T-cell Depletion Group Research Articles

Impact of in vivo T-cell depletion in patients with myelodysplastic syndromes undergoing allogeneic hematopoietic stem cell transplant: a registry study from the Chronic Malignancies Working Party of the EBMT.

While in vivo T-cell depletion (TCD) is widely used, its benefit in patients with MDS still remains a matter of debate. This study evaluates the impact of TCD on outcomes, and compares ATG and alemtuzumab, in patients with MDS. 1284 patients from the EBMT registry were included in this study with 470 patients in the no-TCD group and 814 in the TCD group (alemtuzumab N = 168; ATG N = 646). At 6 months, aGVHD III-IV cumulative incidences (CI) for no-TCD, ATG or alemtuzumab groups were 13% vs 14% vs 11% (ns), respectively. At 5 years, CI of chronic GVHD were 64% vs 52% vs 51% (p < 0.00017); and CI of relapse was 23% vs 25% vs 39% (p < 0.0001) for no TCD, ATG and alemtuzumab respectively; OS was 47% vs 46% vs 34% (p = 0.009) respectively; and GRFS was 21% vs 28% and 20% (p = 0.045) respectively. In multivariable analysis, ATG improved GRFS, and alemtuzumab decreased OS. Both ATG and alemtuzumab decreased risk of chronic GVHD, but the increased risk of relapse with alemtuzumab is associated with a poor GRFS and suggest to not use alemtuzumab in the setting of allo-SCT for high risk disease.

Early CD4+ T cell reconstitution as predictor of outcomes after allogeneic hematopoietic cell transplantation

Background: An association between early CD4+ T cell immune reconstitution (CD4+ IR) and survival after T-replete allogeneic hematopoietic cell transplantation (HCT) has been previously reported. Here we report validation of this relationship in a separate cohort that included recipients of ex vivo T-cell-depleted (TCD) HCT. We studied the relationship between CD4+ IR and clinical outcomes.Methods: A retrospective analysis of children/young adults receiving their first allogeneic HCT for any indication between January 2008 and December 2017 was performed. We related early CD4+ IR (defined as achieving >50 CD4+ T cells/µL on two consecutive measures within 100 days of HCT) to overall survival (OS), relapse, non-relapse mortality (NRM), event-free survival (EFS) and acute graft-versus-host disease (aGVHD). Fine and Gray competing risk models and Cox proportional hazard models were used.Results: In this analysis, 315 patients with a median age of 10.4 years (interquartile range 5.0–16.5 years) were included. The cumulative incidence of CD4+ IR at 100 days was 66.7% in the entire cohort, 54.7% in TCD (N = 208, hazard ratio [HR] 0.47, P < 0.001), 90.0% in uCB (N = 40) and 89.6% in T-replete (N = 47) HCT recipients. In multi-variate analyses, not achieving early CD4+ IR was a predictor of inferior OS (HR 2.35, 95% confidence interval [CI] 1.46–3.79, P < 0.001) and EFS (HR 1.80, 95% CI 1.20–2.69, P = 0.004) and increased NRM (HR 6.58, 95% CI 2.82–15.38, P < 0.001). No impact of CD4+ IR on relapse or aGVHD was found. Within the TCD group, similar associations were observed.Conclusion: In this HCT cohort, including recipients of TCD HCT, we confirmed that early CD4+ IR was an excellent predictor of outcomes. Finding strategies to predict or improve CD4+ IR may influence outcomes.

CD34+ Cell Selection versus Reduced-Intensity Conditioning and Unmodified Grafts for Allogeneic Hematopoietic Cell Transplantation in Patients Age >50 Years with Acute Myelogenous Leukemia and Myelodysplastic Syndrome

Reduced-intensity conditioning (RIC) and T cell depletion (TCD) through CD34+ cell selection without the use of post-transplantation immunosuppression are 2 strategies used to reduce nonrelapse mortality (NRM) in older patients after allogeneic hematopoietic cell transplantation (allo-HCT). To compare the efficacy of the RIC and TCD approaches, we evaluated the outcomes of patients age >50 years with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) who underwent allo-HCT from an HLA-matched donor with one of these strategies. Baseline characteristics were comparable in the patients receiving TCD (n = 204) and those receiving RIC (n = 151), except for a higher proportion of unrelated donors (68% versus 40%; P < .001) and a higher comorbidity burden (Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI] ≥3: 51% versus 38%; P < .001) in the TCD cohort. Analysis of outcomes at 3 years showed a higher chronic graft-versus-host disease (GVHD)/relapse-free survival (CRFS) (51% versus 7%; P < .001), lower incidences of grade II-IV acute GVHD (18% versus 46% at day +180) and chronic GVHD (6% versus 55% at 3 years; P < .001), and a lower incidence of relapse (19% versus 33% at 3 years; P = .001) in the TCD group compared with the RIC group. Relapse-free survival (RFS), overall survival (OS), and NRM were similar in the 2 groups. Combining transplantation approach (RIC versus TCD) and comorbidity burden (HCT-CI 0-2 versus ≥3), patients with an HCT-CI score of 0-2 seemed to benefit from the TCD approach. In conclusion, in this retrospective study, the use of a CD34+ cell-selected graft and a myeloablative conditioning regimen was associated with higher CRFS and similar RFS and OS compared with unmodified allo-RIC in patients age >50 years with AML and MDS.

Associations between antenatal glucocorticoid treatment and offspring early childhood developmental milestones

Reduced-intensity conditioning (RIC) and T cell depletion (TCD) through CD34+ cell selection without the use of post-transplantation immunosuppression are 2 strategies used to reduce nonrelapse mortality (NRM) in older patients after allogeneic hematopoietic cell transplantation (allo-HCT). To compare the efficacy of the RIC and TCD approaches, we evaluated the outcomes of patients age >50 years with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) who underwent allo-HCT from an HLA-matched donor with one of these strategies. Baseline characteristics were comparable in the patients receiving TCD (n = 204) and those receiving RIC (n = 151), except for a higher proportion of unrelated donors (68% versus 40%; P < .001) and a higher comorbidity burden (Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI] ≥3: 51% versus 38%; P < .001) in the TCD cohort. Analysis of outcomes at 3 years showed a higher chronic graft-versus-host disease (GVHD)/relapse-free survival (CRFS) (51% versus 7%; P < .001), lower incidences of grade II-IV acute GVHD (18% versus 46% at day +180) and chronic GVHD (6% versus 55% at 3 years; P < .001), and a lower incidence of relapse (19% versus 33% at 3 years; P = .001) in the TCD group compared with the RIC group. Relapse-free survival (RFS), overall survival (OS), and NRM were similar in the 2 groups. Combining transplantation approach (RIC versus TCD) and comorbidity burden (HCT-CI 0-2 versus ≥3), patients with an HCT-CI score of 0-2 seemed to benefit from the TCD approach. In conclusion, in this retrospective study, the use of a CD34+ cell-selected graft and a myeloablative conditioning regimen was associated with higher CRFS and similar RFS and OS compared with unmodified allo-RIC in patients age >50 years with AML and MDS.

