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.

scholarly journals PTCy-based haploidentical vs matched related or unrelated donor reduced-intensity conditioning transplant for DLBCL

2019 ◽  
Vol 3 (3) ◽  
pp. 360-369 ◽  
Author(s):  
Peter Dreger ◽  
Anna Sureda ◽  
Kwang Woo Ahn ◽  
Mary Eapen ◽  
Carlos Litovich ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Performance Status ◽  
Chronic Gvhd ◽  
B Cell Lymphoma ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Gvhd Prophylaxis ◽  
Matched Donor ◽  
Reduced Intensity

Abstract This study retrospectively compared long-term outcomes of nonmyeloablative/reduced intensity conditioning (NMC/RIC) allogeneic hematopoietic cell transplantation (allo-HCT) from a haploidentical family donor (haplo-HCT) using posttransplant cyclophosphamide (PTCy) with those of matched sibling donor (MSD) and matched unrelated donor (MUD) with or without T-cell depletion (TCD+/TCD−) in patients with relapsed diffuse large B-cell lymphoma (DLBCL). Adult patients with DLBCL who had undergone their first NMC/RIC allo-HCT between 2008 and 2015 were included. Recipients of haplo-HCT were limited to those receiving graft-versus-host disease (GVHD) prophylaxis with PTCy. GVHD prophylaxis in MSD was limited to calcineurin inhibitor (CNI)–based approaches without in vivo TCD, while MUD recipients received CNI-based prophylaxis with or without TCD. Outcome analyses for overall survival (OS) and progression-free survival (PFS), nonrelapse mortality (NRM), and disease relapse/progression were calculated. A total of 1438 patients (haplo, 132; MSD, 525; MUD TCD+, 403; and MUD TCD−, 378) were included. Patients with haplo donors were significantly older, had a better performance status and had more frequently received total body irradiation-based conditioning regimens and bone marrow grafts than MSD and MUD TCD+ or TCD−. 3-year OS, PFS, NRM and relapse/progression incidence after haplo-HCT was 46%, 38%, 22%, and 41%, respectively, and not significantly different from outcomes of matched donor transplants on multivariate analyses. Haplo-HCT was associated with a lower cumulative incidence of chronic GVHD compared with MSD, MUD TCD+/TCD−. NMC/RIC haplo-HCT with PTCy seems to be a valuable alternative for patients with DLBCL considered for allo-HCT but lacking a matched donor.

Transplantation Of Peripheral Blood Progenitor Cells (PBPC) As Compared To Bone Marrow (BM) From Unrelated Related Donors For Hematologic Cancers Using Fludarabine-Alkylating Agent Based Reduced Intensity Conditioning Regimens

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 550-550 ◽  
Author(s):  
Mary Eapen ◽  
Brent R. Logan ◽  
Mary M. Horowitz ◽  
Xiaobo Zhong ◽  
Miguel Angel Perales ◽  
...  
Keyword(s):  
Alkylating Agent ◽  
Chronic Gvhd ◽  
Hazard Ratio ◽  
Reduced Intensity Conditioning ◽  
Agent Based ◽  
Mortality Risks ◽  
Gvhd Prophylaxis ◽  
Conditioning Regimens ◽  
Reduced Intensity

