Homoharringtonine Therapy Induces Responses in

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Homoharringtonine Therapy Induces Responses in Patients With Chronic
Myelogenous Leukemia in Late Chronic Phase
By Susan O’Brien, Hagop Kantarjian, Michael Keating, Miloslav Beran, Charles Koller, L.E. Robertson, Jeane Hester,
MaryBeth Rios, Michael Andreeff, and Moshe Talpaz
Homoharringtonine (HHT) is a plant alkaloid with potentmyelosuppressive activity and little toxicity when used in a
continuous infusion schedule. The antileukemic efficacy of
HHT has been shown in acute myeloid leukemia, but has not
been investigated in chronic myelogenous leukemia (CML).
Seventy-one patients with Philadelphia chromosome-positive Ph’) CML in late chronic phase (time fromdiagnosis to
therapy longer than 12 months) were treated with
a continuous infusion of HHT at a daily doseof 2.5 mg/m2 for14
days for remission induction and for 7 days every month for
maintenance. The median number of courses given was 6
(range, 1 to 35) and 21 patients (30%)continue on treatment.
Forty-two of 58 patients 172%) evaluable for hematologic
response achieved a complete hematologic remission, and
9 (16%) had a partial hematologic remission. Twenty-two of
71 patients (31%) developed a cytogenetic response; it was
major (Ph’ cells lessthan 35%) in 11 (15%) and complete (Ph’
cells 0%) in 5 (7%). Significant myelosuppression occurred in
39% of induction courses and 9% of maintenance courses.
Fever ordocumented infection was present in 26%of induction courses and in only 8% of maintenance courses. Nonmyelosuppressive toxicity was minimal. Homoharringtonine
produced hematologic remissions in themajority of patients
with advanced chronic-phase CML. Cytogenetic response
occurred in some patients without an association with m y
elosuppression, and these responses may beprolonged. Future studies investigating homoharringtonine in combination withother active agents in CML, such as interferon, are
warranted.
0 1995 by The American Society of Hematology.
A
harringtonine was first used in the treatment of leukemia by
the Chinese, who reported activity in both acute myelogenous leukemia (AML) and CML.‘.” Cytogenetic responses
were not described in those studies. Subsequent phase I studies in the United States usingabolus
schedule of HHT
showed hypotension and myelosuppression to be the doselimiting toxic effects.’.* To abrogate the hypotensiveside
effects, HHT was given as a continuous infusion for AML,
and occasional responses were
seen.”” However, hypotension still occurred frequently at daily doses above S mg/m’.
Using a lower daily dose of 2.5 mg/m2 and prolonging the
infusion to 14 to 2 1 days reduced the incidence rate of hypotension to only 3% and with this schedule, the only doselimiting toxic effect was prolonged myelosuppression.” Because of its potent myelosuppressive effects, weinvestigated
HHT in the treatment of CML. Study patients were ineligible
for related BM transplants and in most cases had failed to
respond to therapy with IFN-a. Herein, we describeour
resultsusing HHT in patients with CML in late chronic
phase.
LLOGENEIC BONE MARROW (BM) transplantation
is curative in patients with chronic myelogenous leukemia (CML), but is limited to only 20% of patients because
of restrictions on age and donor compatibility.’Interferon a
(IFN-a) treatment in early chronic-phase CML results in a
hematologic response in 70% to 80% of patientsand in
complete suppression of the Philadelphia chromosome (Ph),
or complete cytogenetic response, in15% to 25% of patients.* These complete cytogenetic responses are long lasting, with 80% of patients remaining alive and in remission
at 8 years.3 Confirmation that the survival benefit
is conferred
by the cytogenetic response hasbeen shown by landmark
analysis that analyzed survival from 12 months into therapy
by response at 12 months; and by multivariate analysis that
identified major cytogenetic response (introduced as a time
varying factor afterpretreatmentprognosticfactors
were
identified) to be an independent prognostic factor for survival.’ An Italianrandomizedstudy
also showed by landmark analysisthe prognosticsignificance for survival of
achieving a cytogenetic response with IF’N-o~.~
When the CML becomes resistant to IFN-a, therapeutic
options are limited, and
palliative treatment such as hydroxyurea is commonly used. Based on the hypothesis that suppression of the Ph chromosome will prolong survival, we
have searched for other agentsthat can produce bothhematologic and cytogenetic remissions in CML.
