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.

scholarly journals Haploidentical Hematopoietic Stem-Cell Transplantation in Adults

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Salem Alshemmari ◽  
Reem Ameen ◽  
Javid Gaziev
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Hematopoietic Stem

Haploidentical hematopoietic stem-cell transplantation is an alternative transplant strategy for patients without an HLA-matched donor. Still, only half of patients who might benefit from transplantation are able to find an HLA-matched related or unrelated donor. Haploidentical donor is readily available for many patients in need of immediate stem-cell transplantation. Historical experience with haploidentical stem-cell transplantation has been characterised by a high rejection rate, graft-versus-host disease, and transplant-related mortality. Important advances have been made in this field during the last 20 years. Many drawbacks of haploidentical transplants such as graft failure and significant GVHD have been overcome due to the development of new extensive T cell depletion methods with mega dose stem-cell administration. However, prolonged immune deficiency and an increased relapse rate remain unresolved problems of T cell depletion. New approaches such as partial ex vivo or in vivo alloreactive T cell depletion and posttransplant cell therapy will allow to improve immune reconstitution in haploidentical transplants. Results of unmanipulated stem-cell transplantation with using ATG and combined immunosuppression in mismatched/haploidentical transplant setting are promising. This paper focuses on recent advances in haploidentical hematopoietic stem-cell transplantation for hematologic malignancies.

scholarly journals Haploidentical transplantation of hematopoietic stem cells

2016 ◽  
Vol 62 (suppl 1) ◽  
pp. 29-33 ◽  
Author(s):  
Nelson Hamerschlak
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell ◽  
Ex Vivo ◽  
Cell Depletion ◽  
Post Transplantation ◽  
T Cell Depletion ◽  
Hematopoietic Stem ◽  
Increased Risk

SUMMARY Objective: To review and discuss the literature on hematopoietic stem cell transplantation (HSCT) with haploidentical donors in Brazil. Method: Literature review. Results: The haploidentical hematopoietic stem cell transplantations have become a safe option in hematology since the 80s, with the possibility of ex-vivo T-cell depletion. However, its broad use worldwide occurred with the advent of haploidentical nonmyeloablative transplants using in vivo T-cell depletion with the administration of post-transplant cyclophosphamide. The results were encouraging, despite the increased risk of infection and post-transplantation recurrence. Recent publications on acute myeloid leukemia, myelodysplastic syndrome and Hodgkin’s lymphoma have shown similar results among haploidentical, unrelated and related full-match transplants. Obviously, these findings of retrospective studies should be confirmed by clinical trials. Conclusions: Transplantation with haploidentical donor has shown to be feasible in Brazil and the first publications and results are showing encouraging results.

Haploidentical Hematopoietic Stem Cell Transplantation without In Vitro T Cell Depletion for Treatment of Hematological Malignancies in Children.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5069-5069
Author(s):  
Daihong Liu ◽  
Xiao Jun Huang ◽  
Kaiyan Liu ◽  
Lanping Xu ◽  
Huan Chen ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Cumulative Incidence ◽  
Risk Group ◽  
T Cell Depletion ◽  
Hematopoietic Stem

Abstract Objective: To evaluate the efficacy and safety of haploidentical hematopoietic stem cell transplantation (HCT) for children with donors from family members. Patients and methods: Forty-two children under fourteen years old with hematologic malignancies underwent haploidentical HCT. The outcome was analyzed. Results: Four (9.5%) of the forty-two patients/donor pairs mismatched in one HLA locus, fifteen (35.7%) pairs in two loci and twenty three (54.8%) in three loci. They were followed up for a median of 612 (40–1779) days. All patients achieved stable engraftment. The cumulative incidence of acute graft-versus-host disease (GVHD) grade 2–4 was 57.2%, and that of grade 3–4 was 13.8%. The cumulative incidence of total and extensive chronic GVHD was 56.7% and 29.5%, respectively. The probability of leukemia-free survival was 65.1% in standard-risk group and 49.6% in high-risk group. Fourteen patients died, four from infection, six from relapse of leukemia, two from heart failure, one from severe acute GVHD, and one from lymphoproliferative disorders. The probability of relapse was 13.8% at 1 year and 27.9% at 2 year after transplantation. Conclusion: The results in this study encourage extending the haploidentical HCT without T-cell depletion to children with an indication for transplantation.

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.

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