ERYTHROPOIETIN 0889-8588/94 $0.00 + .

20

BONE
TRANSPLANTATION
Carole B. Miller, MD, and Sharon Mills, RN, BSN

Bone marrow transplantation is the treatment of choice for selected

patients with high-risk malignancies, including patients with leukemia22.
23.51,57 and lymphoma. 16,28 All patients develop anemia after both autolo-
gous and allogeneic bone marrow transplantation, and red blood cell
transfusion is universal in the post-transplant period. The etiology of the
anemia after bone marrow transplantation is multifactorial, with both
increased utilization and inadequate production of red blood cells play-
ing roles.
Increased utilization of red blood cells occurs as a result of toxicities
of the chemotherapy and immunosuppression. Bleeding is common after
bone marrow transplantation, both as a result of thrombocytopenia and
of direct organ toxicities. Hemorrhagic cystitis31 , 54 is a common compli-
cation after bone marrow transplantation, caused by either a cyclophos-
phamide metabolite, acrolein31 which is directly toxic to the bladder
mucosa, or viral infections, including adenovirus3 and BK virus. 6 Hemor-
rhagic cystitis occurs in 10% to 40% of patients after bone marrow trans-
plant, and when severe in approximately 25% of the cases it can cause
massive hemorrhage with a marked increase in transfusion require-
ments. Gastrointestinal bleeding related to graft-versus-host disease,
viral infections, or gastritis is also an important source of blood loss in
these patients. 24, 37 Thrombocytopenia contributes to excess blood loss
and may be related to decreased platelet production, which may be
protracted in patients after autologous bone marrow transplant with
chemically purged marrow grafts,5o,57 or to immune destruction/' 8, 20 or
to veno-occlusive disease of the liver.27
Another cause of anemia in this population is increased destruction

From The Johns Hopkins Oncology Center, Baltimore, Maryland

HEMATOLOGY /ONCOLOGY CLINICS OF NORTH AMERICA

VOLUME 8 • NUMBER 5 • OCTOBER 1994 975

976 MILLER & MILLS

of red blood cells by hemolysis related to blood group incompatibil-

ity,J3,15 microangiopathy associated with drugs (cyclosporine A)/5 or an
idiopathic hemolytic uremic syndrome. 48
Inadequate production of red blood cells is a primary cause of ane-
mia after bone marrow transplant. After the marrow graft is infused, for
a period of time the marrow stern cell reserve is decreased36, 55 and the
erythroid-producing cells are repopulating the marrow. 5 This is demon-
strated by a period of reticulocytopenia,s which depends on the type of
marrow graft. After an autologous bone marrow transplant with marrow
purged with 4-hydroperoxycyclophosphamide (4HC), the time for recov-
ery of reticulocytes to greater than 2% is 36.4 ± 7.3 days49 and is corre-
lated with hematopoietic progenitor recovery in vitro after treatment
with 4HC. 49 The time to reticulocyte recovery is generally earlier (24 to
28 days) in patients who receive unmanipulated autologous marrow
grafts?5
After allogeneic bone marrow transplant, the recovery of granulo-
cytes generally occurs within 3 to 4 weeks after marrow infusion22, 51;
however, erythroid recovery is often delayed despite adequate erythroid
progenitors present in the marrow as early as 2 weeks after marrow
reinfusion. 9,55 The median time to a reticulocyte count of greater than 2%
in 50 consecutive patients after allogeneic bone marrow transplant at
Johns Hopkins was 31 days, whereas the median time to 500 neutrophils
in the same patients was 17.5 days.
The number of red blood cell transfusions administered after bone
marrow transplants is variable. Table 1 demonstrates transfusion require-
ment in different centers for allogeneic and autologous transplants. For
each type of transplant, a number of factors may influence the transfu-
sion requirement, including treatment and incidence of graft-versus-host
disease, preparative and purging regimens, and viral infections. Also,
recipient-donor blood group compatibility is an important predictor of
the red blood cell transfusion requirement. In a study of 81 patients with
aplastic anemia receiving allografts,s6 the median number of red blood
cell units transfused after transplant was 4.5, 12, and 17.5 units in ABO-
compatible, minor blood group-incompatible and major blood group-
incompatible transplants, respectively. In this cohort of patients, the only
other predictor of an increased red blood cell transfusion requirement
was older recipient age.
Although many factors influence erythroid recovery after bone mar-
row transplantation, the prolonged reticulocytopenia and resultant large
transfusion requirement after bone marrow transplantation is in part
related to a relative erythropoietin deficiency at a time of marrow recov-
ery.
We studied the erythropoietin response in 70 patients after bone
marrow transplantation as compared with the erythropoietin response to
anemia in iron-deficient controls. 40 Figure 1 shows the time course of the
erythropoietin and hemoglobin levels in the patients.
When the whole group of transplant patients are considered, eryth-
ropoietin levels were appropriate for the hemoglobin level pretransplant.
At the time of bone marrow reinfusion after the cytotoxic therapy, eryth-
 ERYTHROPOIETIN AFTER BONE MARROW TRANSPLANTATION 977

