scholarly journals T-cell depletion of HLA-identical transplants in leukemia

Blood ◽  
1991 ◽  
Vol 78 (8) ◽  
pp. 2120-2130 ◽  
Author(s):  
AM Marmont ◽  
MM Horowitz ◽  
RP Gale ◽  
K Sobocinski ◽  
RC Ash ◽  
...  
Keyword(s):  
T Cell ◽  
Treatment Failure ◽  
Chronic Gvhd ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Free Survival ◽  
Dose Rates ◽  
Leukemia Relapse

We analyzed the effects of T-cell depletion on the outcome of HLA- identical sibling bone marrow transplants for leukemia by comparing 731 T-cell-depleted transplants with 2,480 non-T-cell-depleted transplants. T-cell depletion decreased acute graft-versus-host disease (GVHD) (relative risk [RR] 0.45; P less than .0001) and chronic (GVHD) (RR 0.56; P less than .0001). However, it increased graft failure (RR 9.29; P less than .0001). Leukemia relapse also was increased. In first remission acute leukemia or chronic phase chronic myelogenous leukemia, leukemia relapse was 2.75 times more likely after T-cell-depleted transplants (P less than .0001). T-cell depletion increased the risk of treatment failure (RR 1.35; P less than .0003) and decreased leukemia- free survival. We also studied controllable variables associated with outcome of T-cell-depleted transplants. The unique findings were that among recipients of T-cell-depleted transplants for early leukemia, radiation doses greater than or equal to 11 Gy (RR 0.54; P less than .01), dose rates greater than 14 cGy/min (RR 0.56; P less than .002), and additional posttransplant immune suppression with cyclosporine alone (RR 0.53; P less than .0006) or cyclosporine plus methotrexate (RR 0.36; P less than .01) were associated with fewer treatment failures. Use of monoclonal antibodies rather than physical techniques for T-cell depletion (RR 2.01; P less than .03) and fractionated radiation (RR 1.69; P less than .05) were associated with increased treatment failure and lower leukemia-free survival. These data may be useful in designing strategies to improve results of T-cell-depleted transplants.

scholarly journals T-cell depletion of HLA-identical transplants in leukemia

Blood ◽  
1991 ◽  
Vol 78 (8) ◽  
pp. 2120-2130 ◽  
Author(s):  
AM Marmont ◽  
MM Horowitz ◽  
RP Gale ◽  
K Sobocinski ◽  
RC Ash ◽  
...  
Keyword(s):  
T Cell ◽  
Treatment Failure ◽  
Chronic Gvhd ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Free Survival ◽  
Dose Rates ◽  
Leukemia Relapse

Abstract We analyzed the effects of T-cell depletion on the outcome of HLA- identical sibling bone marrow transplants for leukemia by comparing 731 T-cell-depleted transplants with 2,480 non-T-cell-depleted transplants. T-cell depletion decreased acute graft-versus-host disease (GVHD) (relative risk [RR] 0.45; P less than .0001) and chronic (GVHD) (RR 0.56; P less than .0001). However, it increased graft failure (RR 9.29; P less than .0001). Leukemia relapse also was increased. In first remission acute leukemia or chronic phase chronic myelogenous leukemia, leukemia relapse was 2.75 times more likely after T-cell-depleted transplants (P less than .0001). T-cell depletion increased the risk of treatment failure (RR 1.35; P less than .0003) and decreased leukemia- free survival. We also studied controllable variables associated with outcome of T-cell-depleted transplants. The unique findings were that among recipients of T-cell-depleted transplants for early leukemia, radiation doses greater than or equal to 11 Gy (RR 0.54; P less than .01), dose rates greater than 14 cGy/min (RR 0.56; P less than .002), and additional posttransplant immune suppression with cyclosporine alone (RR 0.53; P less than .0006) or cyclosporine plus methotrexate (RR 0.36; P less than .01) were associated with fewer treatment failures. Use of monoclonal antibodies rather than physical techniques for T-cell depletion (RR 2.01; P less than .03) and fractionated radiation (RR 1.69; P less than .05) were associated with increased treatment failure and lower leukemia-free survival. These data may be useful in designing strategies to improve results of T-cell-depleted transplants.

scholarly journals Children with Acute Leukemia Given Hematopoietic Stem Cell Transplantation (HSCT) from an HLA-Compatible Sibling, or an Unrelated Donor (UD) or an HLA-Haploidentical Relative after Alpha/Beta T-Cell Depletion Have a Comparable Outcome

