scholarly journals Largest Single Center Experience Using Dual T-Cell Depletion with ATG and Ptcy for Gvhd Prophylaxis in Peripheral Blood RIC Allo-HSCT

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3344-3344
Author(s):  
Maria Queralt Salas ◽  
Arjun Law ◽  
Wilson Lam ◽  
Fotios V. Michelis ◽  
Dennis Dong Hwan Kim ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multivariate Analysis ◽  
T Cell ◽  
Chronic Gvhd ◽  
Significant Risk ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Single Center Experience ◽  
Gvhd Prophylaxis ◽  
Donor Type

Introduction: Dual T-cell depletion with ATG and PTCy combined with cyclosporine (CsA) in peripheral blood (PB) reduced intensity conditioning (RIC) allo-HSCT results in an impressive control of clinically relevant GVHD. We aim to share the largest and unique single center experience using this novel GVHD combination in allo-HSCT for hematological malignancies. Methods Between October 2015 and April 2019, 365 consecutive adult recipients underwent PB RIC allo-HSCT. Conditioning regimen consisted on fludarabine, busulfan and 200 cGy of total body irradiation. For GVHD prophylaxis all cases received ATG, PTCy (50mg/kg/24h x 2 doses on day +3 and +4) and CsA since day +5. Two hundred fifty-nine (71%) recipients, transplanted between 2015 and May 2018, received a total dose of 4.5mg/kg of rabbit-ATG (given on day -3,-2 and -1). In May 2018, the protocol was reviewed and refined decreasing the dose of ATG to a total of 2mg/kg (given on day -3 and -2). A total of 106 (29%) recipients received the lowered dose of ATG. Data was collected retrospectively and updated on July 2019. Cumulative incidence (Cum.Inc) of GVHD, CMV and EBV reactivation analysis was assessed accounting relapse and death as competing events. The multivariate analysis for OS and RFS was controlled by the following significant variables in the univariate analysis: age at transplant, disease risk index (DRI) (low and moderate v's high and very high), Karnofsky performance status (>80% v's ≤80%), HCT-CI score ≥3 and donor type. Results Baseline characteristics and main post-transplant information and outcome are summarized in Table 1 and 2. The cum.Inc of grade II-IV and grade III-IV at day +100 was respectively 14% (95 confidence interval (CI) 11.1-18.4) and 4.7% (95% CI 2.8-7.2). The cum.Inc of moderate and severe chronic GVHD at 1 year was 13% (95% CI 9.7-16.8). ATG dose and donor type did not influence acute/chronic GVHD rates (Table 3). The cum.Inc of CMV and EBV reactivation at day +180 was comparable between the two cohorts that received different dose of ATG (P>0.05). However, in the cohort that received a lower dose of ATG (2mg/kg), no CMV disease was documented and the percentage of probable or proven EBV-post-transplant lymphoprolipherative disease (P/P-PTLD) was only 3.7%. The percentages of CMV disease and P/P-PTLD in the group that received a dose of ATG of 4.5 mg/kg were respective 4.6% and 8.8%. Overall survival (OS), relapse-free survival (RFS), non-relapse mortality (NRM) and the cumulative incidence (cumInc) of acute GVHD of the entire cohort and according to the ATG dose are shown in the Table 2 and the Table 3. OS and RFS curves of all 365 patients and stratified according to donor type are shown in the Plots 1 to 4. In the multivariate analysis, age at transplant [(HR 1 (95% CI 1.01-1.02); P=0.046], high and very high DRI score [HR 1.8 (95% CI 1.2-3.6); P=0.001], KPS ≤80% [HR 1.8 (95% CI 1.2-2.7); P=0.001], and HCT-CI score ≥3 [HR 1.4 (95% CI 1.01-2.09); P=0.042] were significant risk factors for worse OS. Donor type was not a significant parameter for OS (P>0.05). In the multivariate analysis of risk factors for RFS, high DRI score [HR 1.7 (95% CI 1.2-2.4); P=0.002], and a KPS ≤80% prior allo-HSCT [HR 2 (95% CI 1.4-2.8); P<0.001] were significant risk factors for worse RFS. To receive grafts from a 10/10 MUD was a significant parameter for better RFS [HR 0.6 (95% CI 0.4-0.9); P=0.046]. Conclusions Dual T-cell depletion with ATG and PTCy provides an impressive control of GVHD with acceptable relapse rates using PB stem cell grafts independently of the donor type. This observation suggests that the present combination overcomes the HLA-barrier and its effect on GVHD. Acute GVHD rates are effectively controlled with a dose of ATG of only 2mg/kg when it is combined with PTCy and CsA. Further investigations need to be done to better define the efficacy of a lower dose of ATG controlling chronic GVHD in this setting. Further investigations and refinements need to be done to improve survival rates in those recipients with higher DRI score and worse KPS ≤80% prior transplantation. Disclosures Michelis: CSL Behring: Other: Financial Support. Mattsson:Gilead: Honoraria; Therakos: Honoraria; Celgene: Honoraria.

