Ek. Rowinsky et al., PHASE-I AND PHARMACODYNAMIC STUDY OF THE TOPOISOMERASE I-INHIBITOR TOPOTECAN IN PATIENTS WITH REFRACTORY ACUTE-LEUKEMIA, Journal of clinical oncology, 12(10), 1994, pp. 2193-2203
Purpose: To determine the feasibility of escalating the hydrophilic to
poisomerase I (topo I)-inhibitor topotecan (TPT) above myelosuppressiv
e doses in adults with refractory or relapsed acute leukemias and to a
ssess pharmacodynamic determinants of TPT action. Patients and Methods
: Seventeen patients received 33 courses of TPT as a 5-day infusion at
doses ranging from 0.70 to 2.7 mg/m(2)/d. Pharmacologic studies were
performed to determine the TPT concentrations at steady-state (C-ss) a
nd to examine parameters in the patients' leukemic blasts ex vivo that
may be related to TPT sensitivity, eg, tope I content, p-glycoprotein
(Pgp) expression, and the inhibitory effects of relevant TPT concentr
ations on the growth of blast colonies in clonogenic assays relative t
o the range of TPT C-ss values achieved. Results: Severe mucositis of
the oropharynx and perianal tissues was intolerable at TPT doses great
er than 2.1 mg/m(2)/d, the recommended dose for phase If studies in le
ukemia. One complete response (CR) in a patient with chronic myelogeno
us leukemia in blast crisis (CMLB) and one partial response (PR) in a
patient with acute myelogenous leukemia (AML) were noted. Significant
reductions in circulating blast-cell numbers occurred in all courses,
and complete leukemia clearance from the peripheral blood, albeit tran
sient, wets noted in 11 courses. TPT C-ss values ranged from 4.8 to 72
.5 nmol/L. Colony-forming assays showed that the TPT LD(90) (dose that
inhibits the growth of leukemia blast colonies by 90%) values for bla
sts varied from 6 to 22 nmol/L, a range that overlapped with TPT C-ss
values. In view of these variations in TPT sensitivity, several aspect
s of topo I-mediated drug action were also studied. In 10 of 11 sample
s, the multidrug resistance (Mdr) modulator quinidine altered nuclear
daunorubicin (DNR) accumulation and whole-cell TPT accumulation by les
s than 15%, which suggests that Pgp-mediated effects on drug efflux ar
e insufficient to explain the fourfold range of TPT sensitivities in t
he colony -forming assays. Immunohistochemistry showed that topo I woo
expressed in all of the blasts from individual patients without detec
table cell-to-cell heterogeneity in each marrow. Western blots indicat
ed that topo I content varied over a 10-fold range. Although the sampl
e size was small, topo I content appeared to be higher in acute lympho
blastic leukemia (ALL), intermediate in AML, and lower in CML-B. Topo
I content did not appear to be related to the proliferative status of
the blasts. Conclusion: These results indicate that substantial dose e
scalation of TPT above myelosuppressive doses reached in solid-tumor p
atients is feasible in patients with refractory leukemia, that biologi
cally relevant TPT C-ss values are achievable, and that further develo
pmental trials are warranted. (C) 1994 by American Society of Clinical
Oncology.