Reduced-Intensity Conditioning of Allogeneic Transplantation for Nodal Peripheral T-Cell Lymphomas

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2585-2585 ◽  
Author(s):  
Kazunari Aoki ◽  
Ritsuro Suzuki ◽  
Dai Chihara ◽  
Tatsuya Suzuki ◽  
Sung-Won Kim ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
T Cell ◽  
Elderly Patients ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
Younger Patients ◽  
T Cell Lymphomas ◽  
Reduced Intensity

Abstract Introduction The outcome and the role of allogeneic hematopoietic cell transplantation (Allo-HCT) with reduced-intensity conditioning (RIC) in patients with nodal peripheral T-cell lymphomas (PTCLs) remain unclear. Patients and Methods To address this issue, we retrospectively analyzed the outcome of Allo-HCT for patients with nodal PTCLs using the transplant registry data from the Japan Society for Hematopoietic Cell Transplantation (JSHCT). Patients who fulfilled the following criteria were included in this study: aged 16-69 years, diagnosed with PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), or anaplastic large cell lymphoma (ALCL), and received the first Allo-HCT in Japan between January 1, 2001 and December 31, 2011. In this analysis, conditioning regimen intensity was the main variable of interest. The conditioning regimen was classified as myeloablative conditioning (MAC) if it included total body irradiation (TBI) > 8 Gy, oral busulfan (BU) ≥ 9 mg/kg, intravenous BU ≥ 7.2 mg/kg, or melphalan (MEL) > 140 mg/m2. Otherwise, it was classified as RIC. Results A total of 354 patients (200 PTCL-NOS, 77 AITL, and 77 ALCL) were analyzed. Median follow-up duration of surviving patients was 3.8 years. Donor sources consisted of 122 human-leukocyte-antigen (HLA)-matched bone marrow (BM)/peripheral blood (PB), 122 HLA-mismatched BM/PB, and 110 cord blood. Of the 354 patients, 146 (41.2%) received MAC, which consisted of cyclophosphamide (CY)-TBI-based (n = 84), other TBI-based (n = 24), BU-CY-based (n = 11), fludarabine (FLU)-BU-based (n = 10), FLU-MEL-based (n = 15), and other (n = 2) MAC. The remaining 208 (58.8%) patients received RIC, which consisted of FLU-BU-based (n = 62), FLU-MEL-based (n = 108), and other (n = 38) RIC. Comparison of the patients who received MAC and RIC revealed that the RIC patients were significantly older (median age: 40.5 years vs. 50.3 years; P < 0.001) and more likely to have received autologous-HCT prior to Allo-HCT (15.1% vs. 29.3%; P = 0.002). The unadjusted 3-year cumulative incidence of non-relapse mortality were following: younger patients receiving MAC, 22%; younger patients receiving RIC, 14%; elderly patients receiving MAC, 50%; elderly patients receiving RIC, 30% (P < 0.001; Figure 1). The multivariate analysis showed that patients receiving RIC had a significantly lower non-relapse mortality than patents receiving MAC (HR, 0.51; 95% CI, 0.32-0.80; P = 0.004). Figure 1. Unadjusted non-relapse mortality. Figure 1. Unadjusted non-relapse mortality. The unadjusted 3-year cumulative incidence of relapse mortality were following: younger patients receiving MAC, 35%; younger patients receiving RIC, 30%; elderly patients receiving MAC, 32%; elderly patients receiving RIC, 35% (P = 0.692; Figure 2). The multivariate analysis showed that patients receiving MAC and RIC had a comparable relapse mortality (HR, 1.08; 95% CI, 0.73-1.58; P = 0.711). Figure 2. Unadjusted relapse mortality Figure 2. Unadjusted relapse mortality The unadjusted 3-year overall survival rates were following: MAC for younger patients (aged 16-49 years), 43%; RIC for younger patients, 56%; MAC for elderly patients (aged 50-69 years), 18%; RIC for elderly patients, 35% (P < 0.001; Figure 3). The multivariate analysis showed that patients receiving RIC had a significantly superior overall survival than patients receiving MAC (HR, 0.74; 95% CI, 0.54-1.00; P = 0.047; Table I). Figure 3. Unadjusted overall survival Figure 3. Unadjusted overall survival Table I. Multivariate analysis for overall survival Overall Survival HR (95% CI) P value Conditioning Regimen myeloablative 1.00 - reduced-intensity 0.74 (0.54-1.00) 0.047 Patient Age 16 to 34 1.00 - 35 to 49 1.26 (0.83-1.91) 0.270 50 to 59 2.17 (1.46-3.23) < 0.001 60 to 69 2.24 (1.40-3.59) 0.001 Karnofsly Performance Status 90 to 100 1.00 - 10 to 80 2.02 (1.41-2.91) <0.001 missing 1.50 (1.07-2.10) 0.017 Disease Status complete remission 1.00 - partial remission 1.13 (0.71-1.82) 0.607 resistant relapse 2.02 (1.27-3.21) 0.003 primary induction failure 2.09 (1.33-3.27) 0.001 Conclusion We showed a favorable outcome of Allo-HCT with RIC in patients with nodal PTCLs. The efficacy of RIC Allo-HCT for nodal PTCLs needs to be explored in prospective study. Disclosures No relevant conflicts of interest to declare.

