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Myelodysplastic Syndrome ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Chronic Gvhd ◽  
Immunosuppressive Treatment ◽  
Conditioning Regimen ◽  
The Impact ◽  
Reduced Intensity

6547 Background: Reduced-intensity allogeneic stem cell transplantation (RIT) has emerged as an alternative to myeloablative transplantation in pts with myelodysplastic syndrome (MDS). Given the uncertainty regarding the appropriate conditioning, SFGM-TC conducted a retrospective multicenter study with the attempt to evaluate the impact of conditioning on pts’ outcome. Methods: The record of 61 pts (37 males) with MDS who received a RIT between 1998 and 2003, from 22 French transplantation centres, were reviewed. According to the FAB classification, 11 pts had RA at diagnosis, of whom one had progressed to REAB and one to AML before transplantation. Thirty-two pts had REAB, of whom 2 had progressed to REAB-T and 7 to AML. Twelve pts had REAB-T and 6 CMML, of whom 8 progressed to AML. The median time from diagnosis to RIT was 12 months (6–129). Conditioning regimen consisted of fludarabin (Flu) plus busulfan ( n=29), Flu plus 2-Gy TBI ( n=20) and idarubicin plus aracytine and Flu (n=12). Donors were HLA-identical siblings (n=52) and HLA-matched unrelated (n=9). All pts received peripheral blood stem cells. The median of CD34+ infused cell dose was 5 × 106/kg (0.5–17.3). Results: At the reference date of 1 July 2005, median follow-up was 44.7 months (21–85). Estimated 3-year overall survival (OS), progression free survival (PFS), relapse and transplant-relapse mortality (TRM) were 35%, 27%, 66% and 30%, respectively. Neither of the 3 conditioning regimens used had impact on pts’ outcome. In multivariable analyses, while acute III/IV grade GVHD development was the only factor found to adversely influencing OS (HR=3.6; 95% CI: 1.1–12.2), chronic GVHD development was the only favourably influencing PFS and relapse ratios (HR=0.3; 95% CI: 0.1–0.7 and HR=0.2; 95% CI: 0.1–0.6, respectively). TRM was adversely influenced by male sex of pt (HR=9.2; 95% CI: 1.5–66.6). Conclusions: RIT seems to be an effective treatment in MDS pts irrespective of conditioning type. While acute III/IV grade GVHD appeared to be detrimental, the benefit effect of chronic GVHD was to be bound to GVL effect. New approaches with focus on immunosuppressive treatment are needed to enhance the GVL effect with an acceptable risk of GVHD. No significant financial relationships to disclose.

Impact of antithymocyte globulin (ATG)-containing conditioning regimens on patients undergoing allogeneic stem cell transplantation (allo-CST) for poor risk cytogenetic IPSS myelodysplastic syndrome (PRC-MDS): A report from the French Society of Stem Cell Transplantation and Cell  Therapy (SFGM-TC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6542-6542
Author(s):  
Ibrahim Yakoub-Agha ◽  
Gandhi Laurent Damaj ◽  
Marie Robin ◽  
Stephane Vigouroux ◽  
Alice Garnier ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
French Society ◽  
Poor Risk ◽  
Increased Risk

6542 Background: Due to a risk of relapse of underlying disease in patients with PRC-MDS, the use of ATG, incorporated within the conditioning regimen prior to allo-SCT, is still controversial. Methods: Inclusion criteria included patients aged over 18 (n=101) who received allo-SCT transplanted between 1999 and 2009 from either a sibling (n=68) or HLA-allele-MUD (10/10) (n=33) for PRC-MDS. HLA matching was double-checked by the national Bone Marrow Donor Registry. Results: According to the FAB/WHO classification at diagnosis, 22 pts had RA/RARS/RCMD, 40 RAEB1, 30 REAB2 and 9 RAEB-t/AML. 34 pts had progressed to a more advanced disease before allo-SCT. At diagnosis, 89 patients had an IPSS int-2 or higher. At transplant, 36 pts were responders (CR, PR, CRm) and 62 with progressive disease (relapsed/refractory, untreated or stable disease without hematological improvement). Median age at transplantation was 54 years (range, 22-69). Pts received myeloablative conditioning (n=46) and nonmyeloablative (n=55). In this series, 48 patients received ATG as part of conditioning ('ATG' group), whereas 53 did not ('no-ATG’ group). As of April 1st 2011, 44 patients died of relapse and 22 of TRM. 3-year relapse, overall and event-free survival rates were not significantly different between the two groups. In contrast, the cumulative incidence of grade 2-4 acute GVHD was 48% in the no-ATG group and 30% ATG group (P <.005). Although the cumulative incidence of chronic GVHD was similar in the no-ATG and ATG groups, a trend for a lower TRM was observed in the ATG group (p=.06). In multivariate analysis, the absence of use of ATG was associated with an increased risk of acute grade 2-4 [HR = 1.92, p=.044]. Conclusions: The addition of ATG to the conditioning regimen resulted in a decreased incidence of acute GVHD without increasing relapse rates and compromising survival of patients undergoing allo-SCT for poor risk cytogenetic MDS.

