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

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

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

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.

Improved Long Term Survival with Minimal GVHD after Myeloablative Unrelated Donor Stem Cell Transplantation Using In Vitro and In Vivo T Cell Depletion with CAMPATH-1H.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2761-2761
Author(s):  
Peter A. von dem Borne ◽  
Floor Beaumont ◽  
Ingrid Starrenburg ◽  
Machteld A. Oudshoorn ◽  
Geoff Hale ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Related Mortality

Abstract In allogeneic stem cell transplantation (SCT) T-cell depletion reduces transplant related mortality by diminishing GVHD. We have investigated a myeloablative regimen for matched unrelated donor SCT using both in vivo and in vitro CAMPATH-1H for effective T-cell depletion, utilising DLI at a later time point for graft versus tumor effect if necessary. Thirty patients (median age 33 years, range 18–48) were transplanted from January 1997 to June 2002. Diagnoses were: CML CP (n=9), CML AP (n=2), AML/MDS (n=9), ALL (n=8), NHL (n=1) and Fanconi anemia (n=1). Six patients had one HLA mismatch, the others were identical for HLA A, B, C, DR and DQ. Conditioning consisted of CAMPATH-1H 5mg/d on days −8 to −4, TBI 6 Gy on days −8 and −7 and cyclofosfamide 60 mg/kg on days −6 and −5. T-cell depletion was performed by in vitro incubation of the graft with 20 mg CAMPATH-1H for 30 minutes (Campath “in the bag”). Post-transplant GVHD prophylaxis consisted of cyclosporine A and methotrexate. The stem cell source was bone marrow in 19 patients (63%) and peripheral blood in 11 patients. One graft failure was observed, all other patients had sustained engraftment of donor cells. Acute GVHD was observed in 12 patients (40%), maximally grade I-II skin. No severe acute GVHD (grade III-IV) was experienced. Limited chronic GVHD developed in 2 patients, resolving after treatment. Only in one patient extensive chronic GVHD developed, which did not resolve. CMV reactivation occurred in 23% of patients, one patient developed CMV disease. No EBV disease was observed. Ten patients received donor lymphocyte infusion (DLI) at a median of 17.4 months after SCT (8 patients with relapsed CML, one patient with relapsed ALL, one patient with autoimmune hemolytic anemia). After DLI acute GVHD grade I-II developed in 4 patients, and GVHD grade III-IV in 3. Chronic GVHD developed in 5 patients, of which 2 extensive, resolving in all except one patient. With a median follow up of 37 (range 21–84) months 17 patients are alive (57%). One of the CML patients shows persistence of molecular disease not responding to increasing doses of DLI. All other patients are in CR with the CML patients in molecular remission. Five patients (17%) died because of relapsed disease (2 AML/MDS and 3 ALL). Treatment related mortality was 26% (1 rejection, 2 GVHD, 1 myocardial infarction, 4 infections). In conclusion, matched unrelated donor SCT following myeloablative conditioning using T-cell depletion with CAMPATH-1H in vivo as well as in vitro results in good engraftment, minimal grade I-II GVHD and an overall survival of 57%. Relapse rate was not increased with this strategy. This regimen appears to be successful for young adults with high-risk malignancies.

Comparable Outcomes after Allogeneic Stem-Cell Transplantation with Intravenous Busulfan or Treosulfan-Based Reduced-Intensity and Reduced Toxicity Regimens in Acute Myeloid Leukemia. a Study on Behalf of the Acute Leukemia Working Party of EBMT

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2280-2280
Author(s):  
Avichai Shimoni ◽  
Myriam Labopin ◽  
Bipin N. Savani ◽  
Rose-Marie Hamladji ◽  
Dietrich W. Beelen ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Acute Gvhd ◽  
Advanced Disease ◽  
Chronic Gvhd ◽  
Working Party ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Reduced Toxicity