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 195-195 ◽  
Author(s):  
Alice Bertaina ◽  
Barbarella Lucarelli ◽  
Riccardo Masetti ◽  
Pietro Merli ◽  
Roberto Rondelli ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Leukemia ◽  
Treatment Failure ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Background: Allogeneic HSCT is a widely used treatment for children with acute leukemia (AL) either relapsed or at high risk of treatment failure. However, an HLA-identical sibling is available for only 20-25% of patients and an UD can be located in a suitable time only for a portion of the remaining population. HSCT from an HLA-haploidentical relative (haplo-HSCT) is now considered an alternative option, especially in view of the recent insights in graft manipulation. We recently developed a novel method of more selective T-cell depletion based on physical elimination of α/β T cells (ClinicalTrial.gov identifier: NCT01810120), shown to be effective for both preventing graft-versus-host disease (GvHD) and for conferring improved protection against infections in comparison to haplo-HSCT performed through the infusion of positively selected CD34+ cells. The initial results on 40 patients with AL were reported at the ASH Meeting in 2013 (Bertaina et al). We now present the comparison of the outcome of 80 children with AL given haplo-HSCT after α/β T-cell depletion (group 1) with that of patients transplanted from an HLA-identical sibling (group 2) or an UD (group 3) in the same time period. Patients and methods: All patients with AL were transplanted at the Bambino Gesù Children's Hospital in Rome, Italy, between December 2010 and September 2014; 80 patients were included in group 1, 41 in group 2 and 51 in group 3. Patients were offered α/β T-cell-depleted haplo-HSCT in the absence of suitable conventional donor (HLA identical sibling or 10/10 UD evaluated using high resolution typing) or if affected by rapidly progressive disease not permitting time to identify an UD. Clinical characteristics of patients assigned to the 3 groups and those of their donor are shown in Table1. All children were given a fully myeloablative regimen. No group 1 patient was given any post-transplantation GvHD prophylaxis, while patients of group 2 and 3 were given Cyclosporine-A and short-term methotrexate. Group 1 and 3 patients received ATG Fresenius® (4 mg/Kg/day) from day -5 to -3 for preventing both graft rejection and GvHD. Results: All group 2 and 3 patients had sustained engraftment of donor cells, while 1 of the 80 patients included in group 1 experienced primary graft failure and was rescued by haplo-HSCT from the other parent. The cumulative incidence (CI) of acute GvHD was 30%, 41% and 42%, respectively. Remarkably, all children of the group 1 who developed acute GvHD had a skin-only involvement, while 17% and 16.3% of those of group 2 and 3 had either gut or liver involvement (p<0.001). The CI of chronic GvHD was significantly lower in group 1 children than in those of groups 2 and 3 (p=0.02, see also Figure 1-Panel A). None of the 4 group 1 patients experiencing chronic GvHD had the extensive form of the disease, while the CI of extensive chronic GvHD of group 2 and 3 was 8% and 14%, respectively (p=0.01). Four, 1 and 6 children of patients assigned in group 1, 2 and 3, respectively, died for transplant-related causes; the CI of transplantation-related mortality (TRM) in the 3 groups is shown in Figure 1-Panel B. Relapse was the main cause of treatment failure and occurred at a comparable CI in all the 3 groups (see also Panel C of Figure 1). The 3-year probability of Event-Free Survival (EFS) was comparable in the 3 groups (Figure 1 - Panel D). In multivariate analysis, a Total Body Irradiation (TBI)-containing regimen was the only variable favourably influencing EFS of group 1 children (hazard ratio 2.93, 95% Confidence Interval 1.24-6.95). No variable influenced EFS of group 2 and 3 patients. Conclusions: Overall, these data indicate that haplo-HSCT after α/β T-cell depletion is associated with a risk of TRM and leukemia recurrence comparable to that of transplantation from an HLA-identical sibling or an UD, this translating in a similar probability of EFS. In view of the low incidence of chronic GvHD, this transplant option has to be considered a competitive alternative for children with AL in need of an allograft. Table. Sibling (n=41) MUD (n=51) Haplo (n=80) Sex p=0.77 M 27 32 55 F 14 19 25 Age at Transplantation (years) 10.6 9.4 9.7 p=0.20 Disease p=0.23 ALL 34 35 56 AML 7 16 24 Disease status at Transplantation p=0.13 CR1 20 30 30 CR2 21 20 47 ≥CR3 0 1 3 CMV serology (Donor/Recipient) p=0.001 neg/neg 8 5 6 neg/pos 8 21 7 pos/neg 1 4 11 pos/pos 24 21 56 Source of Stem Cells p<0.0001 BM 40 40 0 PBSC 1 11 80 Conditioning regimens p=0.10 TBI-based 26 29 60 non TBI-based 15 22 20 Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Alternative Donor Hematopoietic Cell Transplantation (HCT) After Reduced Intensity (RIC) or Nonmyeloablative (NST) Conditioning in Advanced Non-Hodgkin Lymphoma (NHL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3380-3380
Author(s):  
Gregory A. Hale ◽  
Smriti Shrestha ◽  
Jennifer LeRademacher ◽  
Hillard M Lazarus ◽  
Ginna G. Laport ◽  
...  
Keyword(s):  
T Cell ◽  
Treatment Failure ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Resistant Disease ◽  
Donor Type ◽  
Alternative Donor ◽  
Risk Of Treatment

