Page 179 - Haematologica-April 2018

Tocilizumab for the prevention of acute GvHD
Table 2. Demographics of tocilizumab trial patients and matched controls, Toc/Tac/MTX (n=35)
66 (23-76)
12 (34)
9 (26) 11 (31) 15 (43)
14 (40) 5 (14) 4 (11) 6 (17) 4 (11)
Tac/MTX (n=130)
64 (23-74)
48 (37)
20 (15) 40 (31) 70 (54)
56 (43) 20 (15) 14 (11) 23 (18) 12 (9)
Age, median (range)
KPS≥90 HCT-CI
0
1-2 3+ Disease
AML (de novo) AML (secondary) ALL
CMML/CML MDS/MPD
NHL 2(6) 5(4) Donor Type
MRD
MUD
Conditioning Regimen
Flu/Bu2 Bu/Cy Flu/Bu4
Graft Source BM
PBSC
Median Follow up Surviving
Patients
13 (37) 22 (63)
17 (49) 5 (14) 13 (37)
6 (17)
29 (83)
15 months (9-20)
48 (37) 82 (63)
63 (48) 17 (13) 50 (38)
22 (17)
108 (83)
13 months (3-72)
AML: acute myelogenous leukemia; ALL: acute lymphoblastic leukemia; CMML: chronic myelomonocytic leukemia; CML: chronic myelogenous leukemia; MDS: myelodysplasia; MPD: myeloproliferative disorder; NHL: non-Hodgkin’s lymphoma; MRD: matched related donor; MUD: matched unrelated donor; BM: bone marrow; PBSC: peripheral blood stem cells; KPS: Karnofsky Performance Score; HCT-CI: Hematopoietic cell transplantation - specific comorbidity index; Bu: busulfan; Cy: cyclophosphamide; Flu: fludarabine; Toc: tocilizumab: Tac: tacrolimus; MTX: methotrexate.
relapse, or DFS at 12 months between the two groups (Figures 6D-6F).
Discussion
Inflammatory cytokine production is a proximate event in the pathophysiology of aGvHD.1-3 While a number of inflammatory molecules are produced as a consequence of the conditioning regimen and the activation and expan- sion of alloreactive donor T cells, IL-6 has emerged as an important cytokine mediator of tissue damage.4,7,8 In the study herein, we demonstrate that inhibition of IL-6 sig- naling by the administration of Toc in addition to standard immune suppression resulted in a significant reduction in grades II-IV aGvHD and an increase in grades II-IV aGvHD-free survival, when compared to a matched con- trol population. The administration of Toc was also observed to be safe when given in the setting of MA or reduced intensity Bu-based conditioning regimens. Moreover, adverse events were largely confined to tran- sient elevations in transaminase values, and infectious complications were not dissimilar to what we have previ- ously observed in this patient population treated with standard immune suppression only.
The results of the current study extend those reported
by Kennedy and colleagues,18 who also examined the effi- cacy of Toc for the prevention of aGvHD. These investi- gators observed an incidence of grades II-IV and III-IV aGvHD at day 100 of 12% and 3%, respectively, which was similar to what we observed (14% and 3% for these same endpoints). There were, however, several important differences between the two studies, which suggest that the results may be more broadly generalizable to allogene- ic HSCT recipients. First of all, the median age of patients in our report was substantially higher (66 versus 48), indi- cating that Toc administration appears to have activity in older patients who comprise an increasing percentage of the transplant population.20 Secondly, patients in the cur- rent report received Bu-based conditioning regimens, whereas those in the study by Kennedy et al. were treated with either total body irradiation and Cy (MA condition- ing) or Flu and melphalan (RIC). Since the intensity of the conditioning regimen affects the degree of inflammatory cytokine production19,29 and incidence of aGvHD,30 the fact that promising results were observed in patients who received different MA and reduced intensity regimens is evidence that inhibition of IL-6 may have activity across a spectrum of preparative regimens. Finally, we were able to provide additional context to our data by demonstrat- ing a reduced incidence of grades II-IV aGvHD as well as an increase in grades II-IV GvHD-free survival when com-
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