A Phase II Trial Combining Radiolabeled Anti-CD45 Antibody with Fludarabine and Low-Dose Total Body Irradiation (TBI) Followed by Related or Unrelated Hematopoietic Cell Transplantation for Patients Under Age 50 with Advanced Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1924-1924
Author(s):  
Raya Mawad ◽  
Ted A. Gooley ◽  
Joseph G Rajendran ◽  
Darrell R. Fisher ◽  
Ajay K. Gopal ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
High Dose ◽  
Reduced Intensity Conditioning ◽  
Younger Patients ◽  
Reduced Intensity Conditioning Regimen ◽  
Total Body ◽  
Reduced Intensity

Abstract Abstract 1924 Innovative therapeutic approaches are needed to reduce the morbidity and high relapse rates in patients with advanced AML or high-risk MDS following myeloablative hematopoietic cell transplantation (HCT). Success with stable donor chimerism and low toxicity following infusion of allogeneic peripheral blood stem cells (PBSC) with reduced-intensity regimens affords an opportunity to induce a graft-versus-leukemia (GVL) effect with minimal acute morbidity. GVL effects, however, appear to be most potent in patients with low tumor burden at the time of HCT. In an attempt to improve outcomes, we previously transplanted 58 patients older than age 50 with advanced AML (beyond first remission) or high-risk MDS (≥5% marrow blasts at the time of HCT) in a Phase I trial using 131I-labeled anti-CD45 antibody (BC8) in conjunction with fludarabine (FLU) and 2Gy total-body irradiation (TBI). Data from this study suggested that 131I-anti-CD45-targeted radiotherapy could be safely integrated into a reduced-intensity conditioning regimen for older, high-risk patients with AML or MDS yielding encouraging survival outcomes. These results prompted us to evaluate a similar strategy in younger patients (ages 16–50) with advanced AML or high-risk MDS who may not be able to receive a high dose HCT conditioning regimen. In this phase I dose–escalation trial 14 patients received a dose of 131I-BC8 that delivered 10–27 Gy of targeted radiation to the healthy organ receiving the highest dose combined with FLU (30 mg/m2 daily for 3 days), 2 Gy TBI, and HLA-matched related (n = 7) or unrelated (n = 7) PBSC grafts. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil. The 131I radiation dose was escalated until the maximum planned dose of 28 Gy was reached without any appreciable dose limiting toxicity. The median patient age was 39.5 (range, 23.8–49.7) years. Thirteen patients had AML, with 9 patients in second complete remission, 3 with primary refractory disease, and 1 in active relapse. One patient had advanced CMML with >5% blasts. Treatment with the 131I-BC8 Ab/FLU/TBI regimen produced a complete remission in 7 patients (50%), and 11 of the 12 evaluable patients had 100% donor CD3+ and CD33+cell engraftment by day 28 after HCT; an additional patient had 79% CD3 and 82% CD33 positive donor marrow cells at day 28. The absolute neutrophil count surpassed 500/μL at a median of 15 (range, 13–22) days. Self-sustained platelet levels of 20,000/μL were reached at a median of 11 (range, 11–27) days after HCT. Five patients (36%) are surviving relapse-free 46 to 99 months (median 87 months) after HCT. Seven patients (50%) have died, with five patients relapsing 0.9 to 45 months after HCT. No non-relapse mortality occured by day 100; however, two patients died 14 and 18 months after HCT of cardiomyopathy and GVHD complications, respectively. This study demonstrates that, in addition to a standard reduced intensity conditioning regimen, an average of 27 Gy of targeted 131I radiotherapy can be delivered to bone marrow, an average of 20Gy to the liver, and an average of 84 Gy to the spleen without a marked increase in day 100 mortality for younger patients. This strategy may thus provide a reasonable alternative for patients with high-risk AML/MDS who may not be able to tolerate a high dose conditioning HCT. Disclosures: No relevant conflicts of interest to declare.