Long term renal survival in patients undergoing T-Cell depleted versus conventional hematopoietic stem cell transplants.

Calcineurin inhibitor-sparing T cell depleted (TCD) hematopoietic stem cell transplants HSCTs are presumed less nephrotoxic than conventional HSCTs. We evaluated incidence and risk factors for kidney failure and chronic kidney disease (CKD) in 231 TCD and 212 conventional HSCT recipients. Kidney failure required a median glomerular filtration rate (GFR) <60 mL/min/1.73 m2 for ≥ 100 days anytime after 180 days post-HSCT. Two year cumulative incidence (CI) of kidney failure was 42% in the conventional vs. 31% in the TCD group (p=0.005). TCD, age, acute kidney injury and number of toxic CNI levels all impacted on kidney failure, which was associated with increased all-cause mortality (hazard ratio 2.86 (95% CI: 1.88–4.36), p <0.001). Renal recovery occurred in 28% of kidney failure patients, while the remaining patients were defined to have chronic kidney disease (CKD). In those with baseline GFR>60 mL/min/1.73 m2 only exposure to nephrotoxic medications was associated with CKD (p=0.033). In the myeloablative conditioning subgroup only total body irradiation was associated with CKD (p=0.013). Of all patients, five (1.13%) required dialysis. These results confirm an impact of TCD on kidney failure but not CKD for which other risk factors such as radiation or nephrotoxic drug exposure may play a role.

Interaction Between Center Effect and Strategy for Graft Vs. Host Disease Prophylaxis on Outcome of T-Cell Depleted and T-Cell Replete Haploidentical Transplants, an Analysis on Behalf of ALWP-EBMT

IntroductionHaploidentical allogenic hematopoietic stem cell transplants (haplo-HSCT) is an emerging alternative transplant procedure for patients with hematologic malignancies that are in need of transplant and do not have a compatible donor. Due to the broad HLA disparity, the haplo-HSCT can be performed with T-cell depletion and megadose of CD34+ cells. Alternatively haplo-HSCT can be performed with non T-cell depleted transplants (T-replete) either in combination with anti-thymoglobuline serum (ATG) or post-transplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis strategy. No randomized study compared yet these strategies for GVHD prophylaxis in the setting of haplo-HSCT. Nevertheless, many centers tend to specialize in one GVHD prophylaxis strategy making it difficult to differentiate the treatment effect from the center effect. Center effect is a known risk factor for outcomes of haplo-HSCT in both T-cell depleted (TCD) and T-replete settings. The objective of the study was to investigate the role of center effects in GVHD prevention strategy, on leukemia-free survival (LFS) and overall survival (OS) in a population of adult patients with acute leukemia receiving haplo-HSCT.Patients and methodsA retrospective multicenter registry study was conducted on patients reported to the European society for Blood and Marrow Transplantation registry. Inclusion criteria were: age > 18 years, lymphoblastic or myeloid acute leukemia (ALL or AML) in first or second complete remission (CR1 or CR2), receiving a haplo-HSCT between 2005 and 2014. In this population (n=606), in order to assess the interaction between center and GVHD prevention treatment, we then included in the study selected patients from the centers that had performed more than 20% of both TCD and T-replete haplo-HSCT during the study period. Center effects on the outcomes consisted of 1) center effect on the baseline risk of event and 2) interaction between center and strategy of GVHD prevention. These center effects were estimated respectively using Cox mixed-effects models and tested using permutation tests. All models were adjusted on patient age, CMV statuses, disease (ALL or AML), secondary leukemia, previous autologous transplant, disease status (CR1 or CR2), peripheral blood vs. bone marrow transplant and conditioning regimen.ResultsAfter selection, 226 patients were available across 29 centers in Europe. Most centers included less than 10 patients. One hundred and one (45%) patients received TCD, 125 T-replete haplo-HSCT (62 (27%) using ATG and 63 (28%) using PT-Cy). Median age at transplant was 50 years in TCD haplo-HSCT patients and 41 years in T-replete patients. Overall, 175 (77%) patients had AML. There were 86 (69%) peripheral blood transplants in the TCD group and 92 (91%) in T-replete. Median follow-up was 2.7 years and median survival was 1.8 years (95%CI: 1.2-4.2).In adjusted analyses, without accounting for center effect, T-replete tended to be associated with better LFS (Hazard Ratio (HR): 0.70 (95%CI 0.45-1.07), p=0.10) and 0S (HR=0.67 (95%CI 0.43-1.04), p=0.076). When center effects were included, there was significant heterogeneity across centers on the baseline risk of both outcomes (LFS: p=0.036 and OS: p=0.048). When accounting for interaction between center and strategy for GVHD prevention, the effect of T-replete vs. TCD on the outcomes did vary across centers (p=0.065 and p=0.031 for interactions in LFS and OS, respectively). These were qualitative interactions: HR for OS associated with T-replete, compared to TCD, varied from 0.46 (better OS) to 1.63 (worse OS) when considering first and third quartiles of the center effects distribution (Figure 1).ConclusionsWe found an interaction between center and strategy for GVHD prevention on outcomes of patients who received a haplo-HSCT. The difference between the 2 strategies (TCD or T-replete) varied across centers and could even be reversed according to the center. This could be in part related to the increase in expertise with each technique in some centers and with the different management of complications, such as infections-related and relapse. [Display omitted] DisclosuresCiceri:MolMed SpA: Consultancy.

Comparison of outcomes at two institutions of patients with ALL receiving ex vivo T-cell-depleted or unmodified allografts

We compared outcomes of adult patients receiving T-cell-depleted (TCD) hematopoietic SCT (HCT) without additional GVHD prophylaxis at Memorial Sloan Kettering Cancer Center (MSKCC, N=52), with those of patients receiving conventional grafts at MD Anderson Cancer Center (MDACC, N=115) for ALL in CR1 or CR2. Patients received myeloablative conditioning. Thirty-nine patients received anti-thymocyte globulin at MSKCC and 29 at MDACC. Cumulative incidence of grades 2-4 acute (P=0.001, 17.3% vs 42.6% at 100 days) and chronic GVHD (P=0.006, 13.5% vs 33.4% at 3 years) were significantly lower in the TCD group. The non-relapse mortality at day 100, 1 and 3 years was 15.4, 25.0 and 35.9% in the TCD group and 9.6, 23.6 and 28.6% in the unmodified group (P=0.368). There was no difference in relapse (P=0.107, 21.3% vs 35.5% at 3 years), OS (P=0.854, 42.6% vs 43.0% at 3 years) or RFS (P=0.653, 42.8% vs 35.9% at 3 years). In an adjusted model, age >50, cytogenetics and CR status were associated with inferior RFS (hazard ratio (HR)=2.16, P=0.003, HR=1.77, P=0.022, HR=2.47, P<0.001), whereas graft type was NS (HR=0.90, P=0.635). OS and RFS rates are similar in patients undergoing TCD or conventional HCT, but TCD effectively reduces the rate of GVHD.