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.

Synergy of Unrelated Donor and Full Intensity Conditioning Breaks the Control of Graft Versus Host Disease By Alemtuzumab

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1206-1206
Author(s):  
Olivia Laverick ◽  
Amy Publicover ◽  
Laura Jardine ◽  
Kile Green ◽  
Alan Potter ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Reduced Intensity Conditioning ◽  
T Cell Depletion ◽  
Gvhd Prophylaxis ◽  
Full Intensity ◽  
Conditioning Intensity ◽  
Reduced Intensity

Abstract Many variables influence the risk of graft versus host disease following hematopoietic stem cell transplantation. Comparison between preparative regimens is hampered by the use of many different combinations of chemotherapy and radiotherapy, varying intensity of conditioning, use of T cell depletion and donors who are either siblings or unrelated volunteers. Many reduced intensity regimens also incorporate enhanced GVHD prophylaxis with in vivo T cell depletion. Here we describe a cohort of patients prepared in a modular fashion with either reduced or full intensity conditioning combined with a uniform GVHD prophylaxis regimen for all transplants with sibling donors (alemtuzumab 30mg) and for all with unrelated donors (UD; alemtuzumab 60mg). Thus it was possible to dissect independently the effect of conditioning intensity and sibling or UD type upon GVHD risk in this settig of in vivo T cell depletion. Patients and analysis: the study was a retrospective analysis of 258 sequential transplants performed in adults with hematological malignancy between September 2005 and September 2013 at a single UK institution. Reduced intensity conditioning (n = 221) included fludarabine 150mg/m2 plus melphalan 140mg/m2 or fludarabine 150mg/m2 plus busulfan 9.6mg/kg. Full intensity transplants (n = 37) received 12Gy TBI plus melphalan 140mg/m2, 12Gy TBI plus cyclophosphamide 120mg/kg, or busulfan 16mg/kg plus cyclophosphamide 120mg/kg. All patients with sibling donors received 30mg alemtuzumab and those with UD received a 60mg of alemtuzumab. UD matching was similar in both reduced intensity and full intensity cohorts (92.2% and 86.5% 10/10 matches, respectively) but patients receiving reduced intensity were older than those receiving full intensity conditioning (median age 51 vs 31; p < 0.001). Outcome was analyzed according to EBMT guidelines. Relapse, non-relapse mortality and cGVHD were treated as competing risks and analysed as cumulative incidence. Outcome: the incidence of acute GVHD grades I-IV was comparable between reduced intensity and full intensity sibling transplants (45% vs 45%; p = NS) indicating a lack of effect of conditioning intensity upon GVHD risk in this setting. There was a slight increase in the risk of GVHD between reduced intensity UD compared with reduced intensity sibling donor transplants (57% vs 45%; p = NS) but a marked synergistic increase between UD transplants performed with full intensity compared with reduced intensity conditioning (100% vs 57%; p = < 0.001). The incidence of grades III-IV acute GVHD was also higher in full intensity UD transplants (16%) compared with reduced intensity UD transplants (5%). The incidence of chronic GVHD was also highest in full intensity UD transplants but both conditioning intensity and UD contributed in an additive manner: the rate of chronic GVHD progressed from 33% to 44% in reduced intensity and full intensity sibling transplants respectively and from 57% to 75% for reduced and full intensity UD transplants, respectively. Two year overall survival was comparable in all groups, ranging from 55% to 70%. In keeping with the higher rates of acute GVHD in full intensity transplants performed with UD, this group experienced the lowest relapse risk (15% vs 29% for all the other groups combined; p = 0.04) but the highest non-relapse mortality, reaching 41% at 2 years compared with 28% for all the other groups combined (p = 0.08). Conclusion: these results show that alemtuzumab provides good protection from acute GVHD in reduced intensity transplantation from sibling and UD. In sibling transplants given identical GVHD prophylaxis, full intensity conditioning does not increase the risk of GVHD. In contrast, a slight increase in GVHD risk with UD transplants seen with reduced intensity conditioning, is amplified in a synergistic manner by full intensity conditioning. This is associated with a high non-relapse mortality, even though the median age of full intensity patients is more than 20 years younger than those receiving reduced intensity conditioning. Disclosures No relevant conflicts of interest to declare.