Abstract We explored whether there are differences in graft-versus-host disease (GVHD) or mortality risks after transplantation of PBPC and BM from unrelated donors in the setting of reduced intensity conditioning. Included are 219 BM and 887 PBPC recipients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or non-Hodgkin lymphoma (NHL). Patients received an alkylating agent and fludarabine as their conditioning regimen and for GVHD prophylaxis, calcineurin inhibitor (CNI) with methotrexate (MTX) or mycophenolate (MMF). Recipients of low dose total body irradiation regimen were excluded, as PBPC was the sole graft used with this regimen. Transplantations occurred in the U.S. between 2000 and 2008. The median ages of BM and PBPC recipients were 57 years. The characteristics of the treatment groups were similar except that BM recipients were more likely to have NHL, receive melphalan + fludarabine, in vivo T-cell depletion and, tacrolimus + MTX GVHD prophylaxis. The median follow-up of BM and PBPC recipients were 6 and 5 years, respectively. Preliminary analysis suggested an interaction between graft type and GVHD prophylaxis. Therefore, the effect of graft type was tested as follows: PBPC, CNI + MTX, PBPC, CNI + MMF, BM, CNI + MTX and BM, CNI + MMF. Results are shown in Tables 1 and 2. After adjusting for age, performance score, disease / disease status and HLA-match, mortality risks were higher after transplantation of PBPC or BM when GVHD prophylaxis included MMF compared to MTX (Table 1). There were no significant differences in mortality risks after transplantation of PBPC relative to BM with CNI + MTX GVHD prophylaxis (Table 2). But mortality risks were higher after transplantation of BM compared to PBPC with CNI + MMF (Table 2). Risks of grade 2-4 acute and chronic GVHD were higher after transplantation of PBPC or BM when GVHD prophylaxis included MMF compared to MTX (Table 1). Relapse risks were higher after transplantation of BM compared to PBPC with CNI + MMF (HR 1.55, p=0.02) but not with CNI + MTX GVHD prophylaxis (HR 1.13, p=0.38). Independent of graft type and GVHD prophylaxis regimens, in vivo T cell depletion was associated with lower risks of acute (HR 0.69, p<0.001) and chronic (HR 0.52, p<0.0001) GVHD but relapse risks were higher (HR 1.24, p=0.02). The data support BM and PBPC are suitable for unrelated donor transplantation when using fludarabine-alkylating agent based reduced intensity conditioning regimens and CNI + MTX GVHD prophylaxis. The data support avoiding CNI + MMF GVHD prophylaxis in this setting. Table 1 Overall Mortality Non-relapse Mortality Acute GVHD Chronic GVHD BM Hazard ratio Hazard ratio Hazard ratio Hazard ratio CNI+MMF vs. CNI+MTX* 2.06 p<0.0001 2.85 p<0.0001 3.30 p<0.0001 1.75 p=0.02 PBPC CNI+MMF vs. CNI+MTX* 1.27 p=0.004 1.56 p=0.001 2.04, p<0.0001 1.29, p=0.007 Table 2 Overall Mortality Non-relapse Mortality Acute GVHD Chronic GVHD Comparison of BM vs. PBPC Hazard ratio Hazard ratio Hazard ratio Hazard ratio BM, CNI + MTX vs. PBPC CNI + MTX* 0.73 p=0.14 0.73 p=0.14 0.88 p=0.54 0.78 p=0.09 BM, CNI + MMF vs. PBPC CNI + MMF* 1.47 p=0.008 1.34 p=0.17 1.43 p=0.05 1.06 p=0.78 * reference group Disclosures: No relevant conflicts of interest to declare.

scholarly journals Poor Outcomes of HLA-Mismatched Allogeneic Hematopoietic Cell Transplantation and High Ferritin Levels after a Reduced-Intensity Conditioning Regimen in Patients with Advanced Myelofibrosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5742-5742
Author(s):  
Han Bi Lee ◽  
Jae-Ho Yoon ◽  
Gi June Min ◽  
Sung-Soo Park ◽  
Silvia Park ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Reduced Intensity Conditioning ◽  
Advisory Committees ◽  
Reduced Intensity

Allogeneic hematopoietic cell transplantation (allo-HCT) preconditioning intensity, donor choice, and graft-versus-host disease (GVHD) prophylaxis for advanced myelofibrosis (MF) have not been fully elucidated. Thirty-five patients with advanced MF were treated with reduced-intensity conditioning (RIC) allo-HCT. We searched for matched sibling (n=16) followed by matched (n=10) or mismatched (n=5) unrelated and familial mismatched donors (n=4). Preconditioning regimen consisted of fludarabine (total 150 mg/m2) and busulfan (total 6.4 mg/kg) with total body irradiation≤ 400cGy. All showed engraftments, but four (11.4%) showed either leukemic relapse (n=3) or delayed graft failure (n=1). Two-year overall survival (OS) and non-relapse mortality (NRM) was 60.0% and 29.9%, respectively. Acute GVHD was observed in 19 patients, and grade III-IV acute GVHD was higher with HLA-mismatch (70% vs. 20%, p=0.008). Significant hepatic GVHD was observed in nine patients (5 acute, 4 chronic), and six of them died. Multivariate analysis revealed inferior OS with HLA-mismatch (HR=6.40, 95%CI 1.6-25.7, p=0.009) and in patients with high ferritin level at post-HCT D+21 (HR=7.22, 95%CI 1.9-27.5, p=0.004), which were related to hepatic GVHD and high NRM. RIC allo-HCT can be a valid choice for advanced MF. However, HLA-mismatch and high post-HCT ferritin levels related to significant hepatic GVHD should be regarded as poor-risk parameters. Disclosures Kim: Handok: Honoraria; Amgen: Honoraria; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

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.