High Engraftment Rate after Second Stem Cell Transplantation for Thalassemia: A Prospective Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1107-1107
Author(s):  
Javid Gaziev ◽  
Guido Lucarelli ◽  
Pietro Sodani ◽  
Paola Polchi ◽  
Katia Paciaroni ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Second Transplantation ◽  
Increased Risk ◽  
Preparative Regimen

Abstract Unlike hematological malignancies patients with thalassemia have an increased risk of graft failure or rejection occurring in up to 15% of patients after myeloablative stem cell transplantation from HLA identical related donors. Patients who reject their grafts and have a return of thalassemic hematopoiesis could benefit from second transplantation with the prospect of cure. Our previous experiences of second SCT using BUCY conditioning regimen alone or in combination with antilymphocyte globulin or total lymphoid irradiation showed a higher graft failure rates (43% to 69%). In 2003 we devised a new preparative regimen in an attempt to improve engraftment rate after second transplantation for thalassemia. The treatment protocol (Protocol 26.1) consisted of pre-conditioning immunosuppression-cytoreduction with hydroxiurea 30 mg/kg/day, azathioprine 3 mg/kg/day (day -45 to -12) and fludarabine 30 mg/m2/day (day -17 to -13) and conditioning regimen with BU 14/16 TT10 CY200 ATG (Thymoglobulin)12,5/10. Thirteen patients with median age of 9 years (range, 4–20 years) were given a second SCT according to this protocol. The median time between the first and second transplant was 29 months (range, 8–204 months). As a stem cell source 4 patients received bone marrow and 9 patients unmanipulated peripheral blood stem cells (PBSC). All but two patients received stem cells from the same donor. Twelve out of 13 patients (92%) had sustained full donor engraftment. One patient had early graft failure and died from cerebral bleeding due to refractory thrombocytopenia despite an autologous back-up. Other two patients died from acute or chronic GvHD -related complications. The probability of survival, thalassemia-free survival, transplant related mortality and rejection were 76%, 76%, 18% and 8% respectively with a median follow-up of 26 months (range, 8–47 months). Four patients developed grade II–III and 1 patient grade IV acute GvHD responsive to steroids and 3 patients had extensive chronic GvHD. Both acute and chronic GvHD occurred in patients who received PBSC. The incidence of CMV and EBV reactivation was 62% and 38% respectively. None of these patients developed EBV related lymphoproliferative disorders. Six patients had BK virus- related hemorragic cystitis (2 moderate, 2 severe and 2 mild cystitis). In conclusion, the high engraftment rate observed in this study suggests that this new preparative regimen is effective curative treatment for second transplant in patients with thalassemia. Disclosure: No relevant conflicts of interest to declare.

Haploidentical stem cell transplantation after a reduced-intensity conditioning regimen for the treatment of advanced hematologic malignancies: posttransplantation CD8-depleted donor lymphocyte infusions contribute to improve T-cell recovery

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4771-4779 ◽  
Author(s):  
Anna Dodero ◽  
Cristiana Carniti ◽  
Anna Raganato ◽  
Antonio Vendramin ◽  
Lucia Farina ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity ◽  
Donor Lymphocyte Infusions