BK Virus-Associated Hemorrhagic Cystitis Following Allogeneic Hematopoietic Stem Cell Transplantation; Incidence and Risk Factors

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5759-5759
Author(s):  
Feras Alfraih ◽  
Amjad Alhussaini ◽  
Farhan Anjum ◽  
Ghuzayel Mubarak Aldawsari ◽  
Fahad Alsharif ◽  
...  
Keyword(s):  
Risk Factors ◽  
T Cell ◽  
Acute Gvhd ◽  
Hemorrhagic Cystitis ◽  
Conditioning Regimen ◽  
Bk Virus ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Factors Associated ◽  
Gvhd Prophylaxis

Abstract Introduction : Hemorrhagic cystitis (HC) is one of common complications after allogeneic hematopoietic SCT (HSCT) with reported incidence varying from 7 to 70%. Several reports have shown that BK is strongly associated with HC (BK-HC) following HSCT. We conducted an institutional retrospective study to analyze the incidence and clinical factors associated with BK-HC following HSCT. Methods : A total of 517 consecutive patients above the age of 14 years receiving HSCT from 2009 and June 2015 were included in this retrospective analysis and evaluated for HC and urinary BK. HC was defined as documented hematuria of any grade and BK viruria was defined as positive at any level by BKV quantitative PCR testing in urine. Patients were stratified, based on hematuria and urinary BK virus, into the following groups (a) BK virus positive hemorrhagic cystitis (BK+HC), (b) BK virus negative hemorrhagic cystitis (BK-HC) and (c) Non-hemorrhagic cystitis (HC-). Screening for microscopic hematuria was performed only for patients with any kind of urinary symptoms. Results: 479 patients (92.6%) were matched related donor and 308 (60%) were male with a median age of 24 (range 14 to 66). Diagnoses were AML for 195 (38%), ALL for 183 (35%) and bone marrow failure for 44 (8.5%). Conditioning regimen was cyclophosphamide based in 427 (82.6%) patients (97%) versus others in 90 (17.4%) patients. GVHD prophylaxis was CSA/MTX for 456 (88.4%) however, T cell depletion was used in 13%. Peripheral blood stem cells were used for 56% of patients. With a median follow-up of 60 months for survivors (range 2 to 116.5 months), 43 (8%) patients showed BK+HC, 264 (51%) BK- HC while 209 (41%) did not have any hematuria (HC- group). Median time from transplantation to BK+ HC was 67 days (range 7 to 1261 days). Univariate analysis for risk factors of BK+ HC showed male, use of T-cell depletion and AML diagnosis were statistically significant factors. Other factors like age, conditioning regimen, GVHD prophylaxis, stem cell source, mismatched and remission status were not statistically significant. BK+ HC group was associated with higher incidence of other infections like CMV viremia (p=0.01) and fungal infection (p<0.01). Incidence of acute GVHD was 62.8% in BK+ HC group, 43% in HC- BK and 33.3% in HC- group (p=<0.01), suggesting higher incidence of acute GVHD in BK+ HC group. There was no difference in incidence of chronic GVHD. Conclusion: Hematuria following allogeneic bone marrow transplantation occurs in almost half of patients (51%) while BK associated HC develops in 8% of patients. Factors associated with BK+ HC were male gender, use of T-cell depletion and AML diagnosis. BK+HC is usually associated with other infections like CMV viremia and fungal infections. Further studies are needed to minimize or prevent BK+ HC following HSCT especially in high risk group. Disclosures No relevant conflicts of interest to declare.