Homoharringtonine(HHT) isaplantalkaloidderived
from the Cephalotuxus fortuneii tree. A mixture of HHT and
From the Department of Hematology, The Universit). of Texas
MD Anderson Cancer Center, Houston.
Submitted October 6, 1994; accepted June 28, 1995.
Address reprint requests to
Susan O’Brien, MD, Department of
Hematology, Box 61, The University of Texas MD Anderson Cancer
Center, 1515 Holcomhe Bfvd, Houston, 7x 77030.
The publication costs ofthis article were defrayed
in part by page
chargepayment. This article must therefore he herebymarked
“advertisement” in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 1995 by The American Society of Hematology.
0006-4971/95/8609-0034$3.00/0
3322
PATIENTS AND METHODS
Study population. Seventy-one
patients
with CML
in
late
chronic phase (defined as a period from diagnosis to therapy longer
was
than 12 months)weretreatedafterwritteninformedconsent
obtained according to institutional guidelines. The 12-month treatment cut-off was chosen based on known differences in response to
therapy of CML patients beyond this point. Patients with a disease
duration of more than I year have inferior hematologic and cytogenetic response rates to IFN-u.”.’‘ Similarly, patients with CML who
receive an allogeneicBM transplant at morethan I year from diagnosis have significantly inferior survival compared with those patients
transplanted within 1 year.’
a Zubrod performance status
Treatment eligibility criteria included
5 2 andnormal renal andhepaticfunctions.Patientswithsevere
heart disease (cardiac classes 111 and W ) were excluded.
Patient characteristics are outlined in Table I . The median patient
age was 46 years (range, 23 to 71 years), and
48% were women.
a Zubrodperformancestatus 5 1 . The
Allbutthreepatientshad
median time from diagnosis of CML to treatment with HHT was
37 months (range,4 to 188 months). Five patients (7%), weretreated
within I year of diagnosis.all of whomhadpreviouslyreceived
Blood, Vol 86, N o 9 (November l), 1995:pp 3322-3326
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3323
HOMOHARRINGTONINE IN CML
Table 1. Patient Characteristics In = 711
Characteristic
No. of Patients
(Oh)
~~~~
Age >50 (yr)
Time from diagnosis to HHT >3 yr
Prior interferon therapy
Interferon resistant
Palpable splenomegaly
Clonal evolution
Disease status
Active
Hematologic remission, 100% Ph’
Patients with active disease (n = 58)
WBC count >50 x 103/pL
Platelet count >500 X 103/pL
Hemoalobin <11.0 a/dL
46 (23-71)
37 (52)
58 (82)
41 (58)
18 (32)
20 (28)
and no palpable splenomegaly. CHR was further classified according
to suppression ofthePh chromosome as follows: no cytogenetic
response, 100% Ph’ metaphases; minimal cytogenetic response,
35% to 95% Ph+ metaphases; partial cytogenetic response, 1% to
34% Ph’ metaphases; complete cytogenetic response, no Ph+ metaphases. Twenty metaphases were analyzed whenever possible (85%
of analyses).
Partial hematologic remission (PHR) required a peripheral WBC
count c 10 X 10’/pL, and 2 50% reduction of palpable splenomegaly and thrombocytosis but residual immature cells were allowed.
RESULTS
26 (45)
27 (47)
19 (33)
IFN-a therapy; two had resistant disease, two had neurotoxicity,
and one was in hematologic remission buthad never achieved a
cytogenetic response. Of the 71 patients, 58 (82%) had previously
received IFN-a therapy; 41 patients (58% of the total, 69% of the
prior IFN-a treated) had documented hematologic resistance to IFNa.
Fifty-eight patients (82%) treated had active disease, and their
median hematologic parameters at the start of therapy were as follows: white blood cell (WBC) count, 43 X lO’/pL, (range, 3.7 to
237 X lO’/pL); hemoglobin level, 11.9 g/dL, (range 7.8 to 15 g/
dL); and platelet count, 426 X 103/pL, (range, 82 to 2,180 X 10’1
pL). Three (4%) of the 71 patients started HHT therapy with WBC
counts below 10 X lO’/pL but were considered to have active disease
because their platelet counts ranged from 688 to 2,005 X lO’/pL.
Eighteen (32%) of the 58 patients had palpable splenomegaly, ranging from 1 to 20 cm below the costal margin. In all 58 patients with
active disease, 100% of metaphases showed thePh chromosome.
Sixteen (28%) of the 58 patients also had an additional clone in 4%
to 100% of metaphases (median, 20%).