Haploidentical Allogeneic Hematopoietic Cell Transplantation in Adults Using Reduced Intensity Conditioning and CD3/CD19-Depleted Grafts: Interim Analysis of a Phase I/II Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1962-1962
Author(s):  
Birgit Federmann ◽  
Martin Bornhauser ◽  
Dietrich W. Beelen ◽  
Gernot Stuhler ◽  
Lambros Kordelas ◽  
...  
Keyword(s):  
Stem Cells ◽  
High Risk ◽  
Complete Remission ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Cd34 Cells ◽  
Risk Patients ◽  
Grade Ii ◽  
Reduced Intensity

Abstract Haploidentical hematopoietic cell transplantation (HHCT) after high dose conditioning with a megadose of CD34-selected stem cells has been complicated by regimen related toxicities, slow engraftment and delayed immune reconstitution leading to high treatment related mortality (TRM). A new regimen using reduced intensity conditioning (RIC) and immunomagnetic CD3/CD19 graft depletion may allow HHCT with lower toxicity and faster engraftment. CD3/CD19 depleted grafts not only contain CD34+ stem cells but also graft-facilitating cells, CD34- progenitors, dendritic and natural killer cells which may allow stable engraftment even without a megadose of CD34+ cells. A multicenter phase I/II study of HHCT using RIC with fludarabine (150–200 mg/m2), thiotepa (10 mg/kg), melphalan (120 mg/m2), OKT-3 (5 mg/day, day -5 to +14) and CD3/CD19 graft depletion has been initiated. No post grafting immunosuppression was applied if the graft contained &lt;5x104 CD3+ cells/kg. To date, 51 patients with a median age of 45 years (range, 19–65) have been enrolled in this study. Diagnosis were AML (n=34), ALL (n=7), NHL (n=6), MM (n=2), and CML (n=2). Patients were “high risk” because of relapsed or refractory disease (n=30), or relapse after preceding HCT (auto=7, allo=14). Stage at HCT was complete remission (n=25) and partial remission (n=26). The CD3/CD19 depleted haploidentical grafts contained a median of 7.1 x 106 (range, 3.4–18x106) CD34+cells/kg, 3.9 x104 (range, 0.6–44x104) CD3+T cells/kg and 2.8x107 (range, 0.02–37.3x107) CD56+cells/kg. The regimen was well tolerated with maximum acute toxicity being CTC-grade 1–2 mucositis. Five cases of reversible peripheral neuropathy and three cases of progressive multifocal leukencephalopathy (PML) occurred posttransplant in heavily pretreated patients. Engraftment was rapid with median time to &gt;500 granulocytes/μL of 12 days (range, 9–50) and to &gt;20000 platelets/μL of 11 days (range, 7–38). Full donor chimerism was reached after 2–4 weeks in all but four patients (median of 14 days (range, 7–215)). Four patients experienced rejection/non-engraftment, two were rescued by a second CD3/CD19 depleted graft from another haploidentical donor. Incidence of grade II-IV acute GVHD was 51% with grade II=16, III=6 and IV=4. So far there are six cases of limited chronic GVHD and one case of extensive chronic GVHD. TRM in the first 100 days was 11/51 (22%) and overall 20/51 (39%). Overall survival is 17/51 patients (33%) with deaths due to relapse (n=14), infection (n=15), PML (n=2), GVHD (n=2) and cardiac failure (n=1), with a median follow-up of alive patients of 397 days (range, 62–1180). This results in a Kaplan-Meier estimate 1-year survival of 37%. So far, we did not observe a statistical significant survival advantage for patient transplanted from a KIR-mismatched donor (28/51 patients). This regimen with low toxicity as well as fast and sustained engraftment is promising in high risk patients lacking a suitable donor. To investigate the treatment protocol earlier in course of disease a new study for high-risk patients with acute leukemia in first complete remission is in preparation.