Partial T-Cell Depletion By Low-Dose Anti-Thymocyte Globulin to Reduce Severe Acute and Chronic Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5470-5470
Author(s):  
Osamu Imataki ◽  
Yumiko Ohbayashi ◽  
Yukiko Ohue ◽  
Harumi Matsuka ◽  
Makiko Uemura ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Low Dose ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Control Group ◽  
T Cell Depletion ◽  
Stem Cell Source ◽  
Gvhd Prophylaxis

Abstract Background: T cells from a stem cell source are inevitably contaminated, and over 5.0×104/kg T cells are thought to induce graft-versus-host disease (GVHD) in HLA-mismatched or haplo-identical stem cell transplantations (SCTs) [4]. To suppress GVHD reactions, a procedure for T-cell depletion (TCD) was developed over the past several decades, especially for HLA-mismatched and haplo-identical SCTs, which are at high risk for GVHD. To reduce the incidence of GVHD, a potentially effective agent is anti-thymocyte globulin (ATG), which is generally administered at a dose of ≥ 5-10 mg/kg. Based on data regarding the use of ATG for the treatment of aplastic anemia, we hypothesized that ATG might accommodate engraftment and inhibit GVHD. We attempted to use a lower dose of ATG to decrease non-relapse mortality (NRM) in Japanese patients undergoing an HLA-matched SCT. Patients and method: We treated patients with hematological diseases who underwent an allogeneic SCT after March 2010 without or with 2.5 mg/kg ATG. The inclusion criteria for underlying disease included both hematological malignancies and bone marrow failures. All consecutive patients transplanted from an allogeneic related or unrelated donor were included. Cord blood transplantations were omitted from this analysis. The patients who underwent an SCT before February 2010 (n=20) were examined as the control group without ATG treatment. ATG was administered 1 day prior to the transplantation day at 2.5 mg/kg with 500 mg/body methylpredonisolone as a preconditioning procedure. GVHD prophylaxis, tacrolimus 0.03 mg/kg and short-term MTX (10-7-7 mg/m2) was adapted for both the ATG group and the control group. Results: Thirty-nine (21 male, 18 female) recipients were recruited (median age 49 yrs, range 19-64 yrs). Their underlying diseases were acute myeloid leukemia (n=14), acute lymphoblastic leukemia (n=10), myelodysplastic syndrome (n=5), lymphoma (n=7), and myeloma, aplastic anemia, and other malignancy (n=1 each). Preparation regimens were myeloablative for 17 patients (14 cyclophosphamide [CY]/total body irradiation [TBI], two busulfan [BU]/CY, and another) and non-myeloablative for the other 22 patients (14 fludarabine/melphalan [Flu/Mel] and eight Flu/BU). All but one patient achieved engraftment, and one secondary graft failure was observed. The overall incidences of acute and chronic GVHD were 63.2% and 15.8% for the ATG-treated patients (40.0% and 25.0% for the control cohort), respectively. Acute GVHD (grades II to IV and III to IV) in the recipients who received ATG occurred in 21.1% and 0.0% (control cohort, 10.0% and 5.0%), respectively. The estimated probability of overall survival (OS) 2.5 yrs after transplantation was 77.8% for the ATG group (controls, 57.1%). The relapse rate 2.5 yrs after transplantation was 21.1% and 20.0% in the ATG and control groups, respectively. The NRM rate was decreased after ATG treatment: 25.0% vs. 10.5% (not significant). The causes of mortality with or without ATG were recurrent diseases (n=1 and 2), infection (n=1 and 0), and adverse events caused by transplant-related complication (n=1 and 5), respectively. No deaths due to acute or chronic GVHD occurred. Discussion: Low-dose ATG could suppress the incidence of severe acute GVHD and chronic GVHD without increasing the NRM, although our study design did not have enough power to make a conclusion about the efficacy of low-dose ATG. However, partial T-cell depletion may be effective for HLA-matched SCT recipients. Our results show that ATG at 2.5 mg/kg can be used safely for the Japanese transplant population of HLA-matched donors. Low-dose ATG is a potential treatment to partially disempower T cells from a stem cell source, which are inevitably contaminated. Recent developments in the prophylaxis for GVHD, such as selective cytotoxic T-cell depletion by using a post-transplant CY regimen, are promising strategies to fully suppress T cells as the GVHD enhancer. Previous studies revealed the clinical efficacy of GVHD prophylaxis but did not clarify the significance of its survival benefit. Likewise, our present findings indicated a lack of survival benefit by ATG treatment in this small study. However, the low-dose ATG contributed to a reduction of severe GVHD. Although early mortality after transplantation is decreasing, late-onset comorbidity including chronic GVHD remains a significant problem. Disclosures No relevant conflicts of interest to declare.