Of 71 study patients, 13 (18%) were in hematologic remission, but
had never achieved a cytogenetic response. Hematologic response to
HHT could not beevaluated in those patients, but theywere included
in the analysis for evaluation of cytogenetic response. All 13 of
these patients had 100% Ph+ metaphases, and 4 of the 13 had additional clones.
Therapy. Homoharringtonine was given as a continuous infusion
through a central venous catheter at a daily dose of 2.5 m g h 2 over
14 days onan outpatient basis. Patients who achieved complete
hematologic remissions received maintenance therapy with 2.5 mg/
m2 HHT for 7 days every month. In subsequent courses, the dose
was held constant, but the number of days could be adjusted to
achieve a nadir granulocyte count of about 1,00O/pLand a nadir
platelet count above 50 X 103/pL. Courses were given at monthly
intervals provided the granulocyte count had recovered to above
2,500/pL and the platelet count to above 100 X lO’/pL. Most patients
who achieved remission did so with one 14-day course. Fourteen
patients (20%) required two courses, four patients (6%) required
three courses and one patient received five induction courses. The
median time from the start of HHT therapy (14-day induction) to
the maintenance courses was five weeks (range, 2 to 18). The median
number of courses of HHT given was 6 (range, 1 to 3 3 , and 21 of
the 71 patients (30%) continue on treatment. Toxicity was graded
according to National Cancer Institute criteria.
Response criteria. Response criteria were those previously defined for 1rn-a triak2 Complete hematologic remission (CHR) required a WBC count s 10 X 103/pL and no peripheral blood blasts,
promyelocytes, or myelocytes; a platelet count S 450 x 103/pL;
Active disease. Of the 58 patients who had active disease, 42 (72%) achieved CHR with HHT therapy (Table 2).
Nine patients (16%) achieved a PHR. Of the 42 patients
attaining CHR, 16 patients (38% of CHR patients, 28% of
total patients with active disease) achieved a cytogenetic
response. This response was minimal in 9, partial in 2, and
complete in 5 patients. Thus, 7 cytogenetic responders developed a majority population of normal diploid cells. Of the 16
patients with active disease and clonal evolution, 11 (69%)
achieved CHR and 5 (29%) achieved PHR. A cytogenetic
response occurred in 3 (27%) of the 11 CHR patients, being
minimal in 2 patients and complete in 1. In 4 (25%) of
the 16 patients with active disease and clonal evolution,
metaphases remained 100% Ph+, but clonal evolution resolved with HHT therapy.
Cytogenetic response in patients in remission. Thirteen
patients had normal blood counts when they began therapy
with HHT. All 13 had100% Ph+ metaphases and 4 had
additional clones in 16% to 91 % of metaphases, Of the 13
patients, 2 had anincrease in their bloodcounts while receiving HHT and were considered therapy resistant. One patient
maintained normal blood counts, but was not considered to
be in continuing CHR because immature cells were present
in the blood. Of the remaining 10 patients, 6 developed a
cytogenetic response thatwas minimal in 2 patients and
partial in 4 patients (Table 2). Two patients who achieved a
partial cytogenetic responsehad clonal evolution that resolved.
Table 2. Response to HHT
No. of Patients ( O h )
CML patients with active disease (n
=
58)
Hematologic response
Complete
Partial
Resistant
Lowest Ph status (% metaphases)
0
1-34
35-95
100
Patients in hematologic remission with
100% Phf metaphases (n = 13)
Lowest Ph status (% metaphases)
100
35-95
1-34
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3324
O'BRIEN ET AL
Table 3. Toxic Effects of HHT
No. of Patients 1%) in
Induction Therapy
In = 71)
Toxicity
Diarrhea
(35)
Nausea/vomiting
Tachycardia or chest pain(1)
Headache
Fatigue/aches
Drug fever
(1)
Table 5. Fever or Infections With HHT
No. of Courses 1961 in
Maintenance Therapy
( n = 3961
25
10 (14)
4* 8 (11)
8 (11)
4 (6)
1
43 (11)
15 (4)
9 (2)
4 courses (maintenance) where tachycardia or chest pain occurred, only 1 documented arrhythmia was noted (bigeminy).
t Three courses (maintenance) were complicatedby drug fever but
all 3 courses were in the same patient.