Adverse Immunologic, Cytogenetic, and Molecular Features of AML in Elderly Patients Could Be Overcome by Allogeneic Hematopoietic Cell Transplantation Following Reduced Intensity Conditioning

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3065-3065
Author(s):  
Haifa Kathrin Al-Ali ◽  
Nadja Jaekel ◽  
Rainer Krahl ◽  
Claudia Nehring ◽  
Cornelia Becker ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Elderly Patients ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Graft Versus Leukemia ◽  
Reduced Intensity ◽  
Graft Versus Leukemia Effect

Abstract Abstract 3065 Allogeneic hematopoietic cell transplantation (HCT) following reduced-intensity-conditioning (RIC) is a curative therapeutic option in elderly patients with AML. Yet, hematological relapse (HR) and non-relapse mortality (NRM) remain major issues. The impact of AML characteristics, post-induction consolidation chemotherapy (PCC) in patients with complete remission (CR), type of donor [unrelated (UD) vs. related (RD)], graft cell count, and Donor-cell-chimerism (DCC) on long-term outcome and management of relapse after HCT following 200 cGy TBI + fludarabine 30 mg/m2 for 3 days followed by mycophenolate mofetil and cyclosporine were analysed in 245 consecutive patients with AML [132 male/113 female; median age 62 years] transplanted at the University of Leipzig. De novo and secondary AML were diagnosed in 151 (62%) and 94 (38%) patients respectively. A positive leukemic CD34-phenotype > 15% was present in 60%.Cytogenetics were high and intermediate (IR)-risk in 64 (26.7%) and 166 (69%) patients respectively. FLT3 -mutations (FLT3 mut) were present in 32 (28%) of the 115 patients with known FLT3 status. CR at HCT was present in 85% (CR1, n=155; CR2, n=53). The number of PCC applied was 0 in 88 (42%), 1 in 93 (45%), and 2 in 25 (12%). Donors were UD in 197 (80%) and RD in 48 (20%) patients. DCC in flow-sorted CD34+-marrow cells at days 28, 56, 84, and at 3 months interval thereafter was monitored by PCR of polymorphic micro satellite regions. After a median follow-up of 3.6 years, survival (OS), leukemia-free-survival (DFS), NRM, and Relapse (RI) at 5-years were 39%, 34%, 32% and 51% respectively. Engraftment was 95.5%. Incidence of acute GvHD > grade 3, limited and chronic GvHD was 22.5%, 20%, and 44.6% respectively. In multivariate analysis, type of AML, cytogenetics, CD34+-phenotype, and graft cell counts (CD3+, CD34+- and natural killer-cells) had no impact on outcome. Irrespective of the number of PCC applied, outcome was similar for CR1 and CR2. For the entire cohort and also for patients with IR-cytogenetics in CR, FLT3 mut did not adversely affect OS or RI. The lower RI after UD-HCT (39%) compared to RD-HCT (63%) (p=0.04) was opposed by a higher NRM after UD-HCT (36%) vs. 13% for RD-HCT (p=0.05) so that long-term OS and LFS were similar for both donor types. Chronic GvHD was associated with a superior OS, LFS and lower RI compared to patients without GvHD or with acute GvHD only (p<0.0005). Irrespective of leukemic CD34+-phenotype, CD34+-DCC day28 <90% was highly predictive of inferior OS (12%) and higher RI (95%) vs. OS of 50% and RI of 39% if CD34+-DCC day28 was > 90% (p<0.0001). In multivariate analysis, UD (p=0.007), female donor/male patient (p=0.02), and a higher CD34+- (p=0.01) but not CD3+-cells in the graft correlated with CD34+-DCC day28 was > 90%. HR and CD34+-DCC <90% without HR were managed by immunomodulation + chemotherapy. Overall, CR was achieved in 29% of HR and 36.4% of CD34+-DCC <90%. Relapse beyond day 100, a declining CD34+-DCC rather than a HR, and induction of GvHD correlated with a superior response and OS after relapse. Donor cells rather than the usual AML prognostic features predict long-term survival and relapse after RIC-HCT. In particular, CD34+-DCC is very effective in predicting outcome and identifying patients at risk of relapse thereby allowing early immunomodulation to enhance the graft-versus-leukemia effect. Yet, research is needed to further optimize the graft-versus-leukemia effect without the injurious effects of GvHD. Disclosures: No relevant conflicts of interest to declare.