Comparison of Outcomes for Non-Myeloablative (NMA) and Myeloablative (MA) Conditioning for Adults with Acute Lymphoblastic Leukaemia (ALL) in First and Second Complete Remission (CR): a Center for International Blood and Marrow Transplant Research (CIBMTR) Analyisis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 872-872 ◽  
Author(s):  
David I. Marks ◽  
Tao Wang ◽  
Waleska S. Peréz ◽  
Donald W. Bunjes ◽  
John F. DiPersio ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
T Cell ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
Conditioning Group ◽  
T Cell Depletion ◽  
Hematopoietic Stem ◽  
Donor Transplant

Abstract Abstract 872 The efficacy of reduced intensity or NMA conditioning for allogeneic hematopoietic stem cell transplantation (HCT) for adults with ALL is uncertain. Using CIBMTR data we compared the outcomes of 92 patients ≥16 years who had NMA conditioning with 1421 patients who had myeloablative conditioning (MC) for allografts using sibling and unrelated donors for ALL in CR1 or CR2. Conditioning in the NMA group included regimens containing busulfan ≤ 9 mg/kg (27), melphalan ≤ 150 mg/m2 (23) or low-dose total body irradiation (36) and others (7). The NMA conditioning group were older (median 45 vs. 28 years, p<0.001) and more received peripheral blood grafts (73% vs. 43%, p<0.001). Other major potential prognostic factors were similar in the two groups. After a median follow-up of 54 vs. 38 months respectively, the NMA vs. MA conditioning groups had slightly less acute grade 2-4 graft-vs-host-disease (GVHD), less chronic GVHD but similar transplant-related mortality (TRM). However the NMA conditioning group experienced slightly more relapse (35% vs. 26%, p=0.08) yet similar overall survival (OS) (Figure): Outcome:MANMAP-value Acute GVHD @ 100 days, grades (2-4)46 (43-49)39 (29-49)0.16 Chronic GVHD @ 3 years42 (39-44)34 (24-44)0.16 TRM @ 3 years, %33 (31-36)32 (23-43)0.86 Relapse @ 3 years, %26 (23-38)35 (25-46)0.08 Leukemia-free survival (LFS) @ 3 years, %41 (38-44)32 (22-43)0.12 OS @ 3 years, %43 (40-46)38 (28-49)0.39 Multivariate analysis showed that a low Karnofsky score (KPS) and T cell depletion were associated with higher TRM but conditioning intensity had no impact on TRM (RR with NMA 0.97, P=0.89). Relapse risk with NMA conditioning was slightly, but not significantly higher ( (RR)=1.34, p=0.15) as was a CR2, particularly with a short (<12 months) initial CR (RR=2.74; longer remission (12 months) RR1.51, P<0.0001). Multivariate analysis demonstrated significantly improved OS with: KPS>80, CR1, lower WBC, no extramedullary disease, a well matched unrelated or a sibling donor, transplant since 2001, in younger patients (<30y), conditioning without TBI and GVHD prophylaxis without T-cell depletion. However ATG use did not affect survival.. The most common cause of death was relapse; which was similar in MA and NMA HCT (46% vs. 35%). Despite the older age in the NMA group, OS and LFS at 3 years was similar to those receiving MA HCT. In comparing the outcomes of NMA and MA conditioning in sibling vs. unrelated donor transplant recipients we found that there was slightly, but not significantly more relapse with NMA [34 (18-52)% vs. 26 (23-30)%, p=NS and 36 (24-49)% vs. 25 (22-28)%, p=NS respectively]. This was associated with similar OS of 40 (23-59)% vs. 50 (45-54)% and 37 (25-50) vs. 38 (34-41)% in the sibling and unrelated donor groups. Conclusions: These data suggest that NMA conditioning is worthy of investigation in prospective clinical trials of adult ALL. These trials should include both well matched unrelated and related donors, but importantly, NMA conditioning may not fully overcome the adverse impact of poor pre-HCT KPS on outcome. >Disclosures: No relevant conflicts of interest to declare.