Toxicity. Side effects of HHT, shown in Table 3, were
mild. Diarrhea, the most common toxic effect, occurred in
33% of induction cycles, but was usually mild (grade l) and
often required no intervention. All side effects diminished
with the subsequent maintenance courses in which HHT
was given for only 7 days. Although occasional patients
complained of vague chest pain or tachycardia (ll%), an
arrhythmia was documented in only one patient during his
tenth cycle of HHT when bigeminy was noted. He received
five more cycles of HHT without experiencing further arrhythmias. No patient had significant hypotension.
In 39% of patients, an absolute granulocyte count (AGC)
below 50OlpL developed and 20% had severe neutropenia
with an AGCbelow 100 pL during remission induction
courses (Table 4). Thrombocytopenia below 30 X 103/pL
occurred in 25% of induction courses. No serious bleeding
episodes occurred. With the reduction in days of HHT on
the maintenance phase of the therapy and adjustment in subsequent courses to reduce myelosuppression, granulocytopenia below 5001pL was noted in 9% of courses, and thrombocytopenia was noted in 5%.
Fever or documented infection occurred in 18 induction
courses (26%); 12 (67%) were associated with granulocytopenia (Table 5). During the shorter maintenance courses,
fever or infection occurred in only 8% of courses. An association with granulocytopenia was less common (21%), and
serious infections (sepsis or pneumonia) occurred in only
2% of courses.
Two patients (3%) died during HHT therapy. One patient
was a 63-year-old man who began treatment with a performance status of 2 and pneumonia. Progressive pneumonia
developed andhedied on day 7 of hisfirst course. The
Table 4. Myelosuppression With HHT
Lowest Count
Granulocytes
<5OO/pL
(20)
< lOO/pL
Platelets
<30 X 1 0 3 1 ~ ~
No. of Courses
(%1 in
fever
Induction Therapy
(n = 71)
Maintenance Therapy
( n = 331)
request
28 (39)
31 (9)
14
Induction Therapy
( n = 71)
Category
Sepsis/pneumonia
Febrile episode
Minor infections
(4)
Total
32
7 (10)
6 (8)
14
(25)
(n
=
396)
9 (2)
9 (2)
5 (7)
18
(8)
6 (2)
other patient was a 55-year-old woman in whom BM aplasia
developed after three courses of HHT. The BM was unresponsive to growth factors, and the patient died on day 1 15
with pneumonia.
Fotlow-up results. Fifty patients (70%) have hadHHT
therapy discontinued for various reasons (Table 6); in 41%,
hematologic resistance or disease evolution had developed.
The median survival of the whole population is 30 months
(Fig 1).
The course of patients who achieved a major cytogenetic
response is shown in Table 7. Four patients have been taken
off the study and seven patients continue to receive HHT.
Patient 6 had no evidence of Ph+ cells after the first course
of HHT, but later showed gradual loss of cytogenetic response and developed hematologic resistance after 18
courses of HHT; l month later, blast crisis occurred . Patient
9 had Ph- status after four cycles of HHT; he refusedfurther
therapy, and blastic phase CML developed 20 months later;
no therapy hadbeen given in the interim. Patient 10 had
10% Ph+ metaphases after receiving two courses of HHT,
but experienced prolonged and severe myelosuppression
with both courses and did notreceive further therapy. Eleven
months later, his blood counts were normal, but after another
6 months blastic-phase CML developed. Patient 11 showed
100% diploid cells after receiving one course of HHT, but
severe pneumonia developed and performance status decreased after the first course, and he received no further
therapy. He remains alive more than 30 months later with
chronic-phase CML. Thus, three of the four patients who
came off study have developed blastic phase CML and died
at 23, 24, and 30 months from the start of HHT.
The remaining seven patients have now received 7 to 35
courses of HHT. Three patients (patients l, 4, 7) continue
to have a major cytogenetic response, with one patient (pa-
Table 6. Reasons for Stopping Therapy With HHT
Reason
resistance
Hematologic
accelerated
crisis
Blast
or phase
Toxicity
Drug
Myelosuppression
Patient
transplantation
EM
(unrelated
donor)
Death
Noncompliance
No. of Patients (%l
25 (35)'
4 (6)
(10)
Tntal
18 (25)
No. of Courses (%) in
Maintenance Therapy
17 (4)
3 t (1)
* Of
No. of Patients (%) in
No. of Courses (%) in
15 (5)
* Includes nine primary resistant patients.
1 (1)
6 (8)
7
4 (6)
2 (3)
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3325
HOMOHARRINGTONINE INCML
tient 4) still showing 100% diploid cells after 18 courses of
HHT.
