Hellstrand_edit_02.qxp 12/2/09 15:58 Page 72
Haematological Malignancies
Figure 1: Kaplan-Meier Plots of Leukaemia-free Survival in Acute Myeloid Leukaemia Patients Receiving Post-consolidation Therapy
with Histamine Dihydrochloride/Interleukin-2 or No Treatment in a Phase III Trial
A All patients B Patients in CR1
100 100
90 90
80 80
70 70
al al
60 60
p<0.01
p=0.01
50 50
40 40
30 30
Leukaemia-free surviv Leukaemia-free surviv
20 20
10 10
0 0
0 6 12 18 24 30 36 42 48 54 60 66 72 0 6 12 18 24 30 36 42 48 54 60 66 72
Months from randomisation Months from randomisation
HDC+IL-2 (n=160) Control (n=160) HDC+IL-2 (n=128) Control (n=132)
C
Patients in CR>1
D
Patients in CR1 <60 years of age
100 100
90 90
80 80
70 70
al al
60 60
p=1 p<0.005
50 50
40 40
30 30
Leukaemia-free surviv Leukaemia-free surviv
20 20
10 10
0 0
0 6 12 18 24 30 36 42 48 54 60 66 72 0 6 12 18 24 30 36 42 48 54 60 66 72
Months from randomisation Months from randomisation
HDC+IL-2 (n=31) Control (n=28) HDC+IL-2 (n=31) Control (n=28)
Leukaemia-free survival (LFS) defined as the time from complete remission (CR) to relapse or death from any cause.
Panel A: shows LFS of all patients randomised primary trial end-point (n=320).
Panel B: shows LFS of patients in first CR (CR1; n=261).
Panel C: shows LFS of patients in second or subsequent CR (CR>1).
Panel D: shows LFS of CR1 patients below 60 years of age.
All analyses were performed according to intent-to-treat. The log-rank test (after stratification for CR and country) was used for statistical analysis.
17
Clinical Results of Combination Immunotherapy with Pre-clinical Pharmacodynamics of
Histamine Dihydrochloride and Interleukin-2 Histamine Dihydrochloride
A recent phase III trial has demonstrated that treatment with histamine Studies in pre-clinical models imply that the principal action of HDC is to
dihydrochloride (HDC, 0.5mg sq bid) in conjunction with low-dose protect T cells and NK cells from inhibition and apoptosis induced by
IL-2 (14MIU/month sq bid) significantly prevented relapse in myeloid cells such as mononuclear or polymorphonuclear phagocytes.
non-transplanted AML patients. The trial was performed in 10 These myeloid cells confer inhibition of T- and NK-cell function and also
countries with 320 participating CR patients. HDC/IL-2 was trigger cell death by apoptosis in cytotoxic lymphocytes.
19
HDC counters
administered by the patients at home in a total of 10 three-week myeloid-cell-induced inhibition of T and NK cells by reducing or inhibiting
courses followed by three- to six-week rest periods for a total of 18 the formation of reactive oxygen species (oxygen radicals) in several types
months. The therapy intended to coincide with the period of highest of myeloid cells.
20
The T and NK cells will remain viable, functional and
relapse risk after achieving CR. HDC/IL-2 therapy was acceptably well reactive to IL-2 in the presence of myeloid cells.
20
For example, the
tolerated with no major impact on quality of life.
17
The benefit of combination of HDC/IL-2, neither compound used alone, activates
HDC/IL-2 appeared to be the result of the prevention of leukaemic cytotoxic lymphocytes to efficiently lyse AML blasts in the presence of
recurrence in patients in first CR (CR1), in particular in those below 60 mononuclear phagocytes.
21,22
In addition, HDC improves the IFN-γ-
years of age (see Figures 1 and 2). producing capacity of T and NK cells and efficiently improves the IL-2-
induced appearance of activation antigens such as CD69 on the surface of
HDC/IL-2 therapy has been developed on the basis of pre-clinical these cells.
23
Figures 2 and 3 depict these immunostimulatory properties of
studies suggesting that HDC improves the immuno-activating HDC, and Table 1 summarises the effects of HDC on T- and NK-cell
properties of IL-2.
18
HDC promotes IL-2 activity by reducing or function in vitro along with studies suggesting that the addition of HDC
inhibiting suppressive signals from adjacent myeloid cells. improves the antitumour activity of IL-2 in tumour-bearing rodents in vivo.
72 EUROPEAN HAEMATOLOGY
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