scholarly journals Improved Gvhd Free, Relapse Free Survival Using Dual T-Cell Depletion with ATG and Ptcy in Matched Unrelated Donor RIC Allo-HSCT

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4594-4594
Author(s):  
Maria Queralt Salas ◽  
Wilson Lam ◽  
Arjun Law ◽  
Fotios V. Michelis ◽  
Dennis Dong Hwan Kim ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Effective Control ◽  
T Cell Depletion ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
The Impact

Introduction The combination of anti-thymoglobulin (ATG), post-transplant cyclophosphamide (PTCy) and cyclosporine (CsA) provides an effective control of graft-versus host disease (GVHD) in allo-HSCT using peripheral blood stem cell (PBSC) grafts, as has been reported by Dr. Viswabandya et al. We aim to report a large, single center experience in reduced intensity conditioning (RIC) allo-HSCT using dual T-cell depletion with ATG and PTCy combined with CsA for GVHD prophylaxis using grafts from 10/10 matched unrelated donors. Patients and methods Between October 2015 and April 2019, 167 adult patients diagnosed with hematological malignancies underwent first 10/10 MUD RIC allo-HSCT. RIC regimen was composed by fludarabine, busulfan, and 200cGy of total body irradiation. For GVHD prophylaxis all recipients received rabbit-ATG, PTCy 50mg/m2/day on day +3 and +4, and CsA since day +5. One hundred sixteen (69.5%) recipients, transplanted between 2015 and May 2018, received a total dose of 4.5mg/kg of rabbit-ATG (given on day -3,-2 and -1). In May 2018, the dose of ATG was lowered to a total of 2mg/kg (given on day -3 and -2). A total of 51 (30.5%) recipients received the lowered dose of ATG. The median follow-up of the entire cohort was 14 months (range: 0.4-44.5). For those patients who got a higher dose of ATG was 20 months and for those who received a lower dose of ATG was 8.8 months. Data was collected retrospectively and updated on July 2019. Cumulative incidence (Cum.Inc) of GVHD analysis was assessed accounting relapse and death as competing events. Results Baseline and post-transplant information are summarized in the Table 1 and 2. Ninety-three (55.7%) recipients were diagnosed with acute myeloid leukemia (AML). The cum.Inc of grade II-IV and grade III-IV acute GVHD at day +100 was respectively 15.6% (95% confidence interval (CI) 10.6-21.6) and 3.6% (95% CI 1.5-7.3). The cum.Inc of acute GVHD was not significantly affected by the dose of ATG (P>0.05). The cum.Inc of chronic GVHD was 10.9% (95% CI 6.6-16.4). Due to the shorter median follow up of the cohort that received a lower dose of ATG, the impact of the reduction of the dose in the cum.Inc of chronic GVHD was not explored. Overall, 48 (28.7%) recipients died and 35 (20.4%) relapsed. Main causes of death were relapse (14.4%) and infection (9.6%). Outcome information is reported in the Table 2 and Plot A, B and C. One-year overall survival (OS), relapse-free survival (RFS) and GVHD-free/RFS (GFRFS) were respectively 75.6%, 70.3%, 60.4%. Table 3 summarizes the impact of the use of a different dose of ATG in acute GVHD and post-transplant outcome. No significant differences were found between the two groups that receive a different dose of ATG. However, median follow-up was shorter in the cohort that received 2mg/kg of ATG. Table 4 reports the main post-allo-HSCT information of patients diagnosed with AML. One-year OS, RFS and GRFRS for this subgroup of patients were 76.8%, 71.9% and 65.9%. Conclusion The unique and modern combination of RIC PB allo-HSCT using ATG, PTCY and CsA for GVHD prophylaxis results in impressive post-transplant outcomes using 10/10 MUD. The use of dual T-cell depletion with ATG and PTCy is safe and provides an extraordinary control of GVHD with acceptable relapse rates using PB stem cell 10/10 MUD grafts. ATG of only 2mg/kg when it is combined with PTCy and CsA, results in an effective control of acute GVHD rates. The optimal dose of ATG for GVHD prophylaxis is not well established. Further investigations need to be done to determine the efficacy of a lower dose of ATG controlling chronic GVHD in this setting. For patients diagnosed with AML, this protocol is safe and an effective approach when a 10/10 MUD is available. Disclosures Michelis: CSL Behring: Other: Financial Support. Mattsson:Celgene: Honoraria; Gilead: Honoraria; Therakos: Honoraria.

