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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 12 (June 15), 1999:
pp. 4149-4153
Sequential Homoharringtonine and Interferon- in the Treatment of
Early Chronic Phase Chronic Myelogenous Leukemia
By
Susan O'Brien,
Hagop Kantarjian,
Charles Koller,
Eric Feldman,
Miloslav Beran,
Michael Andreeff,
Sergio Giralt,
Bruce Cheson,
Michael Keating,
Emil Freireich,
Mary Beth Rios, and
Moshe Talpaz
From the Departments of Leukemia, Bioimmunotherapy, and Blood and
Marrow Transplant, Division of Medicine, The University of Texas M.D.
Anderson Cancer Center, Houston, TX; and the National Cancer Institute,
Bethesda, MD.
 |
ABSTRACT |
Homoharringtonine (HHT) is a novel plant alkaloid that produced a
complete hematologic remission (CHR) in 72% of patients with late
chronic phase chronic myelogenous leukemia (CML). Cytogenetic (CG)
remissions were noted in 31%. In this study, six courses of HHT were
administered to 90 patients with early chronic phase CML (< 1 year
from diagnosis). Patients then received interferon- (IFN-) with a
target dose of 5 MU/m2 daily. Results were compared with
those in a prior group of patients treated with IFN--based therapy
between 1982 and 1990. Ninety-two percent of patients achieved CHR with
HHT; CG responses were observed in 60% and were major in 27%. Both
CHR and CG response rates were significantly higher than those seen in
historical control patients after 6 months of IFN- therapy. After
receiving HHT, patients required lower doses of IFN- to maintain a
CHR. The median dose delivered was 2.4 MU/m2. This
reduction in IFN- dose was associated with a lower incidence of
myalgia and gastrointestinal (GI) disturbances than that seen in
patients treated at the 5 MU/m2 dose. Overall, CG responses
were seen in 66% of the patients who received HHT and IFN- compared
with 61% of the historical control patients. HHT is a very effective
treatment of early chronic phase CML, and ongoing trials are
investigating the simultaneous administration of HHT and IFN-, as
well as that of HHT and low-dose cytosine arabinoside in patients
failing IFN- therapy.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
HOMOHARRINGTONINE (HHT) is a plant
alkaloid derived from an evergreen tree ubiquitous to China. A racemic
mixture of harringtonine and HHT was first used with some success in
China in the treatment of acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML).1,2 Purified HHT supplied by the National Cancer Institute was administered as a bolus in phase I trials
in the United States with hypotension and arrhythmia being
dose-limiting.3,4 Continuous infusion of a low dose of HHT
abrogated the cardiovascular side effects and was limited only by
prolonged myelosuppression.5
We had previously administered a continuous infusion of HHT to patients
with CML in late chronic phase.6 The median time from
diagnosis was 3 years, and most of these patients had failed interferon- (IFN-) therapy. HHT produced a complete hematologic remission (CHR) in 72% of the patients; cytogenetic (CG) responses were seen in 31%. Toxicity was minimal, and the drug could be easily
administered to outpatients with a portable pump.
The encouraging activity of HHT in patients with refractory advanced
disease led us to explore its activity in newly diagnosed patients with
early chronic phase CML ( 12 months from diagnosis). The study was
designed so that patients received six cycles of HHT monthly; they were
later switched to maintenance therapy with IFN-. Our prior
experience with IFN- had shown that its major benefit was noted in
patients treated within 1 year of diagnosis: 30% to 50% of these
patients achieved a major CG response, which translated into a
significant survival advantage.7 Without any long-term data
with HHT, it was considered reasonable to use a 6-month trial to assess
efficacy and allow patients to have early exposure to IFN-. Data
from the prior HHT study in patients with late chronic phase CML had
demonstrated that hematologic remission occurred with one to two
courses and that a CG response was usually evident by 6 months.6
| |
MATERIALS AND METHODS |
Study Group
Ninety patients with newly diagnosed early chronic phase CML received
treatment. Informed consent was obtained according to institutional
guidelines. Eligibility criteria were: age  15 years, documented
Philadelphia chromosome (Ph)-positive or BCR-ABL positive disease,
Zubrod performance status 2, normal renal and hepatic function
(creatinine < 2 mg%, bilirubin < 2 mg%), and the absence of any
neuropsychiatric disorders. Patient risk groups were categorized
according to a clinical model taking into account the following
variables: age, race, spleen size, platelet count, and percentage of
blood basophils.7 Sixteen patients had missing variables,
which prevented their categorization. Results obtained after six cycles
of HHT were compared with those seen in 274 patients treated with
IFN-based therapy at M.D. Anderson Cancer Center (MDACC) between 1982 and 1990. An analysis of response rates and prognostic factors in these
patients was published previously.8 A comparison of patient
characteristics between the two groups is shown in
Table 1.