Allo- HSCT for Advanced Myelodysplastic Syndrome:MSKCC Vs MDACC

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only curative treatment for myelodysplastic syndrome (MDS). Relapse, infections and graft-versus-host disease (GvHD) are the main causes of treatment failure. We compared the outcomes of patients receiving T cell depleted (TCD) grafts at Memorial Sloan-Kettering Cancer Center (MSKCC) with patients receiving unmodified grafts at MD Anderson Cancer Center (MDACC) for advanced MDS (RAEB-1 and 2).Adult patients transplanted between 2001 -2012 were included in this retrospective analysis. All recipients of TCD grafts (N=60) received myeloablative conditioning (MAC) and antithymocyte globulin (ATG) to prevent graft rejection. None of them received post-transplant GvHD prophylaxis. Of the 129 recipients of unmodified grafts, 87 received MAC and 42 reduced intensity conditioning (RIC); GvHD prophylaxis consisted of tacrolimus and mini-dose methotrexate in the majority of patients (N=113). ATG was given to all matched unrelated donor (MUD) recipients. Patients in the unmodified group had more therapy-related MDS (MDS-t), very poor risk cytogenetics by IPSS-R at diagnosis and bone marrow (BM) blast count >5% at transplant. Only the TCD group had mismatched donors (Table 1).Univariate analysis identified a lower incidence of grade II-IV acute GvHD in the TCD group with 100-day cumulative incidence (CI) of 13.3% vs. 34.1% in the unmodified group (p=0.031). There was no difference in grade III-IV acute GvHD with a 10% CI in both groups at day-100 (p=0.546). The incidence of chronic GvHD was lower in the TCD group with a CI at 3-yrs of 3.4% vs. 44.3% in the unmodified group (p < 0.001). The non-relapse mortality (NRM) in both groups was similar. CIs at day 100, 1yr, and 3 yrs in the TCD group were 8.3%, 20.2% and 32.7% vs. 12.4%, 22.5% and 28.1% in the unmodified group (p=0.628). Relapse was lower in the TCD group, with CI at 1 and 3 yrs of 8.5% and 15.5%, vs. 31.0% and 39.4% in the unmodified group (p=0.002). Since the unmodified recipients had worse disease characteristics, further analyses in patients with good/intermediate risk cytogenetic showed that the relapse incidence was similar between these subgroups, with 3-yr CIs of 7.9% in TCD vs. 18% in unmodified group (p=0.185). The most common causes of death in the TCD group were infections (32%) and relapse (28%), while in the unmodified group it was relapse (55%), GVHD (20%) and infections (13%). Considering the differences in disease characteristics between the groups, multivariate regression models were performed for relapse-free survival (RFS) and overall survival (OS) adjusting for MDS-t, high-risk cytogenetics at diagnosis and high blast count at HSCT. No significant differences were observed between the groups for RFS (HR=1.44, p=0.128) and OS (HR= 1.35, p=0.236) (Table 2). High-risk cytogenetics at diagnosis (very poor risk) was the only significant prognostic factor for RFS (HR=5.32, p<0.001) and OS (HR=4.81, p<0.001).Allo-HSCT is an effective treatment for patients with MDS with similar long term survival with either unmodified or TCD allografts. TCD is associated with a lower incidence of acute and chronic GVHD and without an increased risk of relapse.Table 1CharacteristicsTCD (N=60)Unmodified (N= 129)p-valueMedian follow-up, months (range)43.4 (3.8-119.5)49.4 (12.2-136.3)Age, years (range)57.1 (21.9-72.0)57.0 (19.0-72.0)0.769Female gender34 (56.7%)45 (34.9%)0.008MDS-t7 (11.7%)43 (33.3%)0.003Cytogenetic risk at diagnosis ( IPSS-R)0.009Good25 (42.4%)48 (37.2%)Intermediate15 (25.4%)19 (14.7%)Poor11 (18.6%)15 (11.6%)Very poor8 (13.6%)47 (36.4%)Missing1Blasts at transplant< 0.001< 5%48 (81.4%)57 (46.3%)5-9%11 (18.6%)35 (28.5%)10-19%031 (25.2%)Missing16Donor type< 0.001MRD21 (35.0%)65 (50.4%)MUD25 (41.7%)64 (49.6%)MMD14 (23.3%)0Stem cell source0.002BM5 (8.3%)46 (35.7%)PB55 (91.7%)83 (64.3%)Table 2:Multivariate analysisVariablesOS HR (95% CI)RFS HR (95% CI)Disease etiology0.5180.511De novo11MDS-t0.87 (0.56-1.34)0.87 (0.56-1.33)Cytogenetic risk at diagnosis IPSS-R)< 0.001 < 0.001 Good11Intermediate1.41 (0.74-2.68)1.39 (0.73-2.64)Poor2.06 (1.13-3.73)2.49 (1.40-4.44)Very poor4.81 (2.88-8.02)5.32 (3.22-8.80)Blasts at transplant0.2860.502< 5%115-9%1.11 (0.70-1.77)1.03 (0.65-1.62)10-19%1.57 (0.91-2.71)1.37 (0.80-2.34)Type of transplant0.2360.128TCD11Unmodified1.35 (0.82-2.19)1.44 (0.90-2.31) DisclosuresNo relevant conflicts of interest to declare.

Risk Factors For Chronic Eye and Mouth GVHD In Unrelated Hematopoietic Cell Transplantation: T Cell Depletion Is The Only Risk Factor Identified and Appears To Be Favorable