Table 7. Follow-up Chromosome Analysis of Major Cytogenetic
Responders (46 metaphases without Ph chromosome)
DISCUSSION
Although 95% of patients with CML show the Ph chromo95
20
some on cytogenetic analysis, the question remains as to
whether this is a secondary event or whether the presence
of the p210 protein encoded by this translocation is responsible for the development of the disease. Recent evidence
suggesting a causal relationship includes the fact that introduction of the bcr/ubl message into normal hematopoietic
cells results in their malignant tran~formation.’~
In addition,
when murine BM was infected with a retrovirus encoding
p210 bcr/ubZ and then transplanted into irradiated mice, the
recipients of this BM developed hematologic malignancies
that in some cases appeared similar to the chronic phase of
CML.” Clinical evidence supporting the Ph translocation as
the etiology of CML includes the fact that patients who do
achieve a significant cytogenetic response with IFN-a have
a longer interval before disease evolution and prolonged
survival.’ Thus, the impetus for achieving a cytogenetic remission is established. IFN-a is the only agent to date that
can elicit significant cytogenetic responses in patients with
Ph+ CML. However, once the disease becomes resistant to
IFN-a, no therapeutic modalities are available to treat these
patients other than in a palliative mode. Autologous BM
transplant may be feasible in some patients who, after chemotherapy, have a reduction in the percent ofPh’
cells.
However, the effectiveness of this in vivo purging is less in
patients with long-standing disease.I6
In this study, we have shown the significant anti-CML
efficacy of HHT. Used in a low-dose, continuous-infusion
schedule, HHT induced hematologic remissions in twothirds
of patients with late chronic-phase CML. More important,
1 1 (lS%) of 71 patients achieved significant cytogenetic
responses, and these have been maintained in 3 patients, all
of whom have completed more than I year of therapy. All
patients who achieved a cytogenetic response had normalization of blood counts. However, there wasno correlation
between severe myelosuppression and achievement of a cytogenetic response. This is in keeping with the finding that
10-
8-
6-
Patient
1 96
2
3
4
5
6
7
8
9
10
11
Total No. of
Courses
HHT
100
35
31
25
18 100
18
18
12
427
4
2
1
No. of Courses of HHT at Time of Analysis
1-2
6-8
16
60
90
IM
84
64
100
100
8
80
100
35
92
IM
84
85
100
Off study
90
Off study
100
Off study
12-14
16-20
24+
15
IM
0
IM
36
10
5
IM
Off study
0
6
Abbreviation: IM, insufficient metaphases.
most myelosuppression occurred during the initial course
and that the incidence rate of significant granulocytopenia
in a subsequent courses was only 9%. The use of high-dose
chemotherapy for early-stage CML may result in cytogenetic
responses in up to 60% of patients.” However, these response are transient and follow a prolonged period of myelosuppression as is seen with acute leukemia therapy. This
suggests that the temporary disturbance of the BM pool initiallybenefits the normal stem cells in terms of recovery
time, but that, inevitably, the malignant clone will exert its
preferential growth advantage. Interferon is the only agent
for which significant cytogenetic responses have been described in association with the lowering of blood counts to
normal range, but without significant myelosuppression.
The beneficial effects of interferon are most pronounced
in patients who are treated within 1 year of diagnosis. The
use of IFN-a in patients with late chronic-phase CML results
in CHR in 28% and inPh suppression in 5 % . ’ * No major
cytogenetic responses are seen. HHT produced significantly
more hematologic responses (72%) and cytogenetic responses (31%) in these late chronic-phase CML patients.
Moreover, 58% of the patients treated with HHT had disease
that was resistant to IFN-a, and thus, these patients represented a poor-prognosis group.
In summary, HHT produces hematologic remissions in
the majority of patients with advanced chronic-phase CML.
Cytogenetic responses may occur without an association
with myelosuppression in a minority of patients, and these
responses may be prolonged in some patients. Future studies
investigating HHT in combination with other active agents
such as IFN-a for CML are warranted.
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0
6
12
18
24
30
36
42
48
Months
Fig 1. Survival of patients from the start of HHT.
54
I
60
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1995 86: 3322-3326
Homoharringtonine therapy induces responses in patients with
chronic myelogenous leukemia in late chronic phase
S O'Brien, H Kantarjian, M Keating, M Beran, C Koller, LE Robertson, J Hester, MB Rios, M
Andreeff and M Talpaz
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