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Hematopoietic Management in Oncology Practice

Hematopoietic Management in Oncology Practice

ABSTRACT: As the major regulator of erythropoiesis in man, erythropoietin inhibits the programmed cell death of committed erythroid precursors. In cancer patients, a relative erythropoietin deficiency is coupled with a decreased responsiveness to the substance mediated by the effects of inflammatory cytokines on the marrow and on ferrrokinetics, leading to a high incidence of anemia. Two recombinant human erythropoietin (rhEPO) preparations—epoetin alfa (Epogen, Procrit) and epoetin beta (Marogen)—as well as a modified erythropoietic compound (darbepoetin alfa [Aranesp]) are in clinical use. Part 2 of this two-part series on hematopoietic agents reviews the use of these erythropoietic factors and their effect on the anemia that develops in cancer patients. Thrombopoietic factors and progenitor cell–mobilizing factors are also briefly addressed.

As noted in the first half of this
article, which appeared in the
November issue of ONCOLOGY,
the hematopoietic growth factors
have transformed the fields of nephrology,
hematology, and oncology
over the past 2 decades. In part 1 of
the article, we focused on the myeloid
growth factors-particularly recombinant
human (rh) granulocyte colonystimulating
factor (G-CSF, filgrastim
[Neupogen]) and granulocyte-macrophage
colony-stimulating factor
(GM-CSF, sargramostim [Leukine])-
and their role in decreasing the duration
of chemotherapy-induced neutropenia
in cancer patients. Part 2 focuses
on the use of recombinant erythropoietic
agents, and concludes with a brief
discussion of other hematopoietic
growth factors (ie, thrombopoietic and
progenitor cell-mobilizing factors) in
oncologic practice.

Erythropoietic FactorsBiology, Clinical Pharmacology,
and Background

Erythropoietin is the major regulator
of erythropoiesis in man. Unlike
G-CSF, erythropoietin is not a mitogenic
growth factor; it exerts its effects
by inhibiting the programmed cell
death of committed erythroid precursors.
(For this reason, recombinant
human erythropoietin [rhEPO] therapy
given synchronously with myelosuppressive
chemotherapy is not associated
with the increased marrow
toxicity that may occur when rhG-CSF
is given with chemotherapy.)

Erythropoietin deficiency is the
major or sole cause of the hypoplastic
anemia seen in patients with renal failure.
In patients with chronic illnesses
such as cancer, a relative erythropoietin
(EPO) deficiency[1] is coupled
with a decreased responsiveness to
EPO mediated by the effects of inflammatory
cytokines on the marrow and
on ferrrokinetics, leading to a high incidence
of anemia. When these patients
receive chemotherapy, the incidence
and severity of anemia increases.
Anemia is frequently encountered
in cancer patients and is a major
concern in oncology practice.

When human erythropoietin was
cloned, it was found that its in vivo
activity was severely impaired in the
absence of posttranslational glycosylation.
Therefore, rhEPO used in
clinical practice is expressed in mammalian
cells rather than bacteria. Two
rhEPO preparations are currently in
clinical use: epoetin alfa (Epogen,
Procrit) and, unavailable in the United
States, epoetin beta (Marogen). These
two preparations differ in the original
source of the purified protein used for
cloning, slightly in their isoform composition
(the proportion of the prepa-
ration that contains a given number of
sialic acid molecules), and in the stabilizers
added to the product. No clear
difference in the efficacy of the two
preparations has been demonstrated,
and the data for both products will be
included in the discussion of the effects
of rhEPO.