Chronic graft versus host disease (GVHD) affecting eye and mouth are common complications of allogeneic hematopoietic stem cell transplantation (HCT). Although not life threatening, these forms of chronic GVHD are associated with significant morbidity and are difficult to treat. The risk factors associated with the development of chronic eye and mouth GVHD in unrelated donor transplantation (URD-HCT) are unknown. In order to identify risk factors for these two forms of organ specific GVHD we performed a retrospective review of patients who underwent URD-HCT at Princess Margaret Cancer Center, Toronto, Canada between January 2002 and October 2012. During this period 280 patients underwent URD-HCT. The median age was 47 (range 18-71) years and 58% were males. Disease indications for HCT were acute myeloid leukemia or myelodysplastic syndrome (54%), acute lymphoblastic leukemia (15%), chronic myeloid leukemia (10%), lymphoma (8%), myelofibrosis (6%), chronic lymphocytic leukemia (4%) and others (3%). Forty six (16%) patients had single antigen or allele mismatched donors. Graft source was peripheral blood stem cells in 212 (76%) patients and bone marrow in 68 (24%). One hundred eighty eight patients (67%) had full intensity conditioning and 92 (33%) had reduced intensity. GVHD prophylaxis consisted of cyclosporin (CSA) in 31%, CSA with methotrexate (MTX) in 29% and CSA with mycophenolate mofetil (MMF) in 40%. Forty six percent of patients received in vivo T- cell depletion (TCD) with alemtuzumab in addition to CSA-based GVHD prophylaxis. At a median follow up of 30 months (range, 1-134), 136 (49%) patients had developed chronic GVHD. Fifty eight (21%) patients had developed manifestations in eyes and 82 (29%) in mouth. In multivariable analysis no clinical variables were found to be predictive of overall chronic GVHD. In multivariable analysis TCD was the only predictive factor for chronic eye GVHD (HR=0.46; 95% CI, 0.27-0.79, p=0.005). The 5-year cumulative incidence of chronic eye GVHD in the TCD group was 16% vs. 32% in the non-TCD group (p= 0.002) (Figure 1A). Similarly, TCD was the only predictive factor for chronic mouth GVHD in multivariable analysis (HR=0.55; 95% CI, 0.35-0.86, p=0.009). The 5-year cumulative incidence of chronic mouth GVHD in the TCD group was 24% vs. 40% in the non-TCD group (p=0.004) (Figure 1B).Figure 1Figure 1 TCD was not a significant covariable for chronic skin, liver or gut GVHD. Prior grade 2-4 acute GVHD was the only predictive factor for skin and gut involvement and there was no predictive factor was identified for liver involvement. However TCD along with recipient age and source of stem cell was a significant covariable for lung GVHD. There was no difference in 5-year overall survival between the non-TCD and the TCD groups (45% vs. 36 %, p=0.4). These data suggest that TCD is associated with reduced incidence of chronic eye and mouth GVHD in URD-HCT without any significant effect on overall survival. It appears that risk factors for the development of organ-specific GVHD may vary based on the organ of involvement. Disclosures: No relevant conflicts of interest to declare.

Outcomes In Patients With Acute Lymphoblastic Leukemia In First Or Second Complete Remission Receiving Ex-Vivo T-Cell Depleted Or Unmodified Allografts: Comparison Of Results At Two Institutions

Ex vivo T-cell depleted (TCD) allogeneic hematopoietic stem cell transplants (HCT) in patients with acute myeloid leukemia in complete remission (CR)lead to survival and relapse rates comparable to those with unmodified grafts, but with significantly less graft versus host disease (GVHD). TCD-HCT is also effective in patients with acute lymphoblastic leukemia (ALL), however it is not known how outcomes compare with those of patients receiving conventional grafts. In this study we compared the outcomes of patients receiving TCD-HCT at Memorial Sloan-Kettering Cancer Center (MSKCC) with patients receiving conventional grafts at MD Anderson Cancer Center (MDACC) for ALL in first or second CR.Patients 18 years of age or older, undergoing HCT between 2000 and 2010 were included in this retrospective analysis. 52 patients at MSKCC received TCD grafts and 129 patients at MDACC received conventional grafts. All patients at MSKCC received myeloablative HCT conditioning (MAC). No GVHD prophylaxis was given. At MDACC, 115 patients received MAC and 14 received reduced intensity conditioning; GVHD prophylaxis consisted of tacrolimus and mini-dose methotrexate, plus antithymocyte globulin for total dose 4 mg/kg for unrelated donors.Patient characteristics and outcomes are summarized in the Table. A greater percentage of patients in the conventional graft group received transplants from a matched related donor and from bone marrow as a stem cell source. Patients in the TCD group almost exclusively received grafts from peripheral blood. [Display omitted] A significant difference in acute GVHD incidence was observed between the TCD and conventional groups, with 100-day cumulative incidence estimates of 17.3% and 40.3%, respectively (Gray's test p-value=0.007). A significant difference was also observed in chronic GVHD rates, with three-year estimates of 13.5% and 34.8% for the TCD and unmodified groups, respectively (Gray's test p-value=0.004). There was no statistical difference between TCD and unmodified groups with regards to OS (log-rank p-value=0.89, 3 year estimates 42.6% vs. 43.2%) or RFS (log-rank p-value=0.64, 3 year estimates 42.8% and 36.0%). The NRM at day 100, 1 year and 3 years were 15.4%, 26.9% and 37.8% in the TCD group and 10.1%, 23.5% and 28% in the unmodified group (Gray's test p-value=0.22). There was a lower relapse rate among patients who received TCD versus unmodified grafts (3 year estimates 19.4% vs. 36.0%, Gray's test p-value=0.05). Age >50 and was the only factor associated with inferior RFS (HR=1.74, p=0.01) and OS (HR=1.85, p=0.006).HCT is an effective treatment modality for patients with ALL with favorable results with either conventional or TCD allografts. Although the relapse rate was significantly lower after TCD-HCT, this would need to be confirmed in a prospective study. While 3-year OS rates are similar in both groups, TCD effectively reduces the rate of both acute and chronic GVHD.*: Median (range)* *: P-values were estimated using a chi-square test or Fisher's exact test for categorical variables and a Wilcoxon rank-sum test for continuous variables. OS and RFS were compared using a logrank statistics, while NRM, aGVHD and cGHVD were compared using Gray's test.^: Good risk: Hyperdiploidy, del(9p); poor risk: Ph+, t(4;11), t(8;14); complex karyotype (≥5 abnormalities), hypodiploidy/near triploidy; standard risk: other.TCD-T-cell depleted; CR- Complete Remission; TKI- Tyrosine Kinase Inhibitors; RIC-Reduced Intensity Conditioning; MAC- Myeloablative Conditioning; RFS-Relapse Free Survival; OS- Overall Survival; NRM- Non-Relapse Mortality; aGVHD- acute Graft Versus Host Disease; cGVHD- chronic Graft Versus Host Disease [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Improved Early Outcomes with T-Cell Replete (TCR) Compared with T-Cell Depleted (TCD) Haploidentical Stem Cell Transplantation (HaploSCT)