Abstract Abstract 3380 Poster Board III-268 For adult allogeneic HCT candidates lacking a matched family donor, an alternative donor (unrelated or mismatched family) remains the most feasible option. Lower intensity conditioning using RIC or NST regimens is increasingly used in NHL to lower transplant related mortality (TRM) while retaining graft vs. lymphoma effect. We analyzed the outcomes of 248 (61% male) adult recipients of HCT for NHL from alternative donors after RIC/NMA conditioning reported to the CIBMTR from 1997 to 2004. Recipients of any prior transplants and those in first complete remission from follicular NHL were excluded. Outcomes of TRM, progression, progression-free survival (PFS) and overall survival (OS) were analyzed in multivariate regression models adjusting for key pre-transplant variables. Median age was 52 (range, 18-72 yrs); 36% having a Karnofsky performance score ≤90. Follicular NHL (43%) was the major histology with 75% in stages III and IV, 47% with chemotherapy resistant disease and only 18% in CR2. Patients received BM (43%) or PBSC (57%) grafts from unrelated well matched/partially matched/mismatched (61% /19% /9% respectively) or related mismatched (10%) donors. Conditioning included fludarabine with either melphalan (20%), TBI (11%), cyclophosphamide (25%), or busulfan (12%); busulfan/cyclophosphamide (RIC) (2%); BEAM (6%); CBV (8%); and others (16%). Use of RIC/NMA regimens increased yearly during the study period from 7 in 1997 to 121 in 2003. Cumulative incidence of grade II-IV acute GVHD (aGVHD) was 43%; and chronic GVHD (cGVHD) was 36% at 1 year and 44% at 3 years. The TRM at 28 and 100 days was 11% and 24%, respectively. Outcomes at a median follow-up of 44 months summarized in Table 1, Figure 1 and Figure 2. Table 1 Probability (95% CI) Outcomes 1 year 3 years 5 years TRM 31 (25 - 37)% 39 (32 - 45)% 43 (36 - 50)% Relapse/Progression 26 (20 - 31)% 30 (24 - 36)% 31 (26 - 38)% PFS 43 (37 - 50)% 32 (26 - 37)% 26 (19 - 32)% OS 55 (48 - 61)% 41 (34 - 47)% 35 (28 - 42)% In multivariate analysis (Table 2) the use of ATG and HLA mismatch were associated with an increased TRM. Higher age (≥ 60), non-follicular histology, advanced disease status at HCT and later year of HCT were associated with higher risk of relapse. High-grade histology, the use of ATG, and chemotherapy resistant disease at HCT were associated with higher risk of treatment failure or lower PFS. Higher age, shorter interval from diagnosis to HCT, non-TBI conditioning regimens or T-cell depletion and HLA mismatched unrelated donors were associated with lower risk of survival. Acute or chronic GVHD did not influence TRM or PFS. Common causes of death were disease recurrence (n=40), organ failure (n=29), GVHD (n=23). In NHL patients without sibling donor options, alternative donor HCT with RIC/NMA conditioning results in favorable long-term survival although advanced age, histology and resistant disease status remain concerning. Higher grade NHL, use of ATG or T-cell depletion and HLA mismatch were associated with inferior outcomes. Lack of an available sibling donor should not be a barrier to allogeneic HCT in the appropriate patient. Table 2 Variables Relative Risk (95% CI) P-value TRM ATG: No vs. Yes 2.13 (1.40 - 3.25) <0.001 Donor type: Unrelated well matched vs. mismatched 2.07 (1.17 - 3.84) 0.02 Relapse Age: ≤ 60 vs. >60 1.93 (1.07 - 3.48) 0.028 Histology: Follicular vs. Diffuse Large B Cell 3.46 (1.80 - 6.34) <0.001 Status: CR2+ vs. REL Resistant 5.05 (2.13 - 11.99) <0.001 Risk of Treatment Failure Histology: Follicular vs. Lymphoblastic/Burkitts/Burkitt-like 2.11 (1.40 - 3.18) <0.001 Status: CR2+ vs. REL Resistant 2.54 (1.50 - 4.31) 0.001 ATG: No vs. Yes 1.50 (1.07 - 2.10) 0.020 Time from diagnosis to transplant: ≥ 24 vs. 12 – 24 months 1.58 (1.09 – 2.31) 0.017 Risk of Mortality Age: ≤ 60 vs. > 60 1.77 (1.16 - 2.70) 0.009 Time from diagnosis to transplant: ≥ 24 vs. 12 – 24 months 2.26 (1.56 - 3.27) <0.001 TBI: Yes vs. No 2.17 (1.36 - 3.48) 0.001 Donor type: Unrelated well matched vs. mismatched 2.20 (1.24 - 3.90) 0.007 GVHD prophylaxis: FK506/MTX vs. T-cell depletion 6.0 (2.68 - 13.45) <0.001 Figure 1 Figure 1. Figure 2 Figure 2. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Impact of Different In Vivo T Cell Depletion Strategies on Outcomes Following Hematopoietic Stem Cell Transplantation for Idiopathic Aplastic Anaemia: A Study on Behalf of the EBMT SAA Working Party