Abstract Haploidentical hematopoietic stem cell transplantation provides an option for patients with advanced hematologic malignancies lacking a compatible donor. In this prospective phase 1/2 trial, we evaluated the role of reduced-intensity conditioning (RIC) followed by early add-backs of CD8-depleted donor lymphocyte infusions (DLIs). The RIC regimen consisted of thiotepa, fludarabine, cyclophosphamide, and 2 Gy total body irradiation. Twenty-eight patients with advanced lymphoproliferative diseases (n = 24) or acute myeloid leukemia (n = 4) were enrolled. Ex vivo and in vivo T-cell depletion was carried out by CD34+ cell selection and alemtuzumab treatment. The 2-year cumulative incidence of nonrelapse mortality was 26% and the 2-year overall survival (OS) was 44%, with a better outcome for patients with chemosensitive disease (OS, 75%). Overall, 54 CD8-depleted DLIs were administered to 23 patients (82%) at 3 different dose levels without loss of engraftment or acute toxicities. Overall, 6 of 23 patients (26%) developed grade II-IV graft-versus-host disease, mainly at dose level 2. In conclusion, our RIC regimen allowed a stable engraftment with a rather low nonrelapse mortality in poor-risk patients; OS is encouraging with some long-term remissions in lymphoid malignancies. CD8-depleted DLIs are feasible and promote the immune reconstitution.

Identification of Prognostic Factors Predicting the Outcome of Reduced Intensity Allogeneic Stem Cell Transplantation in Mantle Cell Lymphoma. An Analysis from the Lymphoma Working Party of the EBMT

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 457-457 ◽  
Author(s):  
Stephen P Robinson ◽  
Anna Sureda ◽  
Carmen Canals ◽  
Jean-Paul Vernant ◽  
Noel-Jean Milpied ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Performance Status ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Refractory Disease ◽  
T Cell Depletion ◽  
Reduced Intensity

Abstract Mantle cell lymphoma (MCL) is a disease associated with a poor prognosis characterised by inevitable relapse following both conventional chemotherapy and autologous stem cell transplantation (SCT). The role of reduced intensity allogeneic stem cell transplantation (RIST) in MCL remains controversial. We have conducted a retrospective study of RIST in MCL as reported to the EBMT registry in an attempt to define factors predicting the outcome of this procedure. Between 1998 and 2006 279 patients with MCL received a RIST with 210 procedures performed after the year 2001. 219 (78%) were male and the median age at transplant was 55 years (range 30–71). At diagnosis 97% had stage IV disease and 39% had B symptoms. Patients had received a median of 3 lines (range 1–9) of prior therapy and 119 (43%) had undergone a previous autologous SCT. The median time from diagnosis to transplant was 30 months (range 3–161). The disease status at transplant was; complete remission 124, partial remission 95, refractory disease 32 and untested relapse 17. The performance status at transplant was poor in 15 patients. Conditioning for RIST was achieved with fludarabine+alkylating agent in 66%, fludarabine+TBI in 13%, and a variety of other reduced intensity regimens in 20%. Transplants were performed from 193 matched family donors, 60 matched unrelated donors and 22 mismatched donors who provided peripheral blood stem cells in 252 cases and bone marrow in 26. T cell depletion with either CAMPATH or ATG was performed in 85 transplants. 274 patients were evaluable for engraftment of whom 272 engrafted with 4 secondary graft failures. Acute graft versus host disease (GVHD) developed in 149 patients (grade I 45, grade II 52, grade III/IV 50, unknown extent 2). Of 214 patients at risk 30 developed limited chronic GVHD and 58 extensive chronic GVHD. There were 91 transplant related deaths with infection and GVHD accounting for 51 of these deaths. The resulting 100 day, 1 year and 3 year non-relapse mortality rates were 13, 32 and 41% respectively. NRM was associated with poor PS at transplant (RR=3.7 p=0.001) and transplantation prior to 2002 (RR= 1.7 p=0.02) but age, prior transplantation and donor relationship had no significant impact. Sixty one patients relapsed at a median time of 7 months (range 1–50 months) post transplant. The cumulative incidence of relapse at 1 years and 4 years was 19% and 31% respectively. Disease relapse was associated with refractory disease at transplant (RR=4.5 p&lt;0.001), T cell depletion of the graft (RR= 4.2 p&lt;0.001) and the use of fludarabine+low dose TBI conditioning (RR=2.7 p=0.03). The Kaplan-Meier estimate of the PFS at 1 and 3 years was 49% and 29% respectively. PFS was significantly worse for patients with refractory disease (RR=2.2, p&lt;0.001), poor PS (RR2.6, p=0.005) or those transplanted prior to 2002 (RR=1.5, p=0.03). The overall survival at 1 and 3 years was 60% and 43% respectively and was lower in patients with refractory disease (RR 2.3, p&lt;0.001), poor PS (RR 2.3 p=0.01) and those transplanted before 2002 (RR 1.7 p=0.005). In summary the outcome of RIST in MCL has improved in recent years although NRM remains a substantial problem. Survival was significantly worse for patients with a poor performance status or refractory disease at transplant. The type of reduced intensity conditioning regimen employed and the use of T cell depletion may also have a significant impact upon the incidence of relapse after these procedures.

