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Role of ATG in Allogeneic HSCT

ZiYi Lim National University Cancer Institute Singapore 3

BTG – Hong Kong 24

Feb 2012

13,000 12,000 11,000 10,000 9,000 8,000 7,000 6,000 5,000 4,000 3,000 2,000 1,000 0 Allogeneic Transplants for Age > 20yrs, Registered with the CIBMTR 1992-2009 - by Donor Type and Graft Source Related BM/PB Unrelated BM Unrelated PB Unrelated CB * 1992-93 1994-95 1996-97 1998-99 2000-01 2002-03 2004-05 2006-07 2008-09 * Data incomplete

Improvements in HSCT outcomes

Changes in conditioning regimens Improved HLA-typing Improvements in supportive care

30-Apr-20 4

T-cell Depletion Relapse Unmanipulated marrow GVHD

Father of ATG?

1899 • Ground rat spleens > injected into guinea pigs • Hyperimmune serum > agglutinate and destroy rat leukocytes Elie Metchnikoff (1845-1916)

ATG

Polyclonal antibodies Produced by immunizing rabbits/horses with human thymocyte/lymphocyte cell suspensions Bind to broad array of surface antigens Apoptosis – Complement dependent cell lysis – T cells, (B cells/NK cells/DCs at higher doses) Down modulation of surface molecules – PB and lymphoid tissue – Down regulation of inhibitory T cell activity – Inhibits adhesion molecules/leukocyte inflitration

ATG/ALG formulations

Generic Name Producer Horse ALG (Lymphoglobulin) Rabbit ATG (Thymoglobulin) Genzyme, Sangstat, France Rabbit ATG (Fresenius) ATG Fresenius, Germany Horse ATG Pharmacia ATGAM, Pharacia Upjohn, USA

Horse ATG Rabbit ATG

ATG preparations used: issues

    Different sources and immunogens used Multiple target antigens: immune response, adhesion and cell trafficking, heterogeneous cell pathways Batch-to-batch variability Doses and duration of therapy vary considerably and have not been systematically compared.

Use of ATG in Unrelated Adult Donor HSCT

Early Studies

Weiden PL, Doney K, Storb R, Thomas ED. Antihuman thymocyte globulin for prophylaxis of graft-versus-host disease. A randomized trial in patients with leukemia treated with HLA- identical sibling marrow grafts.

Transplantation.

1979;27:227- 230. Ramsay NKC, Kersey JH, Robinson LL, et al. A randomized study of the prevention of acute graft versus host disease.

N Engl J Med.

1982;306:392-397

109 patients with haematological malignancies All received cyclophosphamide/TBI conditioning GvHD prophylaxis with CyA 2 trials: Trial A: ATG (3.75 mg/kg x D-4,-3) vs no ATG Trial B: ATG (3.75 mg/kg x D-5 to -2) vs no ATG

Impact of ATG on Grade III-IV aGvHD Overall Survival

From bloodjournal.hematologylibrary.org

by guest on February 17, 2012. For personal use only.

BLOOD, 15 NOVEMBER 2001 z VOLUME 98, NUMBER 10 2945

Figure 4. Causes of death in 109 patients randomized to receive no ATG (n

53), 7.5 mg/kg ATG (n

29), or 15 mg/kg ATG (n

27).

Acute GVHD was the cause of death in 36% of patients not receiving ATG, 28% of patients receiving 7.5

mg/kg ATG, and 11% of patients receiving 15 mg/kg ATG. Infections were, on the contrary, more frequent in patients receiving high-dose ATG.

Figure 2. Actuarial probability of TRM in trial 1 (upper graph) and in trial 2 (lower graph).

There is no difference in TRM for patients receiving or not receiving ATG in the 2 trials.

Chronic GVHD

Seventy-ﬁve (69%) of 109 patients were alive on day 100 and were at risk for chronic GVHD. In trial 1, extensive chronic GVHD was diagnosed in 65% of patients in the non-ATG group and in 38% of patients in the ATG group (

5 .08). In trial 2, extensive chronic GVHD was diagnosed in 59% of patients in the non-ATG group and in 41% of patients in the ATG group (

5 .3); of course, the follow up of patients in the second trial was shorter than in the ﬁrst.

Overall, 62% of patients not receiving ATG acquired extensive chronic GVHD compared with 39% of patients receiving ATG (

5 .04).

Univariate analysis

We looked for variables predictive of acute GVHD and TRM in univariate analysis in all 109 patients. GVHD grade III-IV was signiﬁcantly reduced in patients younger than 35 (

5 .02) and in patients receiving ATG (

5 .05). TRM was predicted by age (

5 .003) and disease phase (

5 .03). Median number of cells grafted was 3.2

3 10 8 /kg. TRM was 47% versus 36% for patients receiving more than or less than 3.2

3 10 8 /kg (

5 .2). The advantage for the higher cell dose was more evident in patients with early-phase disease (TRM, 26% vs 50%;

5 .09) than with advanced disease (TRM, 44% vs 44%;

5 .9). There was an advantage for high cell dose, though not signiﬁcant, in patients randomized not to receive ATG (TRM, 38% vs 47%;

5 .5) or to receive ATG (TRM, 34% vs 47%).