Allogeneic Hematopoietic Cell Transplantation for the Treatment of Hematologic Malignancies Not in Remission: The Anti-Tumor Effect of Reduced-Intensity Conditioning Is Comparable to That of Conventional Myeloablative Conditioning.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1142-1142
Author(s):  
Dai Maruyama ◽  
Takahiro Fukuda ◽  
Ruri Kato ◽  
Satoshi Yamasaki ◽  
Eiji Usui ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Hematologic Malignancies ◽  
Reduced Intensity Conditioning ◽  
Myeloablative Conditioning ◽  
Reduced Intensity

Abstract Myeloablative conditioning has been used to maximally reduce the tumor burden before hematopoietic cell transplantation (HCT) in patients not in remission. However, the potential of reduced-intensity conditioning has not been fully questioned. To address this point, we retrospectively reviewed the medical records of 132 patients with hematologic malignancies not in remission who underwent allogeneic HCT at our center between 2000 and 2004. Eighty-two patients had myeloid malignancies, and 50 had lymphoid malignancies. Disease status was primary refractory (n=42), refractory relapse (n=65), blastic crisis or accelerated phase of chronic myelogeneous leukemia (CML, n=8), or untreated disease (n=17). Patients with CML in chronic phase, myelodysplastic anemia-refractory anemia, and those in partial remission were not included. Donors included HLA-matched (n=54) or mismatched (m=16) relatives and unrelated volunteers (n=62). Stem cell source was G-CSF-mobilized peripheral blood stem cell (n=70), bone marrow (n=47), or cord blood (n=15). We compared the non-relapse mortality (NRM), relapse or progressive disease (PD), overall survival (OS), and progression-free survival (PFS) of patients who received fludarabine-based reduced-intensity (RIST group, n=80) or conventional myeloablative conditioning (CST group, n=52). The median age of the RIST group was significantly older than that of the CST group (53 years vs 40 years, p<0.0001). The RIST group included higher proportions of patients with lymphoid disease, those with more comorbidity, and those who received grafts from HLA-matched relatives. Disease status was similar between the two groups. The probabilities of achieving complete remission and the incidences of grades II-IV and III-IV acute graft-versus-host disease in the RIST vs CST groups were 70% vs 83%, 50% vs 50%, and 28% vs 23%, respectively. Figure 1 shows the Kaplan-Meier estimate of overall survival stratified according to conditioning regimen. The 2-year probabilities of NRM (38% vs 37%), PD (49% vs 52%), OS (38% vs 29%), and PFS (29% vs 27%) in the RIST vs CST groups were not significantly different. Multivariate analyses revealed that a higher HCT-specific comorbidity index and transplant from donors other than HLA-matched relatives were associated with increased risks of high NRM and poor OS, and patients who did not receive aggressive chemotherapy within 2 months before HCT were associated with a lower risk of PD and better PFS. After adjusting for these variables, the risks of NRM, PD, OS, and PFS in the RIST group were not significantly different from those in the CST group. In conclusion, our study suggests that the anti-tumor effect of RIST is comparable to that of conventional myeloablative HCT, and hence RIST is feasible for the treatment of hematologic malignancies not in remission. A prospective study is warranted to confirm this conclusion. Overall Survival of patients not in remission according to conditioning regimen Overall Survival of patients not in remission according to conditioning regimen

Impact of ATG Dose on the Outcome of Patients Undergoing Reduced Intensity Conditioning Followed by Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies

2016 ◽  
Vol 136 (4) ◽  
pp. 193-200 ◽  
Author(s):  
Jérôme Cornillon ◽  
Marie Balsat ◽  
Aurélie Cabrespine ◽  
Emmanuelle Tavernier-Tardy ◽  
Eric Hermet ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity

Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often proposed for patients with comorbidities. To enhance engraftment and limit graft-versus-host disease (GVHD), antithymoglobulin (ATG) is usually used. However, the dose needed remains unclear unlike myeloablative conditioning. In order to clarify this point, we conducted a retrospective study on patients who received a reduced intensity conditioning allo-HSCT based on a 2-day fludarabine and busulfan treatment with either 1 or 2 days of ATG treatment. One hundred and eight patients received 2.5 mg/kg (ATG2.5) and another 60 patients 5 mg/kg (ATG5). The median follow-up was 36 months. The median overall survival was 39 months and the median disease-free survival 45 months. In multivariate analysis, overall nonrelapse mortality (NRM) was independently influenced by the acute GVHD grade III-IV (p < 0.001) and ATG dose (30 vs. 21% for ATG5; p = 0.008). Despite heterogeneity of populations, using proportional-hazard assumptions, we have been able to observe in multivariate analysis a lower NRM in the ATG5 group. This leads to a statistically higher overall survival for the ATG5 group. In conclusion, 2 days of ATG decrease NRM independently without increasing the risk of relapse or infectious disease.

HLA-Haploidentical Familial Donor Hematopoietic Cell Transplantation without Ex Vivo- T Cell Depletion after Reduced-Intensity Conditioning of Busulfan, Fludarabine, and Anti-Thymocyte Globulin: A Preliminary Report.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3077-3077
Author(s):  
Kyoo-Hyung Lee ◽  
Seong-Jun Choi ◽  
Jung-Hee Lee ◽  
Ho-Jin Shin ◽  
Young-Shin Lee ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Cell Depletion ◽  
Reduced Intensity Conditioning ◽  
T Cell Depletion ◽  
Reduced Intensity

Abstract Animal hematopoietic cell transplantation (HCT) models and several small clinical trials showed that successful engraftment can be achieved across HLA-haplotype difference after reduced-intensity conditioning (RIC). Furthermore, decreased graft-versus-host disease (GVHD) and transplantation-related mortality (TRM) after RIC was shown in a swine leukocyte antigen-haploidentical HCT experiment. Therefore, a protocol investigating the role of RIC in HLA-haploidentical familial donor HCT was initiated in April 2004 and 20 patients [13 male and 7 female; median age 26.5 years (16–65)] without HLA-matched donor enrolled until June 2007. The diagnosis were AML (n=9), ALL (n=4), acute biphenotypic leukemia (n=1), MDS (n=4), and SAA (n=2), and all patients had high-risk features, i.e. first complete remission (CR) but with high-risk chromosomal abnormality (n=1), first CR after salvage (n=1), second CR (n=6), recurrent/refractory state (n=7), immunotherapy failure (n=4), and high-risk MDS (RAEB-1, n=1). The RIC included iv busulfan 3.2 mg/kg × 2, fludarabine 30 mg/m2 × 6, plus anti-thymocyte globulin [Thymoglobuline 3 mg/kg (n=17) or Lymphoglobuline 15 mg/kg (n=3)] × 4. After receiving G-CSF, the donors (13 mothers; 5 offsprings; and 2 HLA-haploidentical siblings) underwent 2 or 3 daily leukapheresis, and the collected cells were given to patients without T cell depletion [medians of; 7.9 (3.7–12.1)×108/kg MNC, 6.9 (3.6–73.5)×106/kg CD34+ cells, and 4.6 (1.8–8.5)×108/kg CD3+ cells]. GVHD prophylaxis was cyclosporine 3 mg/kg/day iv from day -1 and a short course of methotrexate. As a part of separate phase 1 study, the two most-recently enrolled patients received additional donor CD34+ cell-derived NK cells 6 weeks after HCT. Except one patients with SAA who died due to K. pneumoniae sepsis on day 18, all 19 evaluable patients engrafted with ANC> 500/μl median 17 days (12–53) and platelet> 20,000/μl median 23 days (12–100) after HCT. Eight patients experienced acute GVHD (grades I, II, III, and IV; 2, 3, 2, and 1, respectively). Cumulative incidences (CI) of overall and grade II-IV acute GVHD were 40 and 30%, respectively. Eight patients experienced chronic GVHD (limited, 4; extensive, 4; CI, 51%). Fourteen showed positive CMV antigenemia, while 2 suffered CMV colitis, which resolved after treatment. As early as 2 weeks after HCT, 15 of 16 evaluable patients, and, by 4 weeks, all of 17 evaluable patients showed donor chimerism ≥95% on STR-PCR, which was maintained until 24 weeks in all 11 patients tested. Thirteen patients are alive after median follow-up of 13.6 months (1.5–37.9; Kaplan-Meier survival, 55.6%). Of 16 patients with acute leukemia and high-risk MDS, 8 remain alive without recurrence (event-free-survival, 40.9%). Two patients died of K. pneumoniae sepsis and grade IV acute GVHD, respectively (CI of TRM, 11%). Immune recovery in 10 patients without relapse for > 6 months showed robust lymphocyte contents and immunoglobulin levels at 6 months (means of; 1,060/ul CD3+, 222/ul CD4+, 767/ul CD8+ cells, and 1,317 mg/dl IgG) and 12 months. After RIC, consistent engraftment and durable complete donor hematopoietic chimerism can be achieved from HLA-haploidentical familial donor. The frequencies of GVHD and TRM were low.