Based on the observation that the
in vivo potency of a given erythropoietin
isoform is directly related to
the amount of posttranslational
glycosylation, as manifested by total
sialic acid content, the erythropoietin
molecule has been modified through
site-directed mutagenesis, changing
five amino acids to add two additional
glycosylation sites. The resulting glycoprotein,
termed darbepoetin alfa
(Aranesp), has enhanced in vivo potency,
which is related to an approximately
threefold prolongation of its
half-life compared to epoetin alfa.[2]

Both rhEPO and darbepoetin alfa
have been shown to be effective in the
treatment of the anemia that occurs in
patients with renal failure on chronic
hemodialysis. Because of obvious abnormalities
in blood volume homeostasis
in this setting, a rapid rise in
hemoglobin level and red cell mass
can be associated with complications
including hypertension (with convulsions
in severe cases) and thrombosis.
Accordingly, a standard has evolved
in which the anemia of dialysis is corrected
gradually until the target hemoglobin
is achieved. Over the last 15
years, nephrology studies have demonstrated
a clear link between hemoglobin
level, and both the quality of
life and functional status of these patients.
Dialysis physicians have been
commendable in rapidly and diligently
integrating quality-of-life data into
their treatment standards and the target
hemoglobin levels they set for
patients.

Treatment Paradigms and
Transfusion Avoidance
in Cancer Patients

Prior to the introduction of rhEPO
into oncology practice, the only treatment
available for the frequently encountered
anemia was red cell transfusion.
Because of the risks associated
with transfusion, a well-ingrained
practice developed in which only severe
anemia was recognized as warranting
treatment. Understandably,
when rhEPO was introduced, oncologists
used this agent primarily to reduce
the risk of transfusion, and the
inclination was to focus on relatively
severe degrees of anemia. Although
the field has moved on to a focus on
enhanced quality of life and treatment
of mild and moderate degrees of anemia,
for statistical reasons, a reduction
in the risk of transfusion is still used
as a patient benefit end point in
phase III studies.

Initial clinical trials of rhEPO in
cancer patients demonstrated that
patients with anemia often respond
to such therapy with an increase
in hemoglobin level, regardless of
whether they are receiving chemotherapy.
These early data indicated that
patients not receiving chemotherapy
were, if anything, more responsive to
rhEPO.[3] Unfortunately, the design
of the randomized, placebo-controlled
trial involved a relatively low dose and
a treatment period of only 8 weeks,
which was insufficient to demonstrate
a statistically significant impact on the
risk of transfusion for patients not receiving
chemotherapy.[4] This historical
oversight has had a lasting impact
on the field; at present, no erythropoietic
agent has been approved in any
country for the treatment of cancerrelated
anemia in patients not receiving
chemotherapy, despite its apparent
safety and efficacy. Moreover,
much less data is available on the optimal
dose or effects on quality of life
of these agents in this important subset
of anemic cancer patients.

Optimal Dosing of rhEPO
In the early trials of rhEPO for anemia
during chemotherapy, doses of 25,
50, 100, 200, or 300 U/kg five times
weekly for 4 weeks or a total dose of
approximately 10,000 to 120,000 U/wk
were studied.[5,6] The data suggested
a relationship between dose and the
proportion of patients in whom a given
increase in hemoglobin concentration
was observed. Pilot randomized trials
comparing low doses (2,000 to
3,000 U) to higher doses (6,000 to
10,000 U) administered three times
weekly suggested that the higher doses
were more effective in terms of increasing
hemoglobin levels.[7,8] Perhaps
because of cost considerations or
difficulty in administering higher
doses of rhEPO given current preparations,
no definitive study has followed-
up on the early observation that
high response rates were observed
with rhEPO doses of 100,000 U/wk
or greater. The doses of rhEPO taken
forward into phase III studies became
the current standard, but they were not
necessarily the optimal doses for cancer
chemotherapy patients.

In the pivotal randomized, placebo-
controlled trials of rhEPO for
cancer chemotherapy patients, a starting
dose of 150 U/kg or approximately
10,000 U three times weekly
for 12 weeks, with a dose increase to
300 U/kg three times weekly in nonresponding
patients, was shown to be
associated with a reduction in transfusion
risk.[4,9,10] Similar results were
reported in trials that did not include the
dose increase,[11] and no randomized
trial has documented the efficacy of
dose increases of the magnitude used
in these phase III studies. Given that the
response to rhEPO at doses of 10,000 U
three times weekly can take 10 weeks
or more to occur, it remains possible that
responses observed after dose doubling
would have occurred had the dose not
been doubled.