Abstract 320▪▪This icon denotes a clinically relevant abstract Background:HaploSCT has been commonly performed with a TCD graft using CD34+ selection; however, this has been limited by a higher non-relapse mortality (NRM) primarily related to infectious complications. An alternative approach using a TCR bone marrow graft and high-dose post-transplant cyclophosphamide (HDPTCy) in the setting of non-myeloablative conditioning has been reported to have lower NRM and acceptable rates of GVHD. Methods:We hypothesized that TCR HaploSCT using HDPTCy is associated with improved immunologic reconstitution, less NRM and better early outcomes compared with TCD HaploSCT, and analyzed 65 consecutive patients (pts) treated at UTMDACC with the same conditioning regimen, fludarabine (40mg/m2/day × 4), melphalan (140mg/m2) and thiotepa (10mg/kg). TCD HaploSCT pts were treated between 2001 and 2009, while TCR patients after 2009. 6 pts in the TCR group >55 years/comorbidities received reduced doses of melphalan (100mg/m2) and thiotepa (5mg/kg). There was no GVHD prophylaxis in the TCD group, while TCR group received HDPTCy (50mg/kg/day × 2) followed by tacrolimus and mycophenolate. Results:The median follow-up was 10 months (range 3.5–25) for the TCR group and 44 (11–79) months for the TCD group. Median age was 45 years (range 20–63) in the TCR group and 36 years (range 18–56) in the TCD group (p=0.02). 28% were > 50 years in the TCR compared with 6% in the TCD group (p=0.02). Diagnoses were: AML/MDS 50% vs. 79%, ALL 13% vs. 12%, CML 16% vs. 6%, lymphoma/CLL 9% vs. 3% in the TCR vs. TCD groups, respectively. Only 13 (41%) and 12 (36%) of pts were in remission at transplant in both groups, respectively (p=0.7). 10/16 (62.5%) pts with AML/MDS in the TCR group had poor risk cytogenetics vs. 13/26 (50%) pts in the TCD group. The donors were 5/10 allele match in 20/32 (63%) and 16/31 (52%) in the two groups, respectively. Median numbers of CD34+ cells infused were 2.5×10e6/kg in the TCR group and 10.5×10e6/kg in the TCD group. All pts in the TCD group had peripheral blood selected CD34+ cells while all but one received bone marrow stem cells in the TCR group.One pt had early death in each group. Primary engraftment was achieved in 94% in the TCR group and 81% in the TCD group (p=0.1). Day-100 NRM for all pts was 9% in the TCR group vs. 21% for the TCD group, and for pts in remission at transplant 0% vs. 42%, respectively (p=0.01). NRM at 1 year for all pts was 16% for the TCR group vs. 42% for the TCD group (p=0.03) (Figure1), while for pts in remission was 0% vs. 67% (p=0.001). The cumulative incidences of grade II-IV aGVHD was 27% vs. 11% (p=0.5) and cGVHD was 8% vs. 18%, in the TCR and TCD group, respectively (p=0.03). OS and PFS at 1 year post-transplant were 66% vs. 30% (p=0.02) and 45% vs. 21% (p=0.03) for the whole group, and 92% vs. 33% (p=0.03) and 80% vs. 25% (p=0.02) for pts in remission at transplant, respectively (Figure1). [Display omitted] Improved NRM in the TCR group was related to significantly better immunologic reconstitution of T-cell subsets. On day 30 post transplant there was a significantly better recovery of absolute CD4 cells in the TCR group (median 24 vs. 2, p=0.004) and CD8 cells (median 20.5 vs. 1.5, p=0.036). CD4 cells remained significantly lower in the TCD group until after day 180 when the median CD4 count was 200.5 vs. 64 in the TCR group (p=0.04) while the difference in CD8 counts became non-significantly higher in the TCR after day 90 (median 119 vs. 29, p=0.23). Conclusion:TCR HaploSCT is associated with better immunologic reconstitution and improved early outcomes compared with TCD HaploSCT. Disclosures:No relevant conflicts of interest to declare.

Higher infused CD34 + cell dose and overall survival in patients undergoing in vivo T-cell depleted, but not t-cell repleted, allogeneic peripheral blood hematopoietic cell transplantation

Understanding the effect of cellular graft composition on allogeneic hematopoietic cell transplantation (AHCT) outcomes is an area of great interest. The objective of the study was to analyze the correlation between transplant-related outcomes and administered CD34+, CD3+, CD4+ and CD8+ cell doses in patients who had undergone peripheral blood, AHCT and received either in vivo T-cell depleted or T-cell replete allografts. Comparison of consecutive patients who underwent peripheral blood AHCT in our institution between January 2003 and December 2009. The cohort of 149 patients was divided into two groups; non T-cell depleted (NTCD) (n=54) and T-cell depleted (TCD) (n=95). Study endpoints were overall survival (OS), progression free survival (PFS), engraftment kinetics (neutrophil and platelet recovery), incidence of acute graft versus host disease (acute GVHD), chronic GVHD, nonrelapse mortality (NRM) and disease relapse. Multivariate analysis showed that higher infused CD34+ cell dose improved OS (relative risk 0.58, 95% CI 0.34-0.98, P=.04), PFS (relative risk 0.59, 95% CI 0.35-1.00, P=.05) and NRM (relative risk 0.49, 95% CI 0.24-0.99, P=.048) in the TCD group. By multivariate analysis, there was no difference in engraftment, grades II-IV acute GVHD, extensive chronic GVHD and relapse in the two groups relative to the infused cell doses. There was a trend towards improved OS (relative risk 0.54, 95% CI 0.29-1.01, P=.05) with higher CD3+ cell dose in the TCD group. Our findings suggest that higher CD34+ cell dose imparts survival benefit only to in vivo TCD peripheral blood AHCT recipients.

In Vivo T-Cell Depletion Does Not Improve Rates of Graft-Versus-Host Disease and Transplantation Outcomes In Patients Undergoing Peripheral Blood Hematopoietic Cell Transplant.

