PROLONGED ADMINISTRATION OF INTERFERON-ALPHA IN PATIENTS WITH CHRONIC-PHASE PHILADELPHIA-CHROMOSOME-POSITIVE CHRONIC MYELOGENOUS LEUKEMIA BEFORE ALLOGENEIC BONE-MARROW TRANSPLANTATION MAY ADVERSELY AFFECT TRANSPLANT OUTCOME
Dw. Beelen et al., PROLONGED ADMINISTRATION OF INTERFERON-ALPHA IN PATIENTS WITH CHRONIC-PHASE PHILADELPHIA-CHROMOSOME-POSITIVE CHRONIC MYELOGENOUS LEUKEMIA BEFORE ALLOGENEIC BONE-MARROW TRANSPLANTATION MAY ADVERSELY AFFECT TRANSPLANT OUTCOME, Blood, 85(10), 1995, pp. 2981-2990
To assess the influence of pretransplant cytoreductive therapy with sp
ecial reference to interferon-alpha (IFN-alpha) treatment on major end
points of allogeneic bone marrow transplantation (BMT), we studied 133
consecutive patients with Philadelphia chromosome (Ph(1))-positive ch
ronic myelogenous leukemia (CML) in first chronic phase who received m
arrow grafts from HLA-identical family (n = 103) or alternative donors
(n = 30) at a referral-based transplant center. Fifty of these patien
ts (38%) were previously exposed to IFN-a for a median duration of 14
months (range, 1 to 61 months), whereas 83 patients (62%) exclusively
received hydroxyurea and/or busulfan therapy between 1 and 129 months
(median, 15 months) pretransplant. Using the categorized treatment dur
ation with each pretransplant cytoreductive agent as a measure for ind
ividual patient exposure to each agent, prolonged(>12 months) IFN-alph
a administration was identified as the sole significant pretransplant
therapy-related predictor of transplant outcome by proportional hazard
s regression analysis. The adjusted risk ratio (RR) of transplant-rela
ted mortality (TRM) was 2.5-fold higher (95% confidence limits [95% CL
], 1.4 to 4.5; P <.004) compared with other pretransplant therapy and
this was mainly attributable to a 3.1-fold higher RR (95% CL., 1.4 to
6.4; P <.005) of fatal posttransplant infections after prolonged IFN-a
lpha treatment pretransplant. Marrow graft failure developed exclusive
ly among 7 of 30 patients (23%) with donors other than HLA-identical f
amily members and was further restricted to patients who had been prev
iously exposed to IFN-alpha. The probability of graft failure was 49%
+/- 28% in 17 patients pretreated with IFN-alpha compared with 0% for
the other 13 patients with mismatched family or unrelated donors (P <.
008). In addition, a significant delay in neutrophil and platelet coun
t reconstitution was observed among patients with donors other than HL
A-identical family members after pretransplant IFN-alpha exposure. No
influence of pretransplant cytoreductive therapy on either acute and c
hronic graft-versus-host disease or leukemic relapse was detected in t
his study. As a consequence of its adverse effect on TRM, prolonged pr
etransplant IFN-alpha treatment was independently associated with a 2.
5 fold lower likelihood (95% CL, 1.4 to 4.5; P <.003) of 5-year overal
l survival and with a 2.3-fold lower likelihood (95% CL, 1.3 to 4.2; P
<.004) of 5-year disease-free survival postransplant after adjustment
for other significant prognostic factors in multivariate analysis. In
conclusion, the present study strongly suggests that prolonged pretra
nsplant IFN-alpha administration in patients with chronic-phase Ph(1)-
positive CML may be associated with an increased risk of fatal transpl
ant-related complications and an inferior outcome after allogeneic BMT
. Future analyses on transplant results in chronic-phase CML patients
should carefully evaluate the impact of treatment duration or, if appl
icable, of the cumulative doses of IFN-alpha and other cytoreductive a
gents administered pretransplant. (C) 1995 by The American Society of
Hematology.