Allogeneic Stem Cell Transplantation Results in a Low Relapse Rate in Patients with Peripheral T-Cell Lymphoma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 974-974
Author(s):  
Maike Nickelsen ◽  
Carmen Canals ◽  
Charalampia Kyriakou ◽  
Norbert Schmitz ◽  
Agnes Buzyn ◽  
...  
Keyword(s):  
Stem Cell ◽  
Relative Risk ◽  
T Cell ◽  
Cell Lymphoma ◽  
Performance Status ◽  
Chronic Gvhd ◽  
T Cell Lymphoma ◽  
Reduced Intensity Conditioning ◽  
Peripheral T Cell Lymphoma ◽  
Reduced Intensity

Abstract Patients (pts) suffering from mature (peripheral) T-cell lymphoma are known to have a poor outcome compared to pts with aggressive B-cell lymphoma when receiving conventional therapies. However, case reports and single centre experiences show promising results of allogeneic stem cell transplantation (allo SCT) for these pts. We here present a retrospective analysis of 103 pts with mature T-cell lymphoma who received an HLA-identical allo SCT in EBMT centres between 2000 and 2005. Histological subtypes of the patients were anaplastic large cell lymphoma (n=25; 4 anaplastic lymphoma kinase [ALK] positive, 11 ALK negative, 10 ALK unknown), peripheral T-cell lymphoma unspecified (n=51), angioimmunoblastic T-cell lymphoma (n=18) and aggressive T-cell lymphoma unspecified (n=9). Patients with primary cutaneous T-cell lymphoma or T-lymphoblastic lymphoma were excluded. Median follow up for surviving patients was 40 months (6–98), median age at allo SCT 42 years (18–68) and median time to allo SCT 17 months (3–233). 39 pts had failed a prior autologous SCT; 68 pts had chemosensitive disease at allo SCT (of these 15 in CR1) and 30 pts had chemorefractory or untested relapsed or progressive disease. Donors were HLA identical siblings for 73 and matched unrelated donors for 30 pts; 82 pts received peripheral blood stem cells. 54 pts were treated with reduced intensity conditioning before SCT. The cumulative incidence (CI) of acute graft versus host disease (GvHD) 100 days after SCT was 52% and had no effect on non-relapse mortality (NRM) or relapse rate (RR). 34 of 74 evaluable pts experienced chronic GvHD (14 limited, 20 extensive), CI 46% at 2 years. Introducing chronic GvHD as a time dependent covariate, this factor was associated with a higher NRM (p<0.001) and a lower RR (statistically not significant), resulting in a lower progression free survival (PFS) (p=0.001). For all patients CI of NRM and RR at 3 years were 36.7% and 24.9%, respectively, resulting in 41.4% PFS and 46.9% OS. Median time to relapse / progression was 4 (1–18) months. In multivariate COX analysis for PFS refractory disease (relative risk 3.4, p=0.001), prior failed auto SCT (relative risk 2.6, p=0.001) and poor performance status at SCT (relative risk 2.5, p=0.04) were significant adverse factors. Additionally, there were trends for T-cell depleted grafts (p=0.1), CMV status other than negative-negative (p=0.1) and reduced intensity conditioning (p=0.2) to be adverse factors. A subgroup of 39 good risk pts (good performance status, chemosensitive disease, no prior autologous SCT) had a PFS of 59%. This retrospective analysis on allo SCT in peripheral T-cell lymphoma shows an encouraging low RR but efforts have to be made to reduce NRM. Prospective studies are warranted to further define pts who will profit from an early allo SCT.