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1210-1210 ◽  
Author(s):  
Sujith Samarasinghe ◽  
Simona Iacobelli ◽  
Cora Knol ◽  
Rose-Marie Hamladji ◽  
Gerard Socie ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Event Free Survival ◽  
T Cell Depletion ◽  
Educational Support ◽  
Free Survival

Abstract To determine the optimal serotherapy regimen in idiopathic aplastic anaemia stem cell transplantation, we analysed 1837 patients who underwent either in vivo T cell depletion with either ATG (n=1283) or Alemtuzumab (n=261) or no serotherapy (n=293) as part of their conditioning regimen. All patients had either undergone a matched sibling or matched unrelated donor stem cell transplant (at least 6 out of 6). Data was obtained retrospectively from the EBMT SAA database, between the periods 2000-2013. The major endpoints were graft versus host disease, overall survival and event free survival. Events were classified as graft failure, secondary malignancy, relapse and requirement for second transplant. The median follow up was 34 months in the ATG group, 30.9 months in the Alemtuzumab group and 47.9 months in the no serotherapy group. Rate of grade 2-4 acute GVHD was 19.1% without serotherapy; this was higher than that observed with both ATG (13.3%, p<0.001) and Alemtuzumab (6.7%, p<0.001; ATG vs Alemtuzumab: p=0.012). Cumulative incidence of chronic GVHD at 36 months was 30.4% without serotherapy; this was higher than that observed with both ATG (20.8%, p=0.021) and Alemtuzumab (14.7%, p=0.003; ATG vs Alemtuzumab: p=0.083). In multivariate analysis, grade 2-4 acute and chronic GVHD rates were significantly lower with Alemtuzumab compared to no serotherapy (Odds Ratio ratio (OR) = 0.16, p< 0.001 95%CI 0.08-0.31 and HR= 0.38, 95% CI 0.24-0.62, p< 0.001 respectively). Similarly, acute and chronic GVHD were lower with Alemtuzumab compared to ATG (OR = 0.26;p<0.001 95%CI 0.14-0.47 and HR = 0.58; 95%CI 0.38-0.89, p=0.012 , respectively). Acute and chronic GVHD were higher without serotherapy compared to ATG (OR = 1.65; p =0.01 95%CI 1.12-2.41 and HR = 1.51; 95%CI 1.12-2.04, p=0.008 , respectively). There was no difference in event free survival between the three groups. However, overall survival at 36 months was 73.3%, 81.3% and 81.5 in no serotherapy, ATG and alemtuzumab, respectively (ATG vs no serotherapy p=0.01; Alemtuzumab vs no serotherapy p=0.025; Alentuzumab vs ATG p=0.604). In multivariate analysis overall survival favoured in vivo T cell depletion compared to no serotherapy; (Alemtuzumab vs no serotherapy, HR=0.44; 95%CI 0.29-0.67, p<0.001); (no serotherapy vs. ATG HR=1.55; 95%CI 1.19-2.01, p=0.001). Among serotherapy, Alemtuzumab was associated with better OS as compared with ATG (OR=0.68; 95%CI 0.48-0.98, p=0.037). Our results suggest that use of in vivo T cell depletion in sibling and unrelated matched stem cell transplantation in idiopathic aplastic anaemia leads to a survival advantage. Alemtuzumab is associated with less GVHD than ATG without affecting event free survival. Figure 1. Figure 1. Disclosures Snowden: Celgene: Other: Educational support, Speakers Bureau; Janssen: Other: Educational support, Speakers Bureau; MSD: Consultancy, Other: Educational support, Speakers Bureau; Sanofi: Consultancy. Dufour:Pfizer: Consultancy. Risitano:Pfizer: Consultancy; Novartis: Research Funding; Rapharma: Consultancy, Research Funding; Alnylam: Consultancy, Research Funding; Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: this paper includes discussion of the use of alentuzumab for GVHD prophylaxis, which is currently off-label.