Table 1. RED BLOOD CELL TRANSFUSION AFTER ALLOGENEIC OR AUTOLOGOUS

BONE MARROW TRANSPLANTATION
No.
Reference Patients Disease Units RBC

Johns Hopkins 50 AL, CML 21

allogeneic
Storb 20 AA 15 (3-37)
allogeneic 20 AL 10.5 (3-25)
12 CML 18.2 (7-42)
Ireland
allogeneic 11 CML, AL 12.6
autologous 6 ST, AL, LY 9.0
Schapira
allogeneic 17 CML, AL, LY 8 (0-17)
autologous 14 ST,LY, AL, BR 12 (8-19)
Abedi
allogeneic 36 CML, AL 13 (2-52) TCD
4 (0-14)
non-TCD
Petz
allogeneic 125 AL, CML 6.6
Davis
autologous 20 AL 30 ± 29
20 LY 14 ± 8
Benson
autologous 10 BR 12.7
9 ST,AL, LY 21.7
Carey
autologous 34 LY 4

AL = acute leukemia; CML = chronic myelogenous leukemia; LY = lymphoma; AA = aplastic

anemia; BR = breast cancer; ST = solid tumor; TCD = T cell-depleted

400 16

"' 15
:::J 300
E "' 14
Figure 1. Summary of mean ± :s :::J
standard deviation erythropoietin 5- :1::)
200 .9
(solid line) and hemoglobin (dot- ~ 13 c
~
/ ~
ted line) levels in the bone marrow :0
0
transplant patients over time. ~ <+ "' 12
'5l
0
'8. 100

"
Erythropoietin hemoglobin ratios E
OJ
that were significantly different e ~
:c
from pretransplant ratios are des- ~ 11
~~~
",
ignated by an asterisk." (From UJ
o
~~~
....... ..;. ... ,"
Miller CB, Jones RJ, Burns WH, " 10
et al: Impaired erythropoietin
(EPO) reponse after bone marrow
transplantation (BMT) [abstract]. -100 9
Exp Hematol 18:700, 1990; with PRE 2 3 4 5
permission.) Transplant Week
 978 MILLER & MILLS

ropoietin levels were markedly elevated even without anemia, and there
was no correlation between serum erythropoietin and the hemoglobin
level. The marked erythropoietin elevation was independent of the trans-
plant conditioning regimen or use of radiation therapy or type of trans-
plant (allogeneic versus autologous) and persisted for approximately 2
weeks after conclusion of the high-dose cytotoxic chemotherapy. This
increase in erythropoietin levels without anemia has been described by
other investigators.9 , 14, 26, 52 The cause of this increase is unknown and
appears unrelated to hepatotoxicity.
Over the next 2 weeks, erythropoietin levels in most patients de-
creased. At weeks 4 and 5 after transplant, the expected inverse relation-
ship between hemoglobin and erythropoietin levels as seen in the iron-
deficient controls was again not seen. Instead, erythropoietin levels were
correlated with only bilirubin levels, and patients with elevated bilirubin
showed a marked increase in serum erythropoietin. The increased eryth-
ropoietin levels in association with hepatic dysfunction after bone mar-
row transplant is similar to the extreme elevations in erythropoietin
levels seen in anephric renal failure patients who develop hepatitis. 3D
When bone marrow transplant patients with hyperbilirubinemia were
excluded (serum bilirubin greater than 2 mg/ dL), at the time of projected
marrow recovery, for any given degree of anemia, erythropoietin levels
were depressed in both allogeneic and autologous bone marrow trans-
plant patients as compared with iron deficient controls (Fig. 2). This
depressed erythropoietin response to anemia was not related to clinical
nephrotoxicity. In contrast to others/,14 