The findings of the phase III trials
have been confirmed in two large, uncontrolled,
community-based studies in
which a decrease in transfusion rate was
observed during therapy.[12,13] More
recently, a large, uncontrolled community-
based study that used a fixed starting
dose of 40,000 U/wk, with a dose
increase in nonresponding patients to
60,000 U/wk has suggested that similar
results in terms of hemoglobin increase
and transfusion requirements can
be achieved with weekly dosing.[14]
Although this approach has not been
compared to placebo or to three-timesweekly
dosing in randomized trials-
and this dose and schedule therefore
does not appear on the label-it is used
in clinical practice in the United States
for chemotherapy patients. Most clinicians
believe that it produces results
similar to the historical experience with
three-times-weekly dosing.

Recently, a large, well-designed randomized
trial conducted in patients with
lymphoid malignancies compared
rhEPO starting doses of 10,000 U three
times a week to a single weekly dose of
30,000 U.[15] The results suggest that
the two approaches produce equivalent
results in this subset of oncology patients,
and call into question the unproven
assumptions that underlie the
use of an increased weekly dose as
employed in the community-based
study. This is an important point that
requires confirmation and has major
cost implications. If rhEPO given
weekly at a dose of 30,000 U produces
results indistinguishable from a dose of
10,000 U administered three times a
week, we may be able to achieve our
current level of patient benefit with 25%
less cost.

Darbepoetin Alfa
Darbepoetin alfa has been compared
to placebo in two randomized
placebo-controlled clinical trials, in
patients with lung cancer who were receiving
platinum-based chemotherapy[
16] and in patients with lymphoid
malignancy receiving chemotherapy.[
17] Darbepoetin at 2.25 μg/kg/wk,
with dose doubling permitted in nonresponders,
was associated with an increase
in hemoglobin and a significant
reduction in transfusion requirements.
As with rhEPO, the contribution of the
dose increase to patient benefit has not
been demonstrated.

In a phase II, placebo-controlled
trial in patients with lymphoid malignancy,
three doses of darbepoetin alfa
(1, 2.25, and 4.5 μg/wk) appeared to
be superior to placebo in terms of hemoglobin
increase and transfusion
risk.[18] The phase III lung cancer trial
was the basis for the current Food and
Drug Administration approval of
darbepoetin alfa for the treatment of
cancer chemotherapy patients.

In a recent large phase II study in
cancer patients receiving chemotherapy,
the dose-response relationships
for darbepoetin alfa administered
every 1 or 2 weeks were characterized.[
19,20] A clear relationship
was evident between dose and the
magnitude of mean increase in hemoglobin
in each cohort until a dose of
4.5 μg/kg/wk or 9 μg/kg every 2 weeks
was reached; above these "optimal"
doses, further increases in efficacy were
not observed. These trials were randomized
and included a control group
treated with epoetin alfa administered
at starting doses of either 150 U/kg
three times weekly or 40,000 U/wk,
with dose increases permitted for
nonresponding patients. To date, this is
the only randomized trial to compare
various fixed doses of darbepoetin alfa
with the current standard for the use
of rhEPO. In this randomized trial, the
lowest dose of darbepoetin alfa to produce
an increase in hemoglobin indistinguishable
from that achieved with
40,000 U/wk of rhEPO was 3 μg/kg
(~200 μg per dose) given every
2 weeks.

A subsequent larger, communitybased
study has demonstrated similar
hemoglobin responses at this dosage,
with an increase to 5 μg/kg every 2
weeks in nonresponding patients.[21]
Although this approach has not been
compared to placebo in a randomized
clinical trial and is not the label dose
and schedule, it is the darbepoetin regimen
currently used in the United
States in chemotherapy patients. The
lack of a significant difference in the
efficacy of this dosing of darbepoetin
alfa vs standard dosing of epoetin alfa
is the subject of an ongoing large randomized
trial. Darbepoetin alfa can be
administered as infrequently as every
3 weeks with hemoglobin responses
noted in chemotherapy patients, although
the every-3-week dose, which
produces responses similar to those
achieved with current rhEPO dosing,
has not been established in a randomized
trial.