scholarly journals Effect of T-cell depletion as graft-versus-host disease prophylaxis on engraftment, relapse, and disease-free survival in unrelated marrow transplantation for chronic myelogenous leukemia

Blood ◽  
1994 ◽  
Vol 83 (7) ◽  
pp. 1980-1987 ◽  
Author(s):  
WR Drobyski ◽  
RC Ash ◽  
JT Casper ◽  
T McAuliffe ◽  
MM Horowitz ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Disease Free Survival ◽  
Myelogenous Leukemia ◽  
Free Survival ◽  
Entire Cohort ◽  
Graft Versus Host ◽  
Disease Free

Abstract Between January 1988 and March 1993, 48 patients received T-cell- depleted marrow grafts from unrelated donors as treatment for chronic myelogenous leukemia (CML). The median age of the population was 31.7 years (range 5.4 to 53) with 17 of 48 patients greater than 40 years of age. Twenty-seven patients were transplanted in chronic phase, 17 in accelerated phase, and 4 in blast crisis. All patients received a standardized preparative regimen of cyclophosphamide, high-dose cytosine arabinoside, methylprednisolone, and total body irradiation. Marrow grafts were depleted of mature T cells with the alpha beta T- cell receptor antibody T10B9 as graft-versus-host disease (GVHD) prophylaxis. All patients also received posttransplant cyclosporine therapy. Twenty-eight of 48 patients were mismatched with their donors for one or more HLA-A, B, DR, or DQ loci by either serology or high- resolution oligonucleotide genotyping. Nine of 28 were mismatched at multiple HLA loci. Durable engraftment was achieved in 94% (45/48) of patients. The actuarial probability of developing grades II to IV and grades III to IV acute GVHD were 39.6% (95% confidence interval (CI) 26.9 to 53.0) and 8.3% (95% CI 6.1 to 10.9) for the entire cohort. There was no difference in the incidence of grades II to IV acute GVHD between patients receiving matched (36.8%) or mismatched (41.4%) marrow grafts (P = .77). The actuarial probability of relapse at 2 years was 8.8% (95% CI 2.1 to 21.6) for the entire cohort and 18% (95% CI 4 to 41) for patients transplanted in either the accelerated or blast crisis phase (advanced disease). One cytogenetic relapse has occurred among patients transplanted in the chronic phase. The probability of disease- free survival at 2 years was 52% (95% CI 24 to 70) for patients transplanted in chronic phase and 46% (95% CI 25 to 73) for patients transplanted with advanced disease. No difference in disease-free survival was observed between patients receiving matched (49%) or mismatched (51%) marrow grafts (P = .90). This study shows that patients receiving unrelated T-cell-depleted marrow grafts for CML can achieve durable engraftment with a low incidence of severe GVHD and apparent preservation of graft-versus-leukemia reactivity. These data also suggest that T-cell depletion may allow patients who might otherwise experience unacceptable toxicity from GVHD-related complications caused by older age or increased HLA disparity to benefit from unrelated marrow grafts.