Oligoclonal T Cells Associated with Gvhd Following Allogeneic Stem Cell Transplantation Conditioned with Thymoglobulin and Reduced Intensity Total Body Irradiation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4662-4662
Author(s):  
Masoud Manjili ◽  
Catherine H Roberts ◽  
Maciej Kmieciak ◽  
Madhu S Gowda ◽  
Andrea Ferreira-Gonzalez ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Count ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Recovery ◽  
Reduced Intensity

Abstract Abstract 4662 Patients undergoing unrelated donor stem cell transplantation following reduced intensity regimens are prone to acute graft vs host disease (GVHD). In vivo T cell depletion with rabbit anti-thymocyte globulin (r-ATG, Thymoglobulin, Genzyme inc. Cambridge MA) is consistently associated with reduced risk of acute GVHD however poor T cell reconstitution seen with current schedules results in a high incidence of opportunistic infections and relapse. We report data on immune reconstitution in patients participating in an ongoing clinical trial testing a novel conditioning regimen for allogeneic GCSF-mobilized blood stem cell transplantation. Patients were randomized to receive conditioning with either 7.5 or 5.1 mg/kg of r-ATG in divided doses between days -9 and -7, followed by 450 cGy total body irrradiation (TBI) in 3 fractions on day -1 and 0. GVHD prophylaxis was with tacrolimus (day -3 to 120) and mycophenolate mofetil (day 0-30). So far 10 heavily pre-treated (median number of prior therapies 4, prior autologous SCT n=5) patients have been transplanted; 6 from unrelated donors (1 bone marrow), 3 from matched related donors and 1 from an HLA-A mismatched sibling. Diagnosis includes MM (4), NHL (3), and CLL/PLL (3). Median patient age is 57 years. No patients have developed acute GVHD in the first 90 days. All patients achieved prompt engraftment of neutrophils and have demonstrated sustained complete myeloid donor chimerism (median <1% recipient DNA) at 3-6 months post transplant. NK cell recovery is prompt (mean±SD absolute CD56+ cell count 177±85/μL at day 30) and sustained (184±116 at day 90). T cell subset recovery is modest (absolute CD3+ cell count 861±934/μL at day 90) with predominantly cytotoxic T cells (CD3+/4+ cell count 143±116 and CD3+/8+ cell count 708±837). T cell chimerism at day 90 is mixed with either donor ('10% recipient DNA, n=5) or recipient dominance (>10% recipient DNA, n=3). Patients demonstrating dominant donor T cell chimerism at day 90 went on to develop either delayed onset acute GVHD (n=2/8 evaluable) or chronic GVHD (n=2/8) after withdrawal of immunosuppression. Patients demonstrating mixed T cell chimerism with recipient dominance did not develop chronic GVHD; one of these patients has relapsed, following an HLA-A mismatched SCT from his brother, and though he had predominantly recipient derived T cells, his granulocytes were completely donor derived indicating graft tolerance. T cell receptor beta locus was examined by RT-PCR for oligoclonality in all the donor-recipient pairs at baseline, day 90 and at onset of GVHD. Patients with GVHD demonstrated high level of expression of TCR V beta 23 and 24 (n=1/4), 11 (n= 1/4), 18 (n= 1/4), or 11 and 18 (n= 1/4) exclusively, in addition to TCR V beta 14, 16, 17, 22. The latter loci were also expressed in patients who had no GVHD with mixed T cell chimerism; this group of patients also expressed TCR V beta 4 (n=2/2), 13 and 19 (n=1/2) exclusively. All but one of the patients expressed the majority of TCR V beta loci at day 90 (with the exceptions noted above) indicating early polyclonal T cell recovery following transplantation. Asymptomatic CMV and EBV reactivation requiring therapy developed in one patient each. No patients have developed invasive fungal infections. In conclusion conditioning with Thymoglobulin and reduced intensity TBI results in stable myeloid engraftment in patients receiving unrelated and alternative donor transplants. In this small group of patients, GVHD appears to be associated with emergence of oligoclonal T cell populations which in the future may be selectively depleted ex vivo to allow engraftment without risk of chronic GVHD. Disclosures: McCarty: Celgene: Honoraria; Genzyme: Honoraria. Toor:Genzyme: Research Funding.

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