High Overall and GVHD-Free Survival in Patients with Aplastic Anemia Receiving in vivo T-cell Depletion Transplants and Long-Term Complications

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.

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Favourable Long-Term Outcome after Matched Sibling Transplantation for Fanconi-Anemia (FA) and in vivo T-Cell Depletion

Klinische Pädiatrie ◽

10.1055/s-2008-1065326 ◽

2008 ◽

Vol 220 (3) ◽

pp. 147-152 ◽

Cited By ~ 5

Author(s):

K. Huck ◽

H. Hanenberg ◽

W. Nürnberger ◽

D. Dilloo ◽

S. Burdach ◽

...

Keyword(s):

T Cell ◽

Fanconi Anemia ◽

Cell Depletion ◽

Term Outcome ◽

T Cell Depletion ◽

Long Term Outcome ◽

Matched Sibling

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T-cell depletion of HLA-identical transplants in leukemia

Blood ◽

10.1182/blood.v78.8.2120.bloodjournal7882120 ◽

1991 ◽

Vol 78 (8) ◽

pp. 2120-2130 ◽

Cited By ~ 15

Author(s):

AM Marmont ◽

MM Horowitz ◽

RP Gale ◽

K Sobocinski ◽

RC Ash ◽

...

Keyword(s):

T Cell ◽

Treatment Failure ◽

Chronic Gvhd ◽

Chronic Phase ◽

Myelogenous Leukemia ◽

Cell Depletion ◽

T Cell Depletion ◽

Free Survival ◽

Dose Rates ◽

Leukemia Relapse

We analyzed the effects of T-cell depletion on the outcome of HLA- identical sibling bone marrow transplants for leukemia by comparing 731 T-cell-depleted transplants with 2,480 non-T-cell-depleted transplants. T-cell depletion decreased acute graft-versus-host disease (GVHD) (relative risk [RR] 0.45; P less than .0001) and chronic (GVHD) (RR 0.56; P less than .0001). However, it increased graft failure (RR 9.29; P less than .0001). Leukemia relapse also was increased. In first remission acute leukemia or chronic phase chronic myelogenous leukemia, leukemia relapse was 2.75 times more likely after T-cell-depleted transplants (P less than .0001). T-cell depletion increased the risk of treatment failure (RR 1.35; P less than .0003) and decreased leukemia- free survival. We also studied controllable variables associated with outcome of T-cell-depleted transplants. The unique findings were that among recipients of T-cell-depleted transplants for early leukemia, radiation doses greater than or equal to 11 Gy (RR 0.54; P less than .01), dose rates greater than 14 cGy/min (RR 0.56; P less than .002), and additional posttransplant immune suppression with cyclosporine alone (RR 0.53; P less than .0006) or cyclosporine plus methotrexate (RR 0.36; P less than .01) were associated with fewer treatment failures. Use of monoclonal antibodies rather than physical techniques for T-cell depletion (RR 2.01; P less than .03) and fractionated radiation (RR 1.69; P less than .05) were associated with increased treatment failure and lower leukemia-free survival. These data may be useful in designing strategies to improve results of T-cell-depleted transplants.

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In vitro tests for distinguishing possible immune-mediated aplastic anemia from transfusion-induced sensitization

Blood ◽

10.1182/blood.v55.2.211.211 ◽

1980 ◽

Vol 55 (2) ◽

pp. 211-215 ◽

Cited By ~ 74

Author(s):

BJ Torok-Storb ◽

C Sieff ◽

R Storb ◽

J Adamson ◽

ED Thomas

Keyword(s):

T Cells ◽

T Cell ◽

Aplastic Anemia ◽

Colony Growth ◽

Cell Depletion ◽

In Vitro Tests ◽

T Cell Depletion ◽

Immune Mediated ◽

Before And After

Abstract Forty-two patients with aplastic anemia (AA) were studied to determine whether or not transfusion-induced sensitization is responsible for the in vitro inhibition by patient lymphocytes of HLA-identical erythroid burst-forming units (BFU-E). The results indicate that lymphocytes from 12 of 34 transfused patients inhibited normal colony growth. In contrast, lymphocytes from none of the 8 untransfused patients demonstrated inhibition. These data were interpreted to mean that coculture studies would not be useful for identifying immune-mediated AA in transfused patients. Therefore, in order to identify possible immune-related AA, we assayed BFU-E from patient blood before and after T-cell depletion. In all 32 patients studied, BFU-E failed to grow from peripheral blood cells before T-cell depletion, but in 8 cases, normal- appearing BFU-E grew after T cells had been removed. Growth of patient BFU-E colonies was inhibited in 6 cases when patient T cells were added back to the culture, indicating that in these 6 patients, an “autoimmune” mechanism may have been present.

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