Therapy
HHT was supplied by the National Cancer Institute and administered at a
dose of 2.5 mg/m2 daily as a continuous infusion through a
central venous catheter. The first course (induction) lasted for 14 days and therapy was repeated monthly. Once CHR was achieved,
subsequent courses were given over 7 days (maintenance) provided that
the patient's absolute granulocyte count (AGC) had recovered to > 2.5 × 109/L and platelet count had recovered to > 60 × 109/L. If the time it took to achieve these
levels was 42 days, subsequent courses were decreased by 2 days. The
daily dose was never changed, but the number of days was adjusted to
keep the AGC > 109/L and the lowest platelet count > 40 × 109/L. After six cycles of HHT, IFN- was given
subcutaneously (self-administration) at a daily target dose of 5 MU/m2. Dose adjustments for IFN- were as follows: for
grade 3 or 4 toxicities, IFN- was held until resolution to grade
1 then resumed at 50% of the previous dose; for chronic grade 2 toxicities, the IFN- dose was reduced by 25%.
Response Criteria
The response criteria were those previously defined for IFN- trials.
CHR required a white blood cell count 10 × 109/L,
the absence of peripheral blood blasts, promyelocytes and myelocytes, a platelet count 450 × 109/L, and the absence of palpable splenomegaly. CHR was
further classified according to suppression of the Ph chromosome as
follows: no CG response, 100% Ph-positive metaphases, minimal CG
response, 35% to 90% Ph-positive metaphases, partial CG response, 1%
to 34% Ph-positive metaphases, complete CG response, no Ph-positive metaphases. Twenty metaphases were analyzed whenever possible (85% of analyses).
A partial hematologic remission (PHR) required a peripheral white blood
cell (WBC) count 10 × 109/L and a reduction of
palpable splenomegaly and thrombocytosis by 50%, but the presence
of residual immature cells was allowed.
Statistical Consideration
The associations between patient characteristics and response outcome
were evaluated by  2 test.9 The cutpoints for
quantitative variables were those that defined abnormal levels or
others in common use. Distributions of survival and time to progression
were estimated by the method of Kaplan and Meier.10 The
survival intervals were measured from the first day of chemotherapy to
death, and deaths from all causes were included. Time to progression
was measured from the first day of chemotherapy to the first detection
of relapse.
| |
RESULTS |
Hematologic and CG Responses to HHT
Eighty-three patients (92%) achieved CHR with HHT
(Table 2), five patients (6%) had PHR, and
two (2%) patients had resistant disease. CHR occurred with one course
of HHT in 45 patients (54%), two courses in 22 patients (27%), and
three to five courses in 16 patients (19%). The median number of days
of HHT administration for courses 1 through 6 was 14, 8, 7, 7, 6, and
5, respectively. Sixty percent of the patients had a CG response; they
were minor in 33%, major in 23%, and complete in 4%.
One of the two patients who had resistant disease was referred within 1 month of diagnosis, but had accelerated phase CML at the time of
presentation: the patient had a WBC count of 567 × 109/L with 9% basophils, hemoglobin level of 5.1 g/dL, and
the spleen was palpable 20 cm below the costal margin.11
This patient received two induction courses of HHT without having a
significant response, was transiently treated with hydroxyurea, and
received a stem cell transplant (SCT) from a matched unrelated donor.