Multivariate analysis

Phase of disease (early, advanced), patient age (continuous), TBI regimen (2 Gy 3 2 3 3/others), cells dose infused 3 10 8 / kg (continuous), conditioning with ATG, CMV status of donor (CMV-positive, CMV-negative), and CMV status of recipient (CMV-positive, CMV-negative) were entered in a multivariate COX analysis with grade III-IV acute GVHD as an end point: ATG had a signiﬁcant impact on acute GVHD when tested as ATG versus no ATG (

5 .005) and when tested according to dose intensity (no ATG vs 7.5 mg/kg ATG vs 15 mg/kg ATG;

5 .01). Similar variables were entered in a multivariate analysis on 73 patients alive and evaluable on day 100, with extensive chronic GVHD as an end point (yes vs no). ATG had a protective effect on patients with extensive chronic GVHD when entered as ATG versus non-ATG (

5 .03) and when entered according to dose intensity (

5 .05). ATG was not a predictor of TRM in multivariate analysis.

Event-free survival

Finally, patients were studied for event-free survival. Events included acute GVHD grade III-IV, extensive chronic GVHD, relapse, death from leukemia, and death from transplant-related causes. Actuarial event-free survival at 2 years was 20% in the non-ATG patients and 34% in the ATG patients in trial 1 (

5 and 15% versus 17% in the second trial (

5 .8).

.6)

Figure 3. Actuarial probability of survival in trial 1 (upper graph) and in trial 2 (lower graph).

There is no difference in survival for patients receiving or not receiving ATG in the 2 trials.

Discussion

We have explored the role of ATG in the conditioning regimen for patients undergoing transplantation from unrelated donors. Our

Update of original Italian randomised study 75 patients surviving more than 100 days (ATG 38 vs non ATG 37) Median follow-up 5.7 years Assessment of  long-term risk of chronic GVHD  chronic lung dysfunction  quality of life

ATG use associated with a lower incidence of cGvHD ATG and impact on Overall Survival

Use of ATG in Related Adult Donor HSCT

Pilot Study FBATG Sibling Allograft protocol for patients with high risk AML/MDS Retrospective analysis on 62 patients with high risk AML/MDS HLA-matched sibling donor RIC HSCT 41 patients received alemtuzumab (20mg x 5 days intravenously) followed by cyclosporin A post-transplant.

21 patients received ATG (total 6mg/kg over 3 days intravenously) 2 yrs OS: 56.1%+/-8% vs 73.7%+/-10%, p=0.25

Pilot Study FBATG Sibling Allograft protocol for patients with high risk AML/MDS 2 yrs TRM (19.5%+/-7% vs 10.6% +/- 7%, p=0.43) 2 yrs Relapse (28.4%+/-15% vs 51.5%+/-8%, p=0.04) Patients who received ATG had a significantly higher incidence of chronic extensive GvHD (34% vs 6%, p=0.03).

Significantly larger proportion of patients receiving alemtuzumab required subsequent DLI therapy (68% vs 19%)

Use of ATG in Alternative donor HSCT

Donor Source Regimen ATG Outcomes

Lee KH 2011 Sanz J 2012 Ciurea SO 2010 Haplo-related (n=83) Single UCBT (n=88) Haplo-related (n=26) Flu-Bu-ATG Flu-Bu-Thio ATG Flu-Mel_Thio ATG 3mg/kg x4d 2mg/kg x4d 1.5mg/kg x4d aGvHD 20% cGvHD 34% OS 45% aGvHD 24% cGvHD 24% 5-yr DFS 11 44% aGvHD 7% cGvHD 14% Lu DP 2006 Haplo-related (n=135) Bu Cy2 -ATG 2.5mg/kg x4d aGvHD 40% cGvHD 55% 2-yr LFS 64%

Marked increased risk of EBV-related complications with addition of ATG to nonmyeloablative conditioning prior to UCB transplantation Brunstein et al. Blood 2006; 108: 2874-2880

Protocol

Standard: Cyclo+ Busulphan or TBI and ALG in 174 (73%) ALG 15mg/kg bd x 3 days RIC: cyclo/fludarabine/TBI 200cG in 30 (32%) after 2002 Post Tx immune suppression: CSA/MMF (50%); CSA/MP (49%)

Results

15/335 developed EBV-related complications at median of D+133 (52 407) 4 viraemia; 11PTLD 5/9 treated with rituximab responded to treatment survived

Figure 1. Cumulative incidence of Epstein-Barr virus-related complications Brunstein, C. G. et al. Blood 2006;108:2874-2880

Figure 2. Kaplan-Meier probability of overall survival Brunstein, C. G. et al. Blood 2006;108:2874-2880

Summary

ATG effective in reducing acute and chronic GvHD Differences between ATG/ALG preparations and lack of comparative data Balance of ATG usage depends on trade off between anticipated risks and benefits of T-cell depletion Use of ATG and dose of ATG dependent on both donor and host factors More studies are required to determine optimum timing and dose of ATG