AbstractAbstract 4536 Introduction:Allogeneic hematopoietic cell transplant (AHCT) is a potentially curative modality for various benign and malignant hematological disorders. Despite advances in supportive care, graft-versus-host disease (GVHD) remains the leading cause of morbidity and mortality following AHCT. In vivo T-cell depletion (TCD) with alemtuzumab or anti-thymocyte globulin (ATG) is commonly employed to prevent graft rejection and GVHD following AHCT. Published (albeit controversial) data suggest possible benefit with TCD in setting of unrelated donor (URD), HLA-mismatched and peripheral blood AHCT. We report here AHCT outcomes for patients who received alemtuzumab or ATG with transplant conditioning (TCD group) and compare them with patients who received T-cell replete allografts (non-TCD group). Methods:The study cohort consists of 150 consecutive patients who underwent AHCT between January 2003 through December 2009. All patients received peripheral blood allografts from matched sibling or URDs. T-cell depletion consisted of alemtuzumab 40mg in two divided doses on days -4 and -1 (n=39) or Thymoglobulin at a total dose of 6 mg/kg for ablative and reduced intensity conditioning (RIC) transplants and 7.5 mg/kg total dose for non myeloablative allografts (n=51). 4 patients received Atgam at 30mg/kg on days -5 to -3. Results:Of the 150 patients, 62.7% (n=94) were males. Median age was 49yrs (range 17–69). Baseline diagnosis included acute leukemias/myelodysplastic syndrome (n=88; 58.6%), chronic myeloid leukemia (n=19; 12.7%), non-Hodgkin lymphoma (n=27; 18%) and others (10.7%). There were 95 patients (63.3%) in the TCD group and 55 (36.7%) in the non-TCD group. The baseline characteristics of the TCD group and non-TCD group where well matched except for significantly more patients in the TCD group who had high risk disease (86.3% vs. 61.8%, p < 0.05) and received AHCT from URD (62.1% vs. 29.1%, p<0.05). Median follow-up time of surviving patients is 3yrs.Median time to neutrophil engraftment was 15days (range 7–29 days) overall, with no significant difference between the two groups (p = 0.92). Similarly median time to platelet recovery was 18days (range 4–106), with no significant difference between the two groups (p = 0.85). The incidence of grades II-IV acute GVHD (aGVHD II-IV) in the TCD and non-TCD groups was 42.1% (n=40) and 50.9% (n=28) respectively (p = 0.32). For subgroup of patients undergoing matched sibling AHCT the incidence of aGVHD II-IV in TCD and non-TCD groups was 28.9% (n=11) and 50% (n=18) respectively (p= 0.06). For URD AHCT the corresponding rates of aGVHD II-IV were 48.3% (n=28) and 64.7% (n=11) respectively (p = 0.23). Rates of aGVHD II-IV for patients in TCD and non-TCD group receiving HLA mismatched allografts were also not significantly different (p = 0.59). 110 patients were evaluable for chronic GVHD (cGVHD). The incidence of cGVHD in the TCD and non-TCD groups was 41.1% (n=39) and 45.5% (n=25) respectively (p = 0.86). On subgroup analysis of patients undergoing matched sibling, URD and HLA-mismatched transplants no significant difference in rates of cGVHD between the TCD and non-TCD groups was seen (p>0.05). Relapse rate in the TCD group was 32.6% (n=31) and in the non-TCD group 40% (n=22) (p = 0.22). The overall survival at 3 years was 39.2% in the TCD group and 39.3% in the non-TCD group, (p = 0.93). The 3 year progression free survival in the TCD and non-TCD groups were 34.8% and 27.2% respectively (p=0.85). Non relapse mortality at 100 days similarly were 12.8% and 16% and at 3 years were 40% and 41% in the 2 groups (p>0.05). CONCLUSION:Our limited, single institution experience in a cohort of 150 consecutive patients (transplanted within the last decade) suggests no significant benefit with routine use of in vivo TCD with AHCT. These results highlight the need to develop novel and more effective strategies for preventing and treating GVHD and for improving transplantation outcomes. Disclosures:Abraham:Genentech: Membership on an entity's Board of Directors or advisory committees. Hamadani:Celgene corporation: Honoraria, Speakers Bureau; Otsuka Pharmaceutical: Research Funding, Speakers Bureau.

Higher Infused CD34+ Cell Dose Improves Survival In Patients Undergoing In Vivo T-Cell Depleted, but Not T-Cell Replete Peripheral Blood Hematopoietic Cell Transplant

AbstractAbstract 1272 Introduction:Allogeneic hematopoietic cell transplant (HCT) remains a potentially curative modality for various hematological disorders. The cellular composition of the infused allograft has important ramifications for transplantation outcomes, for example higher infused CD34+ cell doses have previously been shown to be is associated with early engraftment, improved survival and possibly increased acute graft-versus-host disease (GVHD) following HCT. The influence of cellular composition of infused allograft on transplant outcomes has been the subject of many previous studies. There is paucity of data on the impact of cellular composition of allograft on transplant outcomes of patients undergoing HCT with in vivo T-cell depletion (TCD) compared to patients receiving T-cell replete allografts. We report here a comparative analysis of the impact of CD34+, CD3+, CD4+ and CD8+ cell doses and survival outcomes of allogeneic, peripheral blood HCT patients receiving in vivo T-cell depletion with alemtuzumab or anti thymocyte globulin (TCD group) versus patients who underwent T-cell replete HCT (non-TCD group). Methods:The study cohort includes 150 consecutive patients who underwent allogeneic HCT between January 2003 through December 2009. All patients received peripheral blood allografts from matched sibling or unrelated donors (URD). In vivo T-cell depletion consisted of alemtuzumab 40mg in two divided doses on days -4 and -1 (n=39) or Thymoglobulin at a total dose of 6 mg/kg for ablative and reduced intensity conditioning (RIC) transplants and 7.5 mg/kg total dose for non myeloablative allografts (n=51).4 patients received Atgam at 30mg/kg on days -5, -4 and -3. Impact of CD34+, CD3+, CD4+ and CD8+ cell doses divided into two groups; >/= 50th and < 50th percentile on overall survival (OS), progression free survival (PFS) and non relapse mortality (NRM) was initially measured by univariate analysis. Multivariate logistic regression analysis was constructed for variables showing significance on univariate analysis (p<0.1). Cellular components of allografts was done by standard flow cytometric techniques. Results:Of the 150 patients, 94 (62.7%) were males. Median age was 49 (range 17–69). Baseline diagnosis included acute leukemia and myelodysplastic syndrome (n=88; 58.6%), chronic myeloid leukemia (n=19; 12.7%), non-Hodgkin lymphoma (n=27; 18%) and others (10.7%). There were 95 patients (63.3%) in the TCD group and 55 (36.7%) in the non-TCD group. The baseline characteristics of the TCD group and non-TCD group were well matched except that significantly more patients in the TCD group had high risk disease (86.3% vs. 61.8%, p = 0.0005) and received allografts from unrelated donors (62.1% vs. 29.1%, p < 0.001). Median doses of the infused cellular components in the allograft were; CD 34+ = 5.8 × 106/Kg (range 1.2 – 16), CD3+ = 30.8 × 107 (4.5 – 100.8), CD4+ = 18.6 × 107 (1.9 – 63) and CD8+ = 11.3 × 107 (0.8 – 52.4). Median follow-up time for surviving patients was 3 years.In the TCD group, multivariate analysis showed that CD34+ cell doses >/= 5.8 × 106 was associated with improved OS (p=0.0085; CI 0.28–0.83), PFS (p=0.03; CI 0.31–0.93) and NRM (p=0.02; CI 0.21–0.89). Multivariate analysis also showed that CD3+ cell dose >/= 30.8×107 improved OS (p=0.03; CI 0.25–0.92), but not PFS (p=0.14; CI 0.16–1.31) and NRM (p=0.15; CI 0.23–1.26). No association was noted between CD4+ and CD8+ cell doses and OS, PFS and NRM (p>0.05), in the TCD group.In the non-TCD group, univariate analysis of CD34+, CD3+, CD4+ and CD8+ cell doses failed to show any statistical significance for NRM, OS and PFS (p>0.1). Conclusion:Our limited, retrospective analysis of 150 peripheral blood allogeneic HCT shows improved OS, PFS and NRM in patients receiving CD34+ cell dose >/= 5.8×106/Kg and improved OS with CD3+ dose >/= 30.8×107/Kg, limited only to the TCD group. No such association was seen in the non-TCD group. We hypothesize that higher CD34+ in TCD transplants probably improved survival by rapid engraftment and by robust immune reconstitution thereby reducing infectious complication otherwise associated with TCD. Disclosures:Abraham:Genentech: Membership on an entity's Board of Directors or advisory committees. Hamadani:Celgene: Honoraria, Speakers Bureau; Otsuka: Research Funding, Speakers Bureau.