The other patient with resistant disease had clonal evolution with
trisomy 21 at the time of diagnosis.
One patient who had a PHR received only one course of HHT because of
the development of atrial fibrillation. He was continued on IFN-
maintenance and achieved a complete CG remission. PHR represented a
significant improvement in disease status in the five patients who had
that response. The median WBC count decreased from 111 × 109/L (range, 29 to 215 × 109/L) to 3 × 109/L (range, 1 to 6 × 109/L).
Three of the five patients had palpable splenomegaly 8, 10, and 25 cm
below the costal margin before HHT, and all had resolution of
splenomegaly. They were categorized as having a PHR because of
persistent peripheral immature cells. Nevertheless, patients failing to
achieve CHR with HHT had very poor outcomes. Excluding the resistant
patient who had SCT and the patient who developed atrial fibrillation,
the median time to accelerated or blastic phase in the remaining four
patients was 7 months (range, 3 to 13 months). Only one patient did not
have evidence of disease progression; this patient died of mesothelioma
while still in the chronic phase of CML.
The CHR rate at 6 months of 92% with HHT was significantly better than
the 6-month CHR rate of 70% with IFN- therapy in the historical
control group (Table 3). The overall CG
remission rate at 6 months with HHT was 59% versus 34% with IFN-based
therapy (P < .001). The largest difference between the two
groups was in the proportion of patients achieving a major CG (partial
and complete) response at 6 months: 27% of patients who received HHT had a major CG response versus 11% of the patients who received IFN- (P < .001).
Ten patients had CG abnormalities in addition to having the Ph
chromosome at the time of initiation of HHT therapy: eight (80%) had a
CHR and six (60%) a CG response (two minor and four major). Thus,
hematologic and CG response rates were not different from those in
patients presenting without clonal evolution. However, patients with
clonal evolution at diagnosis had inferior survival (median, 37 months).
Patient characteristics were analyzed for correlations with major CG
response to HHT. Factors analyzed included age, sex, WBC count,
hemoglobin level, platelet count,  2 microglobulin, presence or absence of palpable splenomegaly, time from diagnosis, and
risk group. The only factor that correlated with a major CG response
was splenomegaly. Fifty-seven patients did not have palpable splenomegaly; 35% of them had a major CG response versus only 15% of
the patients (n = 33) with palpable splenomegaly at the time of treatment.
Toxicity of HHT
Extramedullary.
HHT was well tolerated with 28% of the patients experiencing no side
effects at all. Side effects are shown in Table 3. The most common
toxicity was diarrhea, which was usually mild and required no
intervention. Most of the patients who complained of tachycardia or
vague chest pain did not have an electrocardiogram, as these episodes
were transient and mild, and usually occurred when the patient was not
in the clinic. One patient developed atrial fibrillation on day 9 of
the first course; he did not receive further HHT, but continued
receiving IFN- therapy. Palpitations and lightheadedness developed
in another patient, a 39-year old man, on day 4 of HHT induction
therapy; a Holter monitor showed short runs of ventricular tachycardia.
HHT was continued after the patient was admitted to the intensive care
unit. Chest radiography showed that the patient's central venous
catheter was in the atrium; the catheter was repositioned, and no
further arrythmias occurred. Subsequent courses were given without problems.
Myelosuppression.
Myelosuppression occurred most frequently during the initial 14-day HHT
induction course (Table 3). Twenty-seven percent of the patients had an
AGC < 0.5 × 109/L, although severe neutropenia (AGC < 0.1 × 109/L) was unusual (7%). Neutropenia was
uncommon during maintenance therapy in which the number of days of HHT
administration could be adjusted to avoid significant cytopenia.
Thrombocytopenia < 30 × 109/L was seen in 13% of
the patients during induction therapy and in 5% of maintenance
courses. Seven patients (8%) did not complete six courses of HHT
because of prolonged myelosuppression; the median number of courses
given to them was four (range, 2 to 5). Myelosuppression, defined by an
AGC nadir < 0.5 × 109/L in any HHT course, was not
related to achievement of a major CG response: 25% of the patients who
did not have myelosuppression achieved this response versus 31% with
AGC nadir < 0.5 × 109/L.