Immune Reconstitution after Haploidentical Hematopoietic Cell Transplantation: Impact of Reduced Intensity Conditioning and CD3/CD19-Depleted Grafts

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1175-1175
Author(s):  
Birgit Federmann ◽  
Matthias Haegele ◽  
Christoph Faul ◽  
Wichard Vogel ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Hematopoietic Cell Transplantation ◽  
Nk Cell ◽  
Reduced Intensity Conditioning ◽  
Haploidentical Hematopoietic Cell Transplantation ◽  
Reduced Intensity

Abstract Haploidentical hematopoietic cell transplantation (HHCT) using CD3/CD19 depleted grafts may lead to faster engraftment and immune reconstitution since grafts contain also graft-facilitating-cells, CD34− progenitors, NK cells, and dendritic cells. Reduced intensity conditioning may also have a positive impact on immune reconstitution following HHCT. 26 adults received CD3/CD19 depleted HHCT after RIC (150–200 mg/m2 fludarabine, 10mg/kg thiothepa, 120 mg/m2 melphalan and 5mg/day OKT-3 (day −5 to +14)) at our institution between 2005–2008. We prospectively evaluated engraftment and immune reconstitution. B-, NK-, T- and T-cell subsets (CD3/8, CD4/8, CD4/45RA/RO), TCR-Vβ repertoire and NK-cell receptors (NKP30, NKP44, NKP46, NKG2D, CD158a/b/e, CD85j, NKG2A, CD161) were analyzed by FACS. Grafts contained 8.8×106 CD34+ (range, 4.3–18.0 ×106), 2.9×104 CD3+ (range, 1.2–9.2×104) and 3.6×107 CD56+ (range, 0.02–23.0 ×107) cells/kg. Engraftment was rapid with a median time to &gt;500 granulocytes/μl of 11 days (range, 9–15) and a median time to &gt;20 000 platelets/μl of 11 days (range, 8–23). Full chimerism was reached on day 14 (median; range, 6–26). NK-cell engraftment was rapid, reaching normal values on day 20 (median of 247 CD16+CD56+CD3− cells/μl (range, 1–886)) with NK cells comprising up to 70% of lymphocytes. B-cell reconstitution was delayed with 81 (range, 0–280) and 335 (range, 11–452) CD19+20+ cells/μl on days 150 and 400, respectively. T-cell reconstitution was impaired with 49 (range, 0–586) and 364 (range, 35–536) CD3+ cells/μl on day 60 and day 150, respectively. We observed an increase of CD3+CD8+ cells in contrast to CD3+CD4+ cells early after HHCT with a median of 24 (range, 0–399) vs 16 (range, 0–257) and 159 (range, 1–402) vs 96 (range, 18–289) cells/μl on day 50 and day 200, respectively. CD4+CD45RA+ T cells increased slowly while CD4+CD45RO+ T cells reconstituted faster with a median of 61 CD4+CD45RO+ cells/μl (range, 0–310) vs 24 CD4+CD45RA+ (range, 0 to 152) on day 100. Within the CD4+CD25+ regulatory T cells there was a slow regeneration with median of 14 CD4+CD25+ cells/μl (range, 0–96) on day 100 and 28 CD4+CD25+ cells/μl (range, 19–160) on day 200. CD14+CD45+ monocytes did not reach normal values within the time of observation with 7 CD14+CD45+ cells/μl (range, 0–21) on day 120 and 7 CD14+CD45+ cells (range, 2–381) on day 400. TCR-Vβ repertoire and NK-cell receptor reconstitution was analyzed so far in 7 and 8 patients, respectively. We found a skewed T-cell repertoire with oligoclonal T-cell expansions to day 100 and normalization after day 200. An increased natural cytotoxicity receptor (NKP30, NKP44, NKP46) and NKG2A, but decreased NKG2D and KIR-expression was observed on NK-cells until day 100. In conclusion, T- and B-cell reconstitution is delayed after HHCT using CD3/CD19 depleted grafts and RIC. However, T-cell reconstitution is faster compared to data published with CD34 selected grafts and myeloablative conditioning. A fast NK-cell reconstitution early after HHCT was observed. Thus a combination of reduced intensity conditioning with CD3/CD19 depleted grafts appears to accelerate the immune recovery after haploidentical stem cell transplantation.