Abstract Allogeneic stem cell transplantation (SCT) is a potentially curative therapy for patients with acute myeloid leukemia (AML). Myeloablative conditioning (MAC) is associated with prohibitive rates of non-relapse mortality (NRM) in older and less medically fit patients. Several reduced intensity conditioning regimens (RIC) and more recently the more dose-intensive reduced toxicity myeloablative (RTC) regimens were designed to replace MAC in this setting. The backbone of these regimens is usually fludarabine with busulfan and more recently also with treosulfan, but there is no clear data on the comparative outcomes with these different regimens in the different SCT settings. The current study included 3561 patients with AML given a first allogeneic SCT from an HLA-matched sibling (n=1683) or a 10/10 matched unrelated donor (n=1878) between the years 2000-2014 and reported to the acute leukemia working party (ALWP) of EBMT. Only patients given fludarabine with either intravenous busulfan (ivBu), (FB, n=2990) or treosulfan (FT, n=571) alone were analyzed. Fludarabine and ivBu at 6.4 mg/kg (n=1457) or treosulfan at 30-36 gr/m2 (n=168) were considered RIC regimens while fludarabine with ivBu at a total dose of 9.6-12.8 mg/kg (n=1533) or treosulfan at 42 gr/m2(n=403) were considered RTC regimens according to EBMT criteria. The median age of FB and FT recipients was 55.5 and 58.3 years, respectively (P< 0.0001). The status at SCT was 72.5% CR1, 15.0% CR2 and 12.5% advanced disease in the FB group compared to 55.0%, 20.3% and 24.7% in the FT group, respectively (P<0.0001). More FT recipients had SCT from unrelated donors (64.8% Vs. 50.4%, P<0.0001) but less had in-vivo T-cell depletion (58.4%Vs 70.5%, P<0.0001). Cytogenetic subgroup distribution was similar between the groups. Ninety percent had peripheral blood stem cell grafts in both groups. The median follow-up was 19 and 43 months after FB and FT, respectively. Using univariant analysis, the 2-year relapse incidence (RI) was 32.7% and 35.5%, respectively (P=0.49). NRM was 17.6% and 19.4%, respectively (P=0.09). Leukemia-free survival (LFS) and overall survival (OS) were 49.5% and 54.8% after FB and 45.1% and 52.6% after FT, respectively (P=0.04, P=0.17). Acute GVHD grade II-IV and chronic GVHD were 23.1% and 35.7% after FB and 18.8% and 39.8% after FT, respectively (P=0.03, P=0.04). In all, the GVHD/ relapse-free survival (GRFS) was 36.5% and 31.5%, respectively (P=0.08). After adjusting for the differences in patient characteristics, there was no difference between the FB and FT groups in RI, NRM, LFS, OS and GRFS. However, acute GVHD grade (II-IV) was higher after FB (HR, 1.49, P=0.0004). The same observations were seen when the analysis was limited to RIC or RTC regimens only, or when only patients in remission were analyzed. However, when analyzing only the 516 patients with advanced disease at SCT, 2-year OS was 29.7% and 43.0% after FB and FT (P=0.002) and this difference remained significant in the multivariant analysis (HR, 1.50, p=0.003). Among the entire group, the factors associated with reduced survival were advanced age (HR 1.01, P<0.0001), secondary AML (HR 1.19, P=0.005), CR2 (HR 1.21, P=0.007) and advanced disease (HR 2.02, P<0.0001) compared to CR1, and female donor to male recipient (HR 1.15, P=0.03). Conditioning type and intensity, donor type, CMV status and in vivo T-cell depletion were not significant. Relapse was lower and NRM was higher with RTC compared with RIC, but OS was similar. The same factors predicted for GRFS, a surrogate for quality of life, with the only difference been the positive role of in vivo T-cell depletion (HR 0.8, P=0.0002). In conclusion, RIC and RTC regimens with ivBu or treosulfan-based regimens are associated with similar transplantation outcomes. OS is primarily affected by disease factors such as status of disease at SCT and secondary leukemia. Treosulfan- based conditioning is associated with a lower rate of acute GVHD, but with similar rates of chronic GVHD, NRM and GRFS. Treosulfan conditioning may have some advantage in patients with advanced disease at SCT. Disclosures No relevant conflicts of interest to declare.