Maintenance Therapy With IFN-
After six cycles of HHT, patients received IFN- maintenance therapy
at a target dose of 5 MU/m2. Significant myelosuppression
was observed at this dose and was more severe than had been seen in the
historical control patients who did not receive pretreatment with HHT.
The median dose of IFN- delivered in the first 12 months after HHT
therapy was 2.4 MU/m2 versus 5 MU/m2 in the
historical control patients. Median WBC counts were not significantly
different: 3.5 × 109/L in the patients who received
HHT-IFN and 4.2 × 109/L in the historical control group.
The need for a lower dose of IFN- to achieve normal hematologic
parameters resulted in a reduction in the incidence of some IFN-related
toxicities. GI disturbances and myalgia or bone aches were seen
significantly less frequently in the patients who received HHT-IFN-
than in the historical control group (Table
4). Comparison of CG responses is shown in
Table 5: complete and partial CG remissions were observed in 23% and 21% of patients who received HHT-IFN; these rates were not different from those seen in the historical control group. Thus, sequential treatment with HHT followed
by IFN- resulted in an overall CG response rate of 66% and a major
CG response rate of 44%.
Patient characteristics were analyzed for correlations with major CG
response to the sequence of treatment with HHT followed by IFN-.
Factors analyzed included age, sex, WBC count, hemoglobin level,
platelet count, 2 microglobulin, presence or absence of palpable splenomegaly, time from diagnosis, and risk group. Two factors
correlated with development of a major CG response. As with response to
HHT alone, splenomegaly proved important. Thirty of 57 patients (53%)
without palpable splenomegaly had a major CG response, versus 10 of 33 (30%) with palpable splenomegaly at the time of treatment (P = .04). In addition, the risk model characterized patients likely to
develop a major CG response to HHT-IFN-. Major CG response rates
according to good (n = 30), intermediate (n = 36), poor (n = 8), or not
applicable (n = 17) categories were 63%, 39%, 13%, and 38%, respectively.
Sixty (67%) patients treated with HHT-IFN- are off study versus 180 (66%) of the historical control group. The median time to going off
study was 22 months in the HHT-IFN- group and 18 months in the
historical control group. A comparison of the reasons for going off the
study are shown in Table 6; no significant differences were seen, and hematologic resistance was the major cause
of treatment failure. Patients with CG resistance had a CHR and 100%
Ph-positive cells on bone marrow analysis; they elected to receive
alternative (usually investigational) therapy. The median survival of
patients treated with HHT-IFN has not been reached after a median
follow-up of 53 months (Fig 1).
Stem Cell Transplant Post-HHT-IFN
Twenty-four patients received an allogeneic transplant after treatment
with HHT-IFN-. Seven patients were transplanted in CHR because of
failure to achieve a CG response. All seven patients were alive at a
median follow-up of 49 months (range, 26 to 61 months). Six patients in
whom hematologic resistance to IFN- developed received a transplant.
Two patients are alive 57 and 44 months, respectively. Ten patients
received a transplant during the accelerated (n = 5) or blast phase (N = 5) of CML. All five patients transplanted in blast crisis have died;
two patients transplanted in accelerated phase were alive 31 and 56 months after transplantation. One 32-year old patient received two
courses of HHT and achieved CHR, but elected to receive a transplant
from an unrelated donor. This patient died of unclear causes 6 weeks after transplantation.
| |
DISCUSSION |
HHT is a plant alkaloid with significant activity against CML. It was
initially used to treat patients in late chronic phase CML (median 3 years from diagnosis), two thirds of whom were resistant to
IFN-.6 CHR was noted in 72% of the patients, and CG
responses were seen in 31% (half of which were major). Toxicity was
minimal, and some responses were sustained for several years. These
encouraging results prompted the current trial to assess the activity
of HHT in early chronic phase CML. A decision was made to limit HHT
therapy to six cycles to allow patients to receive IFN- early in the course of CML, because CG response rates with IFN- were
significantly better when administered within 1 year after diagnosis.