Full Haplotype Mismatch Stem Cell Transplantation: Myeloablative with T-Cell Depletion Vs. Reduced Intensity Conditioning without T-Cell Depletion

AbstractAbstract 3533Some groups have continuously tried to reveal the possible role of full-haplotype mismatch stem cell transplantation (SCT) in patients who lack a compatible donor. However, the long-term event-free survival (EFS) rate after high-grade mismatch SCT using conventional myeloablative conditioning with T-cell depletion (TCD), even in complete remission (CR), is still only in the range of 10–30%. Most patients who were transplanted had heavily pretreated acute leukemia. The most important obstacle to overcome is the high rate of infection-related mortality associated with delayed immunological recovery in the setting of full-haplotype mismatch SCT, specifically by way of complete depletion of donor T cells in the graft. In contrast, by using unmanipulated donor cells and less aggressive conditioning regimens without TCD, most groups in Asia have reported EFS >40%. We investigated the role of reduced-intensity conditioning without TCD in HLA-mismatched related-donor SCT, specifically in patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received unmanipulated granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSCs). SCT was performed in 32 consecutive patients. We compared two different protocols: one with more intensive conventional conditioning with TCD (group 1), and one with reduced intensity without TCD (group 2). The protocols differed between the two groups with respect to total body irradiation (1200 cGy in group 1 vs. 800 cGy in group 2) as well as busulfex, fludarabine, and anti-thymocyte globulin (ATG; thymoglobulin, Genzyme) treatments. No patient in group 1 received post-transplant graft versus host disease (GvHD) prophlyaxis or G-CSF. In contrast, all patients in group 2 received 1.25 mg/kg/day ATG for 4 consecutive days, together with our standard GvHD prophylaxis regimen of methotrexate (5 mg/m2 intravenous bolus on days 1, 3, 6, and 11) and tacrolimus starting at day –1. All patients received G-CSF-mobilized PBSCs. The median number of CD34+ cells infused was 14.2 (range, 4.3–20.6) × 106/kg for group 1 and 6.0 (range, 3.6–8.5) × 106/kg for group 2. The median numbers of CD3+ cells infused were 0.03 (range, 0.015–0.057) × 106/kg and 870 (range, 84–1260) × 106/kg, respectively. G-CSF was administered subcutaneously to all patients in group 2 at a dose of 5 mg/kg/day, from day 7 after transplantation until neutrophil recovery. GvHD, relapse, non-relapse mortality (NRM), overall survival, EFS, reconstitution of immunity, and natural killer (NK) cell alloreactivity were compared between the groups. The median patient age was 33 (range, 17–48) years for group 1 and 39 (range, 19–63) years for group 2. The median follow-up for surviving patients was 18 months (range, 8–100). The majority of patients had intermediate or unfavorable cytogenetic features. The transplanted patients were all successfully engrafted. The median times to neutrophil (>0.5 × 109/kg) and platelet (>20 × 109/kg) recovery were 12 and 13 days in group 1, and 11 and 10 days in group 2. The overall rates of acute and chronic GvHD were 50% and 33%, and 80% and 92% in groups 1 and 2, respectively. Of note, NRM differed significantly between the groups: 46.2% in group 1 vs. 9.5% in group 2 (P = 0.0014). The estimated probability of EFS at 2 years was 15.3% for group 1 vs. 59.2% for group 2 (P = 0.05). We did not find NK alloreactivity in any of the patients, based on the NK-killer cell immunoglobulin-like receptor (KIR) disparity between donor and recipient. However, we noted a significant difference in EFS between C1/C1 homozygotes and C1/C2 heterozygotes according to the donor NK-KIR ligands (P = 0.0175). Recovery of CD4+ cell numbers at 3 months after SCT showed a markedly different pattern between the groups, with a median of 4 cells/μl (range, 2–7) in group 1 vs. 311 cells/μl (range, 56–1226) in group 2. Our findings suggest that full-haplotype mismatch SCT using a Korean-adapted protocol is a feasible therapeutic strategy for patients with high-risk AML/MDS, specifically in CR, provided that there is a further defined plan for the investigation of NK/T-cell alloreactivity. Disclosures:No relevant conflicts of interest to declare.