Reduced-Intensity Conditioning (RIC) with Busulfan, Fludarabine and Campath-1H Is Complicated by a High Rate of Graft Failure and Severe Viral Complications in Patients with CLL.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5080-5080 ◽  
Author(s):  
Johannes Schetelig ◽  
Martin Bornhaeuser ◽  
Christian Thiede ◽  
Brigitte Mohr ◽  
Uta Oelschlaegel ◽  
...  
Keyword(s):  
T Cell ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Unknown Etiology ◽  
T Cell Depletion ◽  
Hematopoietic Stem ◽  
One Year

Abstract Recently we demonstrated that RIC with busulfan, fludarabine and ATG followed by allogeneic hematopoietic stem cell transplantation (HSCT) induced molecular remissions in patients (pts) with advanced CLL. However, this approach was hampered by severe GVHD. In an attempt to lower the rate of severe GVHD we replaced ATG by campath in a new study protocol. Patients and Methods: 20 pts with a median age of 54 years (range, 43 to 64) and advanced CLL were included. A median of 3 prior chemotherapy regimens had been given before HSCT, including fludarabine-containing regimens in all but two pts with autoimmune hemolysis. High risk cytogenetic features (17p−, 11q−, +12) were present in 9 pts. After conditioning with busulfan (8 mg/kg), fludarabine (150 mg/m2) and campath (75 mg) on days −9 to −5 peripheral blood stem cells from matched related (n=4) or unrelated donors (n=16) were transplanted. GVHD prophylaxis consisted of CSA monotherapy. Campath levels were analysed in frozen serum samples by BioAnaLab, Oxford, UK. Results: Two pts had no detectable campath level at the day of HSCT, while four pts had levels between 0.5 to 1.8 microgram/mL. Regeneration of neutrophils (>0.5/nl) and platelets (>20/nl) required a median of 17 (range, 14–25) and 10 (range, 0–27) days, respectively. Incomplete T-cell chimerism (<50%) was observed in 7 pts and subsequently 3 pts experienced secondary graft failure on days 134, 152 and 324. Six pts received donor lymphocyte infusions (DLI) for the conversion of incomplete T-cell chimerism (N=4) or progressive disease (N=2). Sponaneous acute GVHD II° to IV° occurred in 9/20 pts. After DLI four additional pts developed acute GVHD II° to IV°. Limited chronic GVHD occurred in 9 and extensive disease in 2 pts. In CMV seropositive pts the day 100 probability of CMV infection was 74% (95% CI, 44% to 100%). Severe encephalitis (HHV6, EBV and JC virus as suspected agents) was observed in 5 pts. Two pts recovered without sequelae, 2 pts are cognitively handicaped and one pt died. Hemorrhagic cystitis (CTC 2/3) occurred in 2 pts. After a median follow-up of 13 months (range, 6 – 26 months), 15 pts are alive. Four pts died from treatment related complications. Causes of death were pneumonia of unknown etiology (N=2), encephalitis (N=1) and GVHD grade IV (N=1). One pt died from severe acute GVHD subsequent to the treatment of relapse with DLI. One-year overall and progression-free survival was 75% (95% CI, 55% to 95%) and 50% (95% CI, 25% to 75%), respectively. The one-year probability of non-relapse mortality was 20% (95% CI, 2% to 38%). The number of binding sites for campath is highly variable in pts with progressive CLL resulting in interindividually highly variable pharmacokinetics. Differences in the extent of in vivo T-cell depletion might therefore explain the individually varying T-cell engraftment pattern. In addition, the high incidence of severe viral infections reflects impaired immunoreconstitution. Including pts after DLI we observed a substantial rate of severe GVHD. Based on these data we decided to skip the strategy of in vivo T-cell depletion with campath in patients with CLL.

Fludarabine-Busulfan Conditioning and In Vivo T-Cell Depletion with Reduced Dose of ATG Followed by Allografting Induces Durable Responses in Patients with Advanced Multiple Myeloma with No Grade III-IV aGvHD.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3029-3029
Author(s):  
Nizar J. Bahlis ◽  
Douglas A. Stewart ◽  
Mary Lynn Savoie ◽  
Christopher Brown ◽  
Andrew Daly ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Cell Depletion ◽  
Cell Transplant ◽  
T Cell Depletion ◽  
Grade Iii