A Retrospective Study of Alemtuzumab Level, T Cell Chimerism and Graft Versus Host Disease Using Intermediate Dose Alemtuzumab for Matched Related and Matched Unrelated Reduced Intensity Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3333-3333
Author(s):  
Andrew Charlton ◽  
Laura Spence ◽  
Venetia Bigley ◽  
Natasha Groves ◽  
Geoff Hale ◽  
...  
Keyword(s):  
T Cell ◽  
Linear Regression ◽  
Surface Area ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Full Dose ◽  
Cell Engraftment ◽  
Gvhd Prophylaxis ◽  
Reduced Intensity

Abstract Abstract 3333 Poster Board III-221 Alemtuzumab (CAMPATH 1H) is a well established agent for effecting in vivo T cell depletion and prevention of GVHD in reduced intensity transplants. Many studies indicate that full dose alemtuzumab (100mg in 5 daily doses of 20mg) induces profound immunodeficiency, almost completely ablating GVHD in Fludarabine and Melphalan (FM) matched related donor (MRD) and matched unrelated donor (MUD) transplants. In contrast, FM conditioning alone exposes patients to a high burden of acute and chronic GVHD. Accordingly, many transplant centres have adopted policies of intermediate alemtuzumab dosing of 50mg or less. While the pharmacokinetics, rate of T cell engraftment and incidence of GVHD are well described using full dose alemtuzumab, much less is known about the in vivo action of alemtuzumab at intermediate doses. Methods We report our experience of alemtuzumab at 30mg (day -2) for MRD and 60mg (30mg day -4 and day -2) for MUD transplants, which was adopted as standard GVHD prophylaxis for FM transplantation at our centre in 2006. We avoided giving alemtuzumab on day -1, since there is a steep drop in alemtuzumab level in the first 24 hours after infusion and the timing of stem cell infusion may vary considerably, especially with unrelated donor grafts. From May 2006 to May 2009, 24 patients received MRD and 27 patients received MUD transplants. Post transplant serum samples were available from 19 MRD transplants and 15 MUD transplants at day +1. In addition, day +3 samples were identified from 10 patients previously transplanted with 100mg alemtuzumab, 10 MUD receiving 60mg and 10 MRD transplants receiving 30mg. All patients gave consent for clinical follow up and post transplant serum sampling for research purposes, according to protocols approved by the local research ethics committee of Northumberland and North Tyneside. Alemtuzumab concentration was measured by a validated flow cytometry assay, as previously described. Results The mean (SEM) alemtuzumab concentration (micrograms/ml) on day +1 was 2.9 (0.3) after 30mg and 4.6 (0.6) after 60mg (t test p<0.01). On day +3 the levels were 2.4 (0.2); 4.0 (0.6); 8.4 (1.9) after 30mg, 60mg and historical controls of 100mg, respectively (p<0.05 between each dosing level). There were significant inverse correlations between patient surface area and alemtuzumab concentration by linear regression for both 30mg (r2 0.51 p<0.01) and 60mg dosing (r2 0.18 p<0.05). A trend for lower alemtuzumab with increasing cell dose was also observed, although this may be related indirectly to patient weight. All patients achieved >95% myeloid engraftment by day 100. Median (range) T cell engraftment was variable and significantly higher after MUD transplants: 70% (9-99%) than MRD transplants: 21% (5-85%; Mann Witney p <0.05). T cell chimerism was inversely correlated with alemtuzumab level in MRD transplants by linear regression (r2 0.37; p <0.05) but this trend was not apparent in MUD transplants. The incidence of acute GVHD was also greater after MUD transplantation at 47% (grade I or II) compared with 11% (grade I only) for MRD recipients. There was no significant relationship between GVHD grade and alemtuzumab level in either group. There were 2/24 non-relapse deaths after MRD and 3/27 following MUD transplantation; none were due to GVHD. The incidence of chronic GVHD is currently being evaluated. Conclusion This analysis demonstrates predictable dose and surface-area relationships with alemtuzumab level in patients receiving FM conditioning. It also reveals that significantly less than 100mg alemtuzumab confers reliable GVHD prophylaxis in both MRD and MUD recipients, although at least twice the level of alemtuzumab is required to achieve comparable GVHD control in MUD transplants. Finally, it is notable that T cell chimerism at day 100 is directly related to alemtuzumab level at day +1 in MRD transplants. We conclude that optimisation of immune reconstitution and GVHD control using alemtuzumab in vivo depends upon due consideration of both recipient and donor factors, notably the size of the recipient and the origin of the graft. Disclosures Groves: BioAnaLab: Employment. Hale:BioAnaLab: Employment, Equity Ownership.

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