The Role of In Vivo T-Cell Depletion On Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation From HLA-Identical Siblings in Patients with Follicular Lymphoma: An European Blood and Marrow Transplantation Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3375-3375
Author(s):  
Julio Delgado ◽  
Carme Canals ◽  
Michel Attal ◽  
Kirsty Thomson ◽  
Antonio Campos ◽  
...  
Keyword(s):  
T Cell ◽  
Follicular Lymphoma ◽  
Research Funding ◽  
Alkylating Agent ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Off Label ◽  
Reduced Intensity

Abstract Abstract 3375 Poster Board III-263 Reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (Allo-HCT) has become a feasible and effective therapeutic approach for younger patients with relapsed or refractory follicular lymphoma (FL). However, there is still much debate regarding the most appropriate conditioning regimen or whether the use of in vivo T-cell depletion (TCD) is beneficial or not for these patients. We analyzed the outcome of 164 patients with advanced FL reported to the EBMT from 1999 to 2007, who underwent RIC Allo-HCT conditioned with fludarabine plus an alkylating agent. Donors were HLA-matched siblings in all cases. Patients receiving transplants from alternative donors or conditioned with other agents were specifically excluded. The alkylating agent was melfalan in 48% of cases, busulfan in 32% and cyclophosphamide in 20%. Forty-six patients (28%) received anti-thymocyte globulin (ATG), 41 (25%) received alemtuzumab and 77 (47%) did not receive TCD in vivo. Median age at transplantation was 50 (range 29-64) years, and patients receiving alemtuzumab were significantly younger [45 (33-63)] than those receiving ATG [52 (29-64)] or no TCD [50 (32-64)], P = 0.05. There were no other differences among groups in terms of disease stage or presence of bulky masses at diagnosis, interval from diagnosis to HCT, number of prior therapies, or disease status at HCT. Engraftment was observed in 161 (98%) patients, with no significant differences among groups. Median follow-up was 43 (1–110) months for survivors. At three years, non-relapse mortality (NRM), relapse rate (RR), progression-free survival (PFS) and overall survival (OS) were 17% (95% CI 12-24%), 23% (17-31%), 60% (52-68%) and 75% (67-82%), respectively, for the entire cohort. The incidence of grade 2-4 acute graft-versus-host disease (GVHD) was significantly higher for patients not receiving any TCD (31%) compared to TCD patients (18%), P = 0.05, and the incidence of chronic GVHD at one year was also significantly higher for the former compared to the latter group (68% vs. 25%, P < 0.001). There were no significant differences in NRM among groups, but there was a trend towards a higher RR in patients receiving alemtuzumab (40%) or ATG (24%) compared to patients receiving no TCD (16%) (P = 0.15), which translated into a trend towards a significantly shorter 3-year PFS for the alemtuzumab group (42% vs. 69%; P = 0.18). However, there were no differences in the 3-year OS among groups, which was 77% for patients receiving alemtuzumab, 73% for those receiving ATG and 77% for patients not receiving any TCD. In conclusion, results with RIC Allo-HCT from HLA-identical siblings were very promising for patients with advanced FL. Both alemtuzumab and ATG were effective in reducing acute and chronic GVHD, but had no significant impact on NRM. There was a trend towards a shorter PFS for patients receiving alemtuzumab, which did not translate into a significantly different OS. Disclosures: Delgado: Bayer Schering Pharma: Consultancy, Research Funding; Genzyme: Research Funding. Off Label Use: The use of alemtuzumab as a T-cell depleting agent in the context of hematopoietic transplantation is considered off-label.

Sign in / Sign up

Export Citation Format

Share Document