Abstract Background: We have investigated a conditioning regimen with Fludarabine and intravenous Busulfan with reduced ATG dose in patients with advanced and poor prognosis myeloma exploring the possibility that a low dose ATG may be sufficient enough to prevent severe GvHD without completely suppressing the graft vs myeloma effect. Methods: 15 patients received a conditioning regimen consisting of fludarabine 50mg/m2 on days -6 to -2 and IV BU (Busulfex, ESP Pharma) at a “myeloablative” dose of 3.2 mg/kg daily days -5 to -2 inclusive. All pts received Thymoglobulin (Genzyme) 4.5 mg/kg in divided doses over 3 consecutive days pre-transplant finishing D0, cyclosporine A and methotrexate with folinic acid. Results: The median age was 49 years (range 40–61). 14 (93.3%) patients had stage III (DS) disease with a median β2-microglobulin 3.12 mg/dl (1.82–5.75) and 7/11 (63.6%) in whom FISH studies were available had deletion 13, 5/15 (33.3%) patients had relapsed or progressed within 2 years of prior autologous stem cell transplant and 4 (26.6%) had progressed while on thalidomide /Dex salvage treatment. The disease status prior to allogeneic transplant was partial response (PR) in 6/15 (40%) and progressive disease (PD) in 9/15 (60%). 2/15 had plasma cell leukemia. The median number of bone marrow plasma cells prior to allo-transplant was 16% (range 3%-85%). Donors were matched siblings (MRD) for 13 (86.7%) and alternate donors in 2 (13.3%, unrelated with 2 C antigen mismatch). Cell source was blood in 14/15 (93.3%). Acute GVHD grade II-IV occurred in only 1 patient (6.6%) with no grade III-IV acute GVHD. Chronic GVHD occurred in 9/15 (60%). The TRM was 6.6%. Among 14/15 patients evaluable for response, the overall response rate (CR+PR) was 53.3% (2 CR, 6 PR, 1 MR and 5 PD); 37.5% (1CR, 2PR, 1MR and 4PD) for pts with PD at the time of the transplant and 71.4% (4PR, 1MR and 1PD) for pts with del13. After a median follow-up of 40.9 months (range 36–65.2), the estimated OS and PFS at 4 years for all patients is 38.9% (CI 95%: 13.1–64.7%) and 20.0% (CI 95%: 0–40.3%) respectively. For patients with del13 the estimated OS and PFS at 4 years is 38.1% (CI 95%: 0–77.9%) and 0% respectively. Conclusion: In vivo T-cell depletion with ATG results in a low rate of severe aGvHD with low treatment-related mortality and a substantial number of long-term survivors among patients with advanced multiple myeloma. The detection of deletion 13 by FISH however remains a predictor of short progression free survival. Figure Figure

The Effect of the CASP8 -6526N Del Promoter Polymorphism on Outcome in T-Cell Depleted Unrelated Donor Haemopoetic Stem Cell Transplants (HSCT)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3001-3001
Author(s):  
Suchitra Krishnamurthy ◽  
Bronwen E. Shaw ◽  
J. L Byrne ◽  
C. Seedhouse ◽  
Neema P Mayor ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Caspase 8 ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Significant Difference ◽  
The Impact

Abstract The 6 nucleotide insertion-deletion polymorphism (-6526N del) in the CASP8 promoter has been demonstrated to destroy an Sp1 binding site, resulting in reduced caspase-8 activity and expression and a reduced susceptibility of 652 6N del/del T-lymphocytes to undergo apoptosis in response to anti-FAS and to tumour infiltrating lymphocytes. As the susceptibility of T-lymphocytes to undergo apoptosis could affect outcome following allogeneic HSCT we have investigated the impact of the CASP8-652 6N del polymorphism in both donors and recipients on the outcomes of patients undergoing unrelated donor HSCT. Genotyping was performed on 186 donor/recipient pairs who underwent an HSCT from a donor from the Anthony Nolan Trust in one of 25 transplant centres in the United Kingdom between 1997 and 2006. All patients were transplanted for a haematological malignancy and had long term clinical data collated. Diagnoses were CML: 40.3%; MDS: 4.3%, ALL: 16.6%; AML: 23.6 %, lymphoproliferative disorders: 10.4 %, multiple myeloma: 4.8%. The frequency of the 3 genotypes in the Caspase 8 promoter region was as follows: RECIPIENTS: WT/WT=0.26; WT/del=0.49; del/del=0.24 and DONORS: WT/WT=0.33; WT/del=0.40; del/del=0.25. Frequencies in both the donor and recipient populations were in Hardy-Weinberg equilibrium. Our findings show that the overall survival (OS) in recipients who received a transplant from a donor with a WT/WT genotype was significantly better as compared to donors with WT/del or del/del genotype (52% v 34% at 5 years; p=0.03). The disease free survival (DFS) at 3 years was also significantly better (39% v 18%; p=0.03). In addition, we found a significant reduction in grade II-IV acute GVHD (17% v 30%; p=0.04) and a trend towards lower incidence of chronic GVHD (42% v 63%; p=0.06) and transplant related mortality (TRM) (19% v 35%; p=0.06) in these patients. No significant difference in disease relapse was seen. The results were particularly striking in the subgroup of recipients where one or two deletions were present (WT/del or del/del genotype). The OS was 62% in those who received a graft from a donor with WT/WT genotype compared to 36% with other donors (p=0.01). This remained significant in multivariate analysis (HR 0.53; CI 0.29, 0.98; p=0.04). This subgroup also had a lower risk of relapse (p=0.02). In this cohort, the majority (156/186) of recipients had in-vivo T-cell depletion using Alemtuzumab. As Alemtuzumab depletes T-cells in part by apoptosis induced via a caspase 8 dependent pathway, we hypothesize that recipients who receive a transplant from a donor with WT/WT genotype are likely to get more effective T-cell depletion and hence less acute GVHD and reduced TRM resulting in improved survival. The mechanism of interaction between donor and recipient genotypes remains to be explored. Figure Figure

