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.

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.

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.

Chronic Graft-Versus-Host Disease after Allogeneic Stem Cell Transplant with in Vivo T-Cell Depletion By Alemtuzumab: Incidence, Outcome and Pattern of Organ Involvement

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3912-3912 ◽  
Author(s):  
Maria Chiara Finazzi ◽  
Cristina Boschini ◽  
Janice Ward ◽  
Charles Craddock ◽  
Alessandro Rambaldi ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Acute Gvhd ◽  
Stem Cell Transplant ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Organ Involvement ◽  
Cell Transplant ◽  
Allogeneic Stem Cell Transplant ◽  
T Cell Depletion

Abstract Introduction Graft-versus-Host Disease (GvHD) is one of the leading causes of mortality and morbidity following allogeneic stem cell transplant. In vivo T cell depletion by alemtuzumab as part of the transplant conditioning is an effective strategy to reduce the risk of GvHD. While it is recognised that the overall incidence of GvHD is reduced by alemtuzumab, the incidence of chronic GvHD as defined by the National Institute of Health (NIH) consensus criteria, the impact on outcome, and the pattern of organ involvement have not been defined yet in this transplant setting. Methods Consecutive patients (n = 323) undergoing allogeneic stem cell transplantation at the Queen Elizabeth Hospital, Birmingham, between January 1 2008 and June 30 2012 were reviewed in this retrospective, single centre study. Medical records were examined and data regarding the development of GvHD were collected; NIH consensus criteria for diagnosis and staging of chronic GvHD were stringently applied. Clinical characteristics of GvHD occurring in patients transplanted following T cell depletion by alemtuzumab administration (n=248) were compared with those of patients transplanted with a T cell replete graft (n=75). Patients receiving alemtuzumab were mainly treated with reduced-intensity conditioning protocols, while patients in the no-T-cell depletion group were mainly treated with a myeloablative, sibling transplant. Results After a median follow up of 38.4 months, the cumulative incidence (CI) of grade II-IV classic acute GvHD was 35% and 48% for patients transplanted respectively with or without T cell depletion by alemtuzumab (p= 0.041, Figure 1); with a CI of grade III-IV classic acute GvHD of 13% and 27% (p=0.007). The 2-years CI of grade II-IV late acute GvHD was not significantly different in the two groups (20% and 23% for patients respectively treated with or without alemtuzumab, p=0.589, Figure 2). T cell depletion by alemtuzumab significantly reduces the 3 years cumulative incidence of classic chronic GvHD (5% versus 31%, p<0.0001, Figure 3.A), but without a significant difference in the incidence of overlap syndrome between patients with and without T cell depletion (3 years CI respectively 6% and 7%, p=0.839, Figure 3.B). The pattern of organ involvement by classic acute GvHD was similar in patients with and without T cell depletion. The pattern of organ involvement by late acute GvHD in the alemtuzumab group was, however, significantly different compared to the T cell replete group (skin-gut-liver involvement reported respectively in 83%-28%-4% of patients and 56%-48%-20% of patients, p=0.003). Distribution of organ involvement by classic chronic and overlap syndrome was similar in the two groups; however, it seems that alemtuzumab prevents the development of lung GvHD (lung GvHD developed in 4 patients over the 75 patients of the no-T-cell depletion group, while none of the 248 patients transplanted with alemtuzumab experienced lung GvHD). In a multivariate analysis, the development of chronic GvHD was an independent predictor of higher mortality risk (HR 1.66, p = 0.04) and severe NIH global score at peak was confirmed as a poor prognostic factor for survival (HR 2.27, p=0.02). The negative impact of chronic GvHD and of the severe forms of chronic GvHD was independent of age and alemtuzumab administration. Conclusion This retrospective analysis provides for the first time data on the incidence rates of NIH-defined GvHD categories in patients transplanted after T cell depletion by alemtuzumab. Patients transplanted with alemtuzumab experienced a lower incidence of classic acute and classic chronic GvHD compared to patients not receiving T cell depletion. In contrast, alemtuzumab conditioning appeared to have no effect on the incidence of late acute GvHD or overlap syndrome, suggesting that these two entities of GvHD are driven by different immunological mechanisms as compared to classic acute and classic chronic GvHD. We also confirmed the utility of the NIH classification of GvHD and of the NIH global severity score to predict survival in alemtuzumab-conditioned allogeneic stem cell transplant. Disclosures No relevant conflicts of interest to declare.