Impact of In Vivo T-Cell Depletion on Outcome of Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT) for Hematologic Malignanciesimpact of In Vivo T-Cell Depletion on Outcome of Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT) for Hematologic Malignancies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2305-2305 ◽  
Author(s):  
Robert J Soiffer ◽  
Jennifer LeRademacher ◽  
Vincent T Ho ◽  
Fangyu Kan ◽  
Andrew Artz ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hazard Ratio ◽  
Cell Depletion ◽  
P Value ◽  
Unrelated Donor ◽  
T Cell Depletion

Abstract Abstract 2305 HCT using RIC regimens has increased steadily over the past decade. In vivo administration of anti-T cell antibodies, such as alemtuzumab and anti-thymocyte globulin (ATG) preparations, is often employed to promote engraftment and limit graft-versus-host disease (GVHD). While these antibodies might reduce the severity and incidence of GVHD, they may also blunt the allo-immune graft-versus-tumor effect of HCT. Transplant outcomes after in vivo T-cell depletion (n=584 ATG; n=213 alemtuzumab) were compared to those after T-cell replete (n=879) RIC transplants for myeloid and lymphoid malignancies. Patients were aged 21–69 yrs and transplanted from 2000–2007. Median follow-up of patients is 3 years. Conditioning regimens consisted of an alkylating agent (melphalan, busulfan, or cyclophosphamide) with fludarabine. 792 patients (47%) received allografts from a HLA-matched sibling, 650 (39%) from an 8/8 and 234 (14%) from a 7/8 HLA-matched unrelated donor. In vivo T-cell depletion was used for 35% of matched sibling HCT, 57% of 8/8 and 64% of 7/8 HLA matched unrelated donor HCT. Results of multivariable analysis adjusted for age, disease and disease stage, donor, year of transplant, conditioning regimen, and GVHD prophylaxis are shown in Table below. Grade 2–4 acute GVHD was lower with alemtuzumab containing regimens (20%) than ATG containing (41%) or T replete (42%) regimens. Chronic GVHD occurred in 27% of recipients of alemtuzumab, 43% of ATG, and 57% of T replete regimens, respectively. Compared to T-cell replete regimens, relapse risks were higher with ATG and alemtuzumab containing regimens (38%, 49% and 51%, respectively) and non-relapse mortality, higher with ATG containing regimens only. Treatment failure (relapse or death) was higher with both ATG and alemtuzumab containing regimens compared to T replete regimens. Overall mortality was highest with ATG containing regimens. These observations are independent of disease, disease status and donor type including 7/8 HLA-matched HCT. The 3-year probabilities of disease-free survival (DFS) were 25%, 30% and 39% with ATG-containing, alemtuzumab-containing and T-cell replete regimens, respectively. Corresponding probabilities for overall survival were 38%, 50% and 46%. There were no differences in disease-free and overall survival at 3-years by ATG source or dose. The incidence of EBV-PTLD was higher with alemtuzumab and ATG containing compared to T-cell replete regimens (2% vs. 2% vs. 0.2%). These results suggest in-vivo T-cell depletion with RIC regimens containing an alkylating agent and fludarabine significantly lowers DFS despite lower GVHD. The routine use of in-vivo T-cell depletion in this setting warrants a cautious approach in the absence of a prospective randomized trial. Alemtuzumab vs. T-cell replete ATG vs. T-cell replete Alemtuzumab vs. ATG Hazard ratio, p-value Hazard ratio, p-value Hazard ratio, p-value Grade 2-4 acute GVHD 0.33, p<0.0001 0.88, p=0.12 0.38, p<0.001 Grade 3-4 acute GVHD 0.42, p<0.0001 0.86, p=0.20 0.48, p=0.001 Chronic GVHD 0.34, p<0.0001 0.69, p<0.0001 0.49, p<0.0001 Non-relapse mortality 1.04, p=0.85 1.34, p=0.01 0.78, p=0.19 Relapse 1.54, p=0.0001 1.53, p<0.0001 1.01, p=0.94 Treatment failure 1.40, p=0.0003 1.46, p<0.0001 0.96, p=0.67 Overall mortality 1.09, p=0.46 1.25, p=0.002 0.87, p=0.22 Disclosures: No relevant conflicts of interest to declare.