Another reason was to compare the efficacy of HHT with that of IFN-
and other regimens in newly diagnosed CML (eg, intensive chemotherapy).
The majority of patients with early chronic phase CML achieved a CHR
with HHT. In fact, failing to achieve CHR with HHT appeared to identify
a small subset of patients with a particularly poor prognosis. Although
CHR is a desirable target in initial therapy of CML, this result can be
achieved with other commonly used drugs such as hydroxyurea and
busulfan. A more important parameter is major CG response. Multiple
trials have demonstrated that achievement of such a response is rare
with oral agents, but can occur in a subset of patients after IFN-
therapy and has a significant positive impact on
survival.8,12-14
The CG response rate to HHT was 60%, twice the response rate obtained
with HHT in patients in late chronic phase, and 45% of CG responses
were major. HHT-induced CG responses were usually not associated with
significant myelosuppression, but were reminiscent of those induced by
IFN-, with gradual improvement over time.
When these results were compared with those in an historical population
of patients with early chronic phase CML who received IFN-based
regimens, the analysis showed a significantly higher hematologic
response rate with HHT than with IFN- (92% v 71%). CG
response rates also appeared to be higher with HHT (60% v
34%), but the analysis was limited to results after 6 months because HHT was not given longer than that. Responses to IFN- were slower to
occur, with a median time to a major CG response of 12 months. Whether
the major CG response rate with HHT would have been higher if HHT had
been given for a longer period cannot be determined.
While HHT appears to be more favorable than IFN-, caveats to this
observation are that (1) the durability of CG responses with HHT
compared with those with IFN- are yet to be determined, and (2) that
unlike with IFN-, the experience with HHT is too preliminary to
provide sufficient confidence in its long-term impact on survival.
In the present study, HHT was well tolerated, with mild extramedullary
toxicity. No prophylactic antiemetics were required, and alopecia was
rare. Seven patients could not complete the planned six cycles of
therapy because of cumulative myelosuppression; two other patients
could not complete all six cycles because of other toxicities. An
inconvenient aspect of HHT administration was the need for a central
venous catheter to support the continuous infusion, which was mandated
by prior experience documenting arrythmias and hypotension with bolus
and even extended (6-hour) infusion schedules. Alternate routes of HHT
administration, such as subcutaneous or oral, have never been explored
and could potentially provide for easier administration of HHT if
proven to be efficacious.
After HHT administration, patients required minimal doses of IFN- to
maintain a CHR. This resulted in a reduction of the incidence of some
IFN-related toxicities such as bone and muscle pain and GI
disturbances. This positive aspect of pretreatment with HHT was
counterbalanced with concern as to whether long-term response rates
would be as high with HHT followed by IFN-, because the lower doses
of IFN- could potentially result in lower CG response rates.
Fortunately, this was not the case. Overall CG response rates in the
patients in the present study were identical with those in historical
control patients. This was true even though the dose of IFN- was
significantly lower in the present trial (2.4 MU/m2
v 5 MU/m2). Although HHT followed by IFN- did
not improve long-term response rates over those seen with IFN-
alone, the aim of the present study was to assess the activity of HHT
in newly diagnosed patients.
In summary, HHT is a novel alkaloid with pronounced activity in the
treatment of CML. It induced CHR and CG response rates equal or
superior to those with IFN-. Whether these responses are as durable
as those with IFN- and translate into improved survival could not be
evaluated in the current trial. The 6-month HHT trial was mandated by
the need for cautionary introduction of a novel agent in the early
chronic phase and by the necessity to add IFN- (the established
beneficial treatment of CML) early on. Future trials will incorporate
simultaneous combinations of HHT, IFN-, and low-dose cytosine
arabinoside, and continue HHT for significantly longer periods than in
this six-course HHT trial.
| |
FOOTNOTES |
Submitted October 27, 1998; accepted February 17, 1999.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Susan O'Brien, MD, Department of Leukemia,
UT M.D. Anderson Cancer Center, 1515 Holcombe Blv, Box 61, Houston, TX
77030.
| |
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ABSTRACT
INTRODUCTION