In Vivo T Cell Depletion with Thymoglobulin or Alemtuzumab Is Associated with Worse Outcome Following Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia Patients Transplanted in Remission

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3115-3115
Author(s):  
Scott R. Solomon ◽  
Melissa Sanacore ◽  
Xu Zhang ◽  
Katelin Connor ◽  
Melhem Solh ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Myeloid Leukemia ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Hematopoietic Stem

Abstract In vivo T Cell Depletion with Thymoglobulin or Alemtuzumab Is Associated With Worse Outcome Following Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia Patients Transplanted in Remission. Allogeneic hematopoietic stem cell transplantation (HSCT) reduces relapse risk in adults with acute myeloid leukemia (AML) due in large part to the potent graft-versus-leukemia effect of donor lymphocytes. However, this benefit must be balanced by the increased morbidity and mortality associated with graft-versus-host disease (GVHD). Serotherapy, in the form of thymoglobulin or alemtuzumab, has been used for in vivo T cell depletion as a strategy to reduce GVHD. We analyzed 144 consecutive AML patients transplanted in remission (CR1 - 111, CR≥2 - 33) from either a matched related (MRD, n=44), unrelated (MUD, n=62), or haploidentical (haplo, n=38) marrow of PBSC donor, in order to analyze the effect of serotherapy, in relation to other disease-, patient- and transplant-related risk factors, on post-transplant outcomes. Patients were transplanted at a single institution between 3/15/06 to 12/19/14. Baseline characteristics of the patient cohort included age >50 in 88 (61%), KPS<90 in 93 (65%), CMI ≥3 in 61 (42%) of patients. Disease risk index (DRI) was defined as low, intermediate, and high in 5 (4%), 110 (76%), and 29 (20%) patients respectively per the revised Dana Farber/CIBMTR criteria. Myeloablative chemotherapy was given in 96 (67%) patients, and PBSC was the source of stem cells in 120 (83%) patients. Serotherapy was utilized in 21 (15%) patients [thymoglobulin - 8, alemtuzumab - 13]. Serotherapy patients were more likely to be older (median age 59 vs. 52 years, p=0.013) and have a MUD (81% vs. 37%, p<0.001), but otherwise had similar baseline characteristics in regards to disease status, DRI, regimen intensity. Acute GVHD grade II-IV occurred in 38% of patients, whereas chronic GVHD was seen in 44%. Chronic GVHD occurred less often in patients receiving serotherapy (19% vs. 49%, p=0.016). Estimated one year non-relapse mortality (NRM) at 1 and 3 years was 4% and 13% respectively and was statistically similar in serotherapy and non-serotherapy patients. The estimated 3 year OS, DFS, and relapse was 58%, 51%, and 37% respectively for the whole cohort; 64%, 55%, and 33% in non-serotherapy patients vs. 29%, 27%, and 57% in serotherapy patients (figure 1). Cox analysis was performed utilizing the following variables: age, disease status, DRI, KPS, CMI, transplant type (MRD, MUD, haplo), conditioning intensity, stem cell source, use of serotherapy, year of transplant, acute and chronic GVHD. Variables were selected by a 10% threshold. Acute and chronic GVHD were modeled as time-dependent variables. In multivariate analysis, unfavorable risk factors for survival included only two variables: the use of serotherapy (HR 3.11, p<0.001) and high risk DRI (HR 1.89, p=0.038). Use of serotherapy also had a negative effect on relapse (HR 2.69, p=0.003) and DFS (HR 2.73, p<0.001), with no effect on NRM. Following allogeneic HSCT for AML patients in remission, the use of serotherapy for in vivo T cell depletion had a major negative impact on survival due to increased relapse risk. Figure 1. Figure 1. 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

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.

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

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

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

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

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

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

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