Transplantation Of TcRαβ/CD19 Depleted Stem Cells From Haploidentical Donors In Children: Current Results

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 692-692 ◽  
Author(s):  
Peter Lang ◽  
Tobias Feuchtinger ◽  
Heiko-Manuel Teltschik ◽  
Michael Schumm ◽  
Patrick Schlegel ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Αβ T Cells

Abstract T-cell depletion of the graft is an effective method to prevent or completely avoid Graft-versus-Host Disease (GvHD) in haploidentical stem cell transplantation. In order to increase the T-cell depletion efficacy while maintaining the anti-tumor and anti-infectious properties of the graft, we have investigated a new T-cell depletion method which removes αβ+ T-lymphocytes via a biotinylated anti-TcRαβ antibody followed by an anti-biotin antibody conjugated to magnetic microbeads while retaining γδ+ T-lymphocytes, Natural killer (NK) cells and other cells in the graft. In addition, CD19+ B-lymphocytes were concomitantly depleted for the prevention of posttransplant EBV-associated lymphoproliferative disease. The CliniMACS system was used for manipulation of peripheral stem cell grafts from full haplotype mismatched family donors in 35 patients. Results The overall depletion of αβ+ T-cells was highly effective with 4.6 log (range 3.8–5.0). Patients received a median number of only 14 x 103/kg residual αβ+ T-cells. Recovery of CD34+ stem cells was 72%, and the median number of infused CD34+ stem cells was 12 x 106/kg (range 5-38 x 106/kg). Additionally, the patients received 2 types of potential antileukemic effector cells: 107 x 106/kg (range 35 -192 x 106/kg) CD56+ NK-cells and 11 x 106/kg (range 5–30 x 106/kg) γδ+ T-lymphocytes. Diagnoses were ALL (n=20), AML/MDS/JMML (n=9), nonmalignant diseases (n=4), solid tumors (n=2); disease status: CR2-CR6 (n=17), active disease (n=18). 23 patients received a second or third SCT (65%). A toxicity reduced conditioning regimen (fludarabin 40mg/m² or clofarabin 50mg/m² (day -8 to d -5), thiotepa 10mg/kg (d -4), melphalan 70mg/m² (d -3 and d -2) was used. The anti CD3 specific OKT3 antibody was used as rejection prophylaxis from day -8 to day -1 without affecting cotransfused effector cells because of its short half-life period in the first 7 patients. However, due to its restricted availability, the substance was substituted since 2011 by a reduced ATG-F dose (15mg/kg) given at start of the conditioning regimen in order not to impair NK and γδ+ T-cells of the grafts (1 mg/kg d -12, 4 mg/kg d -11, 5 mg/kg d -10 and -9; n=28 patients). Short course MMF (until day +30) was given in 25 patients. Graft rejection occurred in 14% of the patients. However, after reconditioning and second stem cell donation, final engraftment was achieved in all patients. The median time to reach neutrophil and platelet recovery in patients with primary engraftment was 10 and 11 days respectively. All patients showed a rapid immune reconstitution with 250 (OKT3 conditioning) and 273 (ATG conditioning) CD3+ T-cells/µl, 30 (OKT3) and 47 (ATG) CD3+4+/µl and 300 (OKT3) and 382 (ATG) CD56+ NK-cells/µl at day +30 posttransplant. γδ+ T-cells started to expand faster than αβ+ T-cells in the early post-transplant period (156 vs. 82 cells/µl at day +30) whereas at day +90, αβ+ T-cells were predominant (170 vs. 134 cells/µl). Acute GvHD grade 0-I occurred in 25 patients (71%); 6 patients had GvHD II (17%), 3 patients had GvHD III (9%) and one patients experienced GvHD grade IV (3%). 3 patients experienced chronic GvHD (8%). Incidence of acute GvHD was not influenced by the number of residual T cells or by the type of serotherapy. 1 year EFS for patients with acute leukemias was 66% (any CR) and 14% (active disease).TRM at 1 year was 20%. Conclusions These data indicate that transplantation of TcR αβ+/CD19 depleted cells from a haploidentical donor results in sustained engraftment, remarkably fast immune reconstitution and low incidence of both acute and chronic GvHD. OKT3 could be substituted by ATG without negative effects. The anti-leukemic efficacy of this approach in comparison to other methods of T-cell depletion needs to be evaluated with a longer patient follow-up. Disclosures: No relevant conflicts of interest to declare.