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.

In-Vivo T-Cell Depletion with Rabbit Anti-Thymocyte Globulin (r-ATG) Prevents Severe Acute and Chronic Graft Versus Host Disease (GVHD) and Allows Safe Allogeneic Stem Cell Transplantation (allo-SCT) From Mismatched, Unrelated Donors

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1977-1977
Author(s):  
James L. Slack ◽  
Jose F. Leis ◽  
Craig B. Reeder ◽  
Joseph R. Mikhael ◽  
Pierre Noel ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Hematologic Malignancies ◽  
Cell Depletion ◽  
Donor Pool ◽  
T Cell Depletion ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors

Abstract Abstract 1977 Introduction: Transplant options are limited for adult patients (pts) who lack a fully matched related or unrelated donor. We hypothesized that in-vivo T-cell depletion with r-ATG would allow safe allo-SCT from mismatched, unrelated donors, thus expanding the potential donor pool for pts with hematologic malignancies who require allo-SCT. Patients and Methods: Thirty seven adult pts (age 20 – 70, median 45) underwent a first unrelated, mismatched, allo-SCT between 1/1/2006 and 6/30/2011 at Mayo Clinic Arizona for hematologic malignancy (35 PBSC, 2 marrow). All pts had at least a one allele or one antigen mismatch (MM) at HLA-A, -B, -C, or -DRB1, and all except one pt received r-ATG as part of the GVHD prophylaxis strategy (dose range 2.5 – 10 mg/kg in daily dose of 2.5 mg/kg depending on degree of mismatch, with the last dose generally given on day −1). One pt received Campath after experiencing anaphylaxis to r-ATG. Pts were transplanted for acute myeloid leukemia (n = 19; 10 CR1, 6 CR2, 3 other), acute lymphoblastic leukemia (n = 8; 4 CR1, 4 CR>/= 2), chronic myeloid leukemia (n = 1), myelodysplastic syndrome (n = 5), or non-Hodgkin lymphoma (n = 4). Conditioning was myeloablative in 20, reduced intensity in 16, and non-myeloablative in 1. Mismatches were as follows: 1-allele MM (n = 7); 1 antigen MM (n = 15); 2 allele MM (n = 4); 1 antigen, 1 allele MM (n = 7); and 2 antigen MM (n = 4). Additional GVHD prophylaxis included tacrolimus plus either methotrexate (n =21), mycophenolate mofetil (n = 14), or other (n = 2). Results: The median follow-up for surviving pts is 12 months. As of 6/30/11, 31 pts were alive, and 6 had died of the following causes: multiorgan failure (n = 1), relapse (n = 3), and veno-occlusive disease (n = 2). To date, there have been no deaths related to acute or chronic GVHD. The 1- and 2-year estimated rates of overall survival are 84.5%/78.8% (Fig. 1); of progression-free survival 79.7%/72.0%. The estimated rate of relapse at 1 and 2 years is 11.8%/18.7%, and of non-relapse mortality 8.1%/10.5%. Four pts (10.8%) have developed severe (grades III-IV) acute GVHD by day 100 (days 19, 27, 30, 43; one pt after withdrawal of prograf due to transplant-associated microangiopathy). No late onset severe acute GVHD has been seen. Moderate to severe NIH-defined chronic GVHD occurred in a single pt at risk (cumulative incidence estimate 2.4% at 1 year, 4.7% at 2 years; Fig. 2). Four pts have reactivated EBV, with one developing PTLD (all have been treated with Rituximab). CMV reactivation was seen in 24 pts (65%), CMV disease in 4, with no deaths directly related to CMV. Conclusions: In vivo T-cell depletion with r-ATG abrogates severe acute and chronic GVHD, and allows use of mismatched unrelated donors for allo-SCT in adult pts with otherwise incurable hematologic malignancies. Long-term survivors are generally free of severe chronic GVHD, with good quality of life. There does not appear to be an increased incidence of disease relapse, and non-relapse mortality is low. This approach is safe, effective, and considerably expands the donor pool for adult pts who require allo-SCT. Disclosures: Reeder: Celgene: Research Funding; Millennium Pharmaceuticals Inc.: Research Funding; Novartis: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding.

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.

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