The data linking mild anemia to
fatigue and a decreased quality of life,
and moderate and severe anemia to a
worsening of these symptoms and an
increased risk of transfusion are compelling.[
22] They support a practice
policy of early intervention in patients
receiving chemotherapy with either
rhEPO at a weekly dose of 40,000 U
(an alternative being 10,000 U thrice
weekly) or darbepoetin at a dose of
200 μg administered every 2 weeks (an
alternative being 100 μg weekly).

Improving Schedules to Enhance
Quality of Life and Functional
Status in Cancer Patients

The most important advance in anemia
management over the past 5 years
has been the recognition-initially
resisted due to deeply ingrained prejudices
and clinical habits-that mild
and moderate degrees of anemia
(hemoglobin concentrations of 10 to
12 g/dL) are associated with significant
levels of fatigue and compromise
quality of life and functional status in
cancer patients. More importantly, it
has become clear that treatment of anemia
is associated with significant improvement
in fatigue and quality of
life.[9,10,13,14,22,23] In retrospect,
this should not have been surprising;
the relationship between hemoglobin
and symptom status in humans had
been well characterized in the setting
of dialysis a decade earlier, and there
were no grounds to assume that cancer
patients would be different.

Recently, data from more than
4,000 cancer chemotherapy patients
treated with rhEPO three times weekly
have been analyzed to characterize the
relationship between hemoglobin level
and quality of life in this population
(Figure 1).[24] The results demonstrate
that as the hemoglobin level rises
from 8 to 12 g/dL, quality of life and
energy level improve; the greatest gain
occurs as the hemoglobin level rises
from 11 to 12 g/dL. Stated another way,
the levels of anemia that we are most
prone to ignore in oncology practice are
those associated with the greatest symptoms
and the greatest opportunity for
benefit, if treated. Despite these data,
standards similar to those developed by
nephrologists for dialysis patients have
not been developed in oncology, and
many, if not most, chemotherapy patients
with hemoglobin levels less than
10 g/dL receive no hematopoietic treatment,
with milder degrees of anemia
even more likely to go untreated.

Tailoring Therapy in
the Cancer Setting

One possible explanation for the
lower level of enthusiasm for erythropoietic
therapy in the oncology
community may be that, unlike the
situation in nephrology, the optimal
approach to treatment for the cancer
patient has not been developed. Cancer
chemotherapy patients are usually
treated for 20 weeks or less, and in cancer
patients the erythron is relatively
resistant to therapy. The dose-finding
studies of darbepoetin alfa demonstrated
that a clear relationship exists
between dose and the rapidity of response
and that when an intent-to-treat
analysis is performed on the data, the
median time to response (defined as a
hemoglobin increase of 2 g/dL not due
to a red cell transfusion) with the doses
of rhEPO or darbepoetin alfa currently
employed is approximately 10 weeks.
When optimal doses of darbepoetin
alfa were given, the median time to response
was 7 weeks, and the overall
proportion of responding patients was
greater.[20] Because no known complications
are associated with rapid increases
in hemoglobin in patients with
adequate renal function, the treatment
of anemia in the setting of cancer chemotherapy
may require higher, more
effective initial doses of either rhEPO
or darbepoetin alfa than have been
used, with doses decreased once symptomatic
relief and an increase in hemoglobin
level have been achieved
(Figure 2).

A pilot randomized trial of this
"front-loaded" dosing paradigm, tailored
to drug efficacy and safety profiles
and the unique requirements of
the anemic, symptomatic oncology
patient has been published, with results
suggesting that this approach will
be superior; a large, randomized controlled
trial is in progress.[25] Unlike
dialysis patients, chemotherapy patients
are treated with erythropoietic
agents for weeks, not years; an approach
tailored to their needs should
be characterized by both a high proportion
of responders and a rapid response,
especially when patients are
significantly symptomatic.