Allogeneic Stem Cell Transplantation (allo-SCT) for Acute Myeloid Leukemia (AML): Low Incidence of Relapse and Graft Versus Host Disease (GVHD) in Patients (pts) Transplanted without Active Leukemia Using in-Vivo T-Cell Depletion with Rabbit Anti-Thymocyte Globulin (r-ATG)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4527-4527
Author(s):  
James L. Slack ◽  
Jose F. Leis ◽  
Craig B. Reeder ◽  
Joseph R. Mikhael ◽  
Raoul Tibes ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
T Cell Depletion

Abstract Abstract 4527 Introduction: The prognosis for pts with intermediate or high risk AML remains dismal, with relapse rates typically in the 60–80% range after treatment with chemotherapy alone. While allo-SCT can decrease the risk of relapse to 10–20%, widespread use of this modality is limited by relatively high rates of non-relapse mortality (NRM), often due to severe acute and/or chronic GVHD. Attenuation of severe GVHD, without a concomitant increase in relapse or NRM, should improve outcomes and result in cure of a larger fraction of AML pts. We therefore investigated the use of in-vivo T-cell depletion with r-ATG in pts with intermediate- or high-risk AML but without active leukemia at the time of allo-SCT. Patients and Methods: Pts (n = 43) were included in this retrospective analysis if they were between 18 and 65 years of age and had no evidence of active AML at the time of allo-SCT (see Table). All pts had 1 or more high-risk features: 1) adverse or intermediate risk cytogenetics (without NPM1 mutation if cytogenetically normal); 2) therapy-related or secondary AML; 3) high WBC count at diagnosis; 4) failure to achieve CR after 1 cycle of induction; or 5) not in CR1 at allo-SCT. Among the 43 pts, 10 received grafts from related donors, 14 from 10/10 matched unrelated donors (URDs), and 19 from mismatched URDs (9/10, n = 11; 8/10, n = 8). All pts received r-ATG according to institutional standard operating policy, with doses ranging from 2.5 – 10 mg/kg depending on donor type and degree of mismatch. All transplants were performed using PBSC. Additional GVHD prophylaxis included tacrolimus plus either methotrexate or mycophenolate mofetil. Results: The median age was 47 (range 20 – 65), and median follow-up for surviving pts is 12 (range 1 – 66) months. As of 8/5/11, 39 pts were alive, and 4 had died from multiorgan failure (n = 1), relapse (n = 1), GVHD (n = 1), and veno-occlusive disease (n = 1). The 2-year estimate of PFS is 84.7% (Fig. 1). The 2-year cumulative incidence of relapse is 6.8% (2 pts, days 97 and 147), and of non-relapse mortality 9.4%. Three pts developed severe (grades III-IV) acute GVHD by day 100 (cumulative incidence 4.6% at day 100) with no additional cases of severe acute GVHD beyond day 100. To date, 4 pts have developed moderate/severe chronic GVHD (cumulative incidence 16.8% at 2 yrs), with one death at day 344 related to complications of acute and chronic GVHD. CMV reactivation occurred in 29 pts (56%), with no deaths related to CMV. Three pts have reactivated EBV, with one case of PTLD (all treated with Rituximab). Conclusions: In this retrospective analysis of single center data, the inclusion of r-ATG in the GVHD prophylactic strategy appeared to significantly attenuate the incidence and severity of both acute and chronic GVHD. Although follow-up is relatively early, the incidence of relapse and NRM does not appear to be increased compared to contemporaneous pts treated without ATG. Given that almost half of the pts received grafts from mismatched URDs, this abrogation in risk of GVHD is significant and clinically relevant. While randomized studies are needed, these data suggest that in-vivo T-cell depletion with r-ATG ameliorates severe GVHD, without increasing relapse or non-relapse mortality, in AML pts without overt leukemia at the time of allo-SCT. Using this strategy, cure rates of 70 – 80% may be realistic and attainable for younger (</= age 65) AML patients who achieve a leukemia-free state and who have a reasonably matched related or unrelated donor. Disclosures: Reeder: Celgene: Research Funding; Millennium Pharmaceuticals Inc.: Research Funding; Novartis: Research Funding.