HLA-Mismatch Is Associated With Worse Outcomes After Unrelated Donor Reduced Intensity Conditioning Hematopoietic Cell Transplantation: A Cibmtr Analysis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 547-547 ◽  
Author(s):  
John Koreth ◽  
Kwang Woo Ahn ◽  
Joseph Pidala ◽  
James L. Gajewski ◽  
Hailin Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Gvhd Prophylaxis ◽  
Conditioning Intensity

Abstract In myeloablative unrelated donor allogeneic hematopoietic cell transplantation (HCT) a 1-locus HLA-mismatch (-A, -B, -C, -DRB1) is associated with lower survival compared to fully matched pairs. However data in reduced-intensity and non-myeloablative conditioning (together called RIC) HCT are limited. We analyzed adult AML/ALL/CML/MDS recipients of first 8/8 HLA-matched or 1-locus mismatched unrelated donor (MUD, MMUD) RIC HCT performed in the period 1999-2011 and registered in the CIBMTR. HLA-A, -B, -C and -DRB1 loci were typed in all pairs at high resolution; -DQB1 and -DPB1 loci could not be evaluated in all pairs. Transplants involving ex-vivo T-cell depletion, CD34+ selection, or post-transplant cyclophosphamide were excluded. Overall survival (OS) was the primary outcome. Secondary outcomes included non-relapse mortality (NRM), relapse, disease-free survival (DFS) and acute and chronic GVHD. Individual locus mismatch was also assessed. Apart from HLA matching, variables related to patient (age, race, sex, KPS, diagnosis, disease-risk), donor (age, parity), both (sex match/ABO match/CMV match) treatment (conditioning intensity, TBI use, in-vivo T-cell depletion (ATG), graft source (PB, BM) and GVHD prophylaxis (CyA-, Tac-based)) were considered. 2588 RIC HCT (8/8 MUD: 2025; 7/8 MMUD: 563) from 144 centers and 12 countries were analyzed. Median follow up in 8/8 MUD and 7/8 MMUD was 38 and 48 months respectively. Diagnoses were AML (65%), ALL (8%), CML (7%), MDS (20%). Conditioning intensity was RIC (79%), NMA (21%). 58% received in-vivo T-cell depletion. Graft source was PBSC (85%), BM (15%). GVHD prophylaxis was Tac-based (70%), CyA-based (27%). Mismatches involved HLA-A (188), -B (81), -C (219), and -DRB1 (75); with -DPB1 and -DQB1 typing available in 1382 and 2502 cases respectively. Compared to 8/8 MUD, 7/8 MMUD recipients were more likely to be younger and ethnic minorities and to have older and parous donors. In univariate analyses DQB1- and -DPB1 mismatch was not associated with worse OS, DFS, or NRM and was not further evaluated. There was a trend toward more grade II-IV acute GVHD in -DPB1 double (p=0.02) but not single mismatches. In multivariate models 7/8 MMUD RIC HCT had worse grade II-IV and III-IV acute GVHD, NRM, DFS and OS, but not relapse or chronic GVHD (Table). No significant interactions were identified between degree of HLA matching and other clinical variables. Adjusted 1- and 3-year NRM for 8/8 MUD vs. 7/8 MMUD was 20.4% vs. 28.9% (p<0.0001) and 29.2% vs. 38.1% (p<0.0007) respectively. Adjusted 1- and 3-year OS was 54.7% vs. 48.8% (p=0.01) and 37.4% vs. 30.9% (p=0.005) respectively (Figure). There was no difference between allele and antigen mismatches. HLA-A, -B, -C, and -DRB1 locus mismatches were each associated with 1 or more impaired outcomes (acute GVHD, NRM, DFS, and/or OS). Table 1 7/8 vs. 8/8 HLA HR (95% CI) p-value Acute GVHD II-IV 1.29 (1.09-1.53) 0.003 Acute GVHD III-IV 1.69 (1.00-3.36) 0.05 Chronic GVHD 1.11 (0.96-1.28) 0.15 Relapse 1.01 (0.87-1.17) 0.92 NRM 1.52 (1.29-1.79) <0.0001 DFS 1.20 (1.07-1.34) 0.0015 OS 1.25 (1.11-1.40) 0.0001 Compared to 8/8 MUD, both 7/8 allele and antigen MMUD RIC HCT have greater treatment toxicity and worse survival, of a magnitude similar to that seen in myeloablative transplantation. An isolated mismatch at HLA-A, -B, -C, or -DRB1 was associated with 1 or more adverse outcomes. In unrelated donor RIC HCT, matching for all alleles of HLA-A, -B, -C and -DRB1 loci results in superior outcomes. Disclosures: No relevant conflicts of interest to declare.

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