20 Years of Experience with Hematopoietic Stem Cell Transplantation for β-Thalassemia Major.

Background: Hematopoietic stem cell transplantation (HSCT), the sole cure for β-thalassemia major (TM), is plagued by graft rejection or disease recurrence (10–30%). The risk of recurrence is influenced by age, type of allograft, presence of graft-versus-host-disease (GVHD), ferritin levels and hepatic iron overload. Complete donor hematopoiesis was believed essential for sustained marrow engraftment, but according to pre-clinical/clinical data, stable mixed chimera is also curative. We report our experience using T cell depletion (TCD) as prevention of GVHD versus fludarabine-based conditioning in unmanipulated HSCT.Material & Methods: 35 patients (6 mo-7 yr; median 29 mo; 10 female and 25 male) with TM were transplanted (1984–95) with HLA-matched donors siblings (29), parents (2), grandparents (2), cousin (1) and aunt (1). Conditioning encompassed total lymphoid irradiation (TLI) of 2 cGy/dx4 followed by busulfan 4 mg/kg/dx4 and cyclophosphamide 50 mg/kg/dx4; TCD was performed in vitro with CAMPATH1M (21) or CAMPATH1G “in the bag” (14). No GVHD-prophylaxis was given.Based on our results with non-myeloablative regimens, we used since 1996 fludarabine-based conditioning for TM. A total of 24 patients (2–23 yr; median 5 yr; 14 female and 10 male) were transplanted with unmanipulated inocula from HLA-matched siblings (20), matched grand-father (1), mismatched sibling (1) and MUD (2). For 21 patients conditioning consisted of fludarabine 30 mg/m2/dx6, busulfex (BU) 3.2 mg/kg/dx4; 2 patients received BU 3.2 mg/kg/dx2, and 1 patient received TBI 2 cGy/dx1 without BU. All patients received ATG (Frisenius) 10 mg/kg/dx4 and Cyclosporine from day -4 for GVHD-prophylaxis.Results: In the TCD group, no GVHD occurred; 5 patient (14.3%) died from transplant related complications, 5 patients (14.3%) rejected the graft and in 3 patients (8.6%) recurrence of TM occurred; 11 patients (31.4%) were 100% donor, 10 patients (28.6%) had stable mixed chimera (70–96% donor); one patient had 5% of donor cells 5 years after transplant and with allogeneic HSCT from the same donor following ambulatory non-myeloablative conditioning, complete displacement of host cells was accomplished (R.Or et al. Br J of Haem 1996: 94;285–7).In the fludarabine based group no transplant related mortality occurred; 4 patients (16.7%) rejected the graft (2 patients with BUx2; 1 patient transplanted from a mismatched sibling; 1 patient with unrelated donor), but all survived with autologous rescue. All 7 patients (29.2%) suffering from acute GVHD responded to treatment. 11 patients (45.8%) had 100% donor cells; 9 patients (37.5%) had stable mixed chimera and overall survival up to 9 years after HSCT is 100%.Conclusions: TCD is a feasible conditioning preventing completely GVHD. Unstable mixed chimera can be converted to full donor with donor lymphocyte infusion. TCD requires more intensive conditioning to prevent allograft rejection, but is associated with increased transplant related mortality.Fludarabine based conditioning is well tolerated with minimal procedure related morbidity and no mortality. The incidence of acute GVHD was low and treatable. Low dose BU is not sufficient for consistent engraftment; mixed chimera was frequent, yet stable and associated with functionally normal hematopoiesis. With reduced intensity conditioning, age seems no longer to be contraindication for HSCT for TM.

A prospective analysis of immune recovery in children following allogeneic transplantation of t-cell-depleted or non-T-cell-depleted hematopoietic cells from HLA-disparate family donors

Transplantation of HLA-disparate hematopoietic stem cells from related donors is an alternative for the treatment of patients lacking an HLA-matched family or unrelated donor. In the cases of a single HLA antigen disparity, extensive T-cell depletion (TCD) is not required, yet antithymocyte globulin (ATG) must be administered to prevent GvHD or graft rejection. The major concern after HLA-mismatched transplants remains immune reconstitution. Therefore, we prospectively studied the recovery of lymphocyte subsets among 22 children transplanted from partially HLA-matched family donors. We compared two groups of patients: (1) the TCD group included children (n = 1.3) who received grafts after TCD (MACS) due to an HLA disparity for more than one antigen; (2) The non-TCD group included children with either one HLA-mismatched antigen, n = 7; or more than one disparate antigen (n = 2) who received T-cell-repleted grafts and ATG. The study demonstrated rapid NK cell reconstitution among the TCD group. TCD compromised T-cell reconstitution, thus preventing GvHD, but resulting in a higher incidence of severe infectious complications, graft rejection, and disease relapse. Increasing mixed chimerism required the application of donor T-cell addbacks, thus potentiating the risk of GvHD. Primary graft rejection occurred in eight children, who required further transplants. In the non-TCD group faster T-cell reconstitution (predominantly CD3+CD8+ cells) resulted in a lower rate of relapse and infection, yet a higher rate of GvHD, including two fatal cases. Due to improved immune reconstitution, in spite of an increased risk of GvHD, non-TCD transplants from single HLA-mismatched family donors remain a valuable option for children without matched donors.

Influence of T cell depletion method on circulating γδ T cell reconstitution and potential role in the graft-versus-leukemia effect

Our laboratory previously reported that leukemia patients who developed > or = 10% gammadelta+ T cells during the first six months after receiving an anti-TCRalphabeta T-cell-depleted (TCD) graft from a partially mismatched related donor (PMRD) had a disease-free survival (DFS) advantage. These gammadelta+ T cells were V81+CD3+CD4-CD8-CD69+HLADR+ and are cytotoxic to K562 cells. In order to determine whether the anti-alphabeta TCD regimen was associated with these findings, we compared the reconstitution of gammadelta+ T cells from patients who received TCD PMRD grafts using the anti-TCRc4 MAb TIOB9-1A31 (previously reported) with similar patients who received grafts using the anti-CD3 MAb OKT3. Increased cytotoxic Vdelta1+ T cells were seen in 10 of 43 T10B9 TCD patients compared to 7 of 100 in the OKT3 TCD group (23% versus 7%, p = 0.010). T10B9 patients with increased gammadelta+ T cells also exhibited a higher range of increased gammadelta+ T cells and the length of time the gammadelta+ T cells remained high was longer when compared to OKT3 patients. Patients with increased gammadelta+ T cells whose grafts were T-cell depleted with T10B9 showed a significant decrease in relapse (p = 0.038). Similar rates and reduction in relapse were seen in OKT3 TCD patients, although significance was not reached due to the small number of patients with increased gammadelta+ T cells. Estimated 3 year disease-free survival was significantly improved in T10B9 patients with increased gammadelta+ T cells (0.79 versus 0.31, p = 0.009), a trend also seen in OKT3 patients (p = 0.091). These observations indicate that Vdelta1+CD4-CD8-cytotoxic T cells are associated with lower relapse rates and improved survival, and thus may have a role in a graft-versus-leukemia effect.

Increased risk of relapse in patients with chronic myelogenous leukemia given T-cell depleted marrow compared to methotrexate combined with cyclosporin or monotherapy for the prevention of graft-versus-host disease.

Fifty-two patients with chronic myelogenous leukemia (CML) who underwent bone marrow transplantation (BMT) at Huddinge Hospital were analyzed retrospectively regarding type of graft-versus-host disease (GvHD) prophylaxis. With T-cell depletion (TCD) (n = 13) the incidence of grade II-IV acute GvHD was 8% compared to 27% among patients given short course methotrexate (MTX) + cyclosporin (CSA) (n = 23) (ns) and 60% in patients who received MTX or CSA alone (n = 16) (p = 0.006 vs TCD and 0.03 vs MTX + CSA). The incidence of chronic GvHD was 56%, 31% and 75%, in the three groups, respectively (p = 0.02 combination vs monotherapy). Probability of relapse differed significantly, with most relapses in the TCD group, 62% compared to 20% in the MTX + CSA group (p = 0.02) and no relapse in the monotherapy group (p = 0.01 TCD vs monotherapy). Patient survival at 6 years was 54%, 59% and 38%, in the three groups, respectively (ns). Relapse-free survival was 23% in the TCD group, 55% in the combination group (p = 0.06) and 38% in the monotherapy group (ns). We conclude that TCD in patients with CML is correlated with an increased risk of relapse and a tendency towards a decreased long-term relapse-free survival compared to patients receiving other kind of GvHD prophylaxis.