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

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

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

Modulated Cyclophosphamide-Based In Vivo T-Cell Depletion Promotes Engraftment With Minimal Gvhd and Low Toxicity In Fanconi Anemia Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4561-4561
Author(s):  
Monica S Thakar ◽  
Mark C. Walters ◽  
Brenda M. Sandmaier ◽  
Rainer Storb ◽  
Mary E. D. Flowers ◽  
...  
Keyword(s):  
T Cell ◽  
Fanconi Anemia ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Old Patients ◽  
Post Transplant ◽  
Small Series

Building on a successful non-myeloablative conditioning regimen developed in Seattle (Blood 2003), Luznik and O´Donnell et al created a protocol that incorporates post-transplant cyclophosphamide (CY) after human leukocyte antigen (HLA)-haploidentical hematopoietic cell transplantation (HCT) (BBMT 2008). This method both promotes engraftment while selectively-depleting alloreactive donor T cells to prevent graft-versus-host disease (GVHD). We have previously shown that Fanconi Anemia (FA) patients can be treated with CY 60 mg/kg in a conditioning regimen with minimal toxicity (BBMT 2007), thus we adapted this post-HCT CY strategy for in vivo T-cell depletion in patients with FA. Between 2008 and 2012, four patients from three North American centers with FA and severe marrow failure in the absence of HLA-matched donors underwent HLA-haploidentical HCT. All four patients were referred for transplantation with minimal to no transfusion burden and all were in excellent clinical condition with HCT-CI scores of 0-2 and Lansky scores of 90-100%. Median age at transplant was 9.7 (6.9-11.9) years old. Patients were transplanted at a median of 1.6 (range, 0.6 -7.1) years after FA diagnosis. Conditioning consisted of fludarabine (150 mg/m2) and 2 Gy total body irradiation; one patient also received CY (10 mg/kg), which was deleted in subsequent patients to decrease the risk of mucositis. Marrow was infused on day 0, followed by post-grafting immunosuppression with CY (25 mg/kg/day, days +3, +4), mycophenolate mofetil, and cyclosporine, the latter two beginning at day +5 with plans to continue until days +35 and +180, respectively. Full donor engraftment was seen in all patients. Two patients developed acute grade I GVHD and none of the four patients has developed chronic extensive GVHD to date. With a follow-up of 5 years, 1 year, 11 months, and 9 months, all four patients are alive with stable, full donor chimerism, and are transfusion independent. While two patients required cyclosporine beyond day +180, only one patient currently remains on low-dose immunosuppression for treatment of limited chronic skin GVHD, which has now resolved. Our results confirm that modulated post-HCT CY can be used in patients with FA to promote engraftment across histocompatibility barriers. Despite concerns for both excessive toxicity related to CY and severe GVHD related to minimizing the dose of post-transplant CY, none of the FA patients in our small series experienced these problems. Our findings also suggest that transplant should not be delayed when there is lack of an HLA-matched donor. FA patients with few comorbidities and minimal transfusion burden can successfully undergo this HLA-haploidentical HCT approach. Disclosures: Off Label Use: MMF.

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.

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