Another equally rational strategy
for optimizing the quality of life and
functional status of cancer patients
would be to initiate erythropoietic
agents much earlier in the course of
anemia, before significant symptoms
develop (ie, hemoglobin levels between
11.5 and 12 g/dL) and when
lower doses of agent administered less
frequently are likely to arrest the decline
in hemoglobin level. The current
practice, in many centers, of withholding
therapy until patients are compromised
and hemoglobin levels are less
than 10 g/dL, is clearly not best for patients.
Paradoxically, this "late-intervention"
approach, which is often defended
as being resource-conserving,
may be misguided and actually increase
costs by necessitating more aggressive
dosing of erythropoietic agents
to rescue severely symptomatic patients
at imminent risk for transfusion. Early
intervention trials with both rhEPO and
darbepoetin alfa are in progress.

Myelodysplastic Syndromes

Chronic, hypoplastic anemia associated
with myelodysplastic syndrome
(MDS) is a common and difficult
problem in oncology practice. Patients
with this disorder are frequently elderly,
tolerate anemia poorly, become
transfusion dependent, and develop
complications of transfusion including
alloimmunization and iron overload.
Sufficient data have accumulated regarding
rhEPO therapy in this setting
to demonstrate that it is safe, and not
associated with an increased risk of
progression to acute leukemia or with
lineage steal. Unfortunately, rhEPO
therapy is frequently ineffective, failing
to increase hemoglobin levels in
approximately 60% of patients.[26]

Recombinant human erythropoietin
doses of 200 to 3,000 U/kg/wk
administered intravenously, and 150 to
2,000 U/kg administered subcutaneously
have been studied, with hemoglobin
increases noted mainly at doses
of at least 60,000 U/wk and primarily
in the subset of MDS patients with
refractory anemia and sideroblastic
anemia.[27-35] As noted above, the
addition of myeloid growth factor to
rhEPO therapy appears to be safe and
may increase the erythropoietic response
in patients with MDS.

For patients with symptomatic refractory
anemia without excess blasts,
it is reasonable for the clinician to initiate
an 8-week trial of rhEPO therapy,
with or without myeloid growth factor
therapy, utilizing the highest dose
that is feasible in the particular reimbursement
environment.[36,37] For
responding patients, therapy can be
continued and doses adjusted to maintain
an asymptomatic hemoglobin
level. No data are available for
darbepoetin alfa in this setting.

Safety of Erythropoietic Agents
in Hematologic Oncology

In cancer patients who do not also
have renal failure, rhEPO and
darbepoetin alfa therapy have been
extraordinarily well tolerated. In placebo-
controlled studies, a significant
increase in hypertension, convulsions,
or thrombosis has not been noted, and
in studies published to date, there is no
suggestion of any association between
toxicity and a rapid rise in hemoglobin
level. These observations are important,
as they point the way to the
development of treatment paradigms
tailored to the need of cancer patients.
In most studies to date, rhEPO and
darbepoetin alfa therapy have been associated
with injection site pain. In randomized
trials, no difference between
the safety profiles of rhEPO and
darbepoetin alfa has been observed.

Pure Red Cell Aplasia
Recent reports from Europe have
described an increase in the incidence
of pure red cell aplasia (PRCA) in
dialysis patients undergoing erythropoietic
therapy.[38] This syndrome, which
is associated with the development of
antibodies that neutralize the effects of
endogenous erythropoietin, rhEPO, and
darbepoetin alfa, had previously occurred
with a very low frequency in
patients receiving rhEPO. The increase
in incidence observed over the past 3
years has been traced to a particular new
preparation of epoetin alfa, which had
been developed to eliminate the need
for human albumin as a stabilizing
agent and to address the theoretical
risk of prion-mediated disease transmission
in Europe.

It is important to note that no increase
has occurred in the incidence
of PRCA associated with epoetin beta
or the epoetin alfa preparation used in
the United States and that PRCA has
not been documented in any cancer
patients with any preparation. To date,
PRCA has not been reported in any
patient treated with darbepoetin alfa
who had not also received the new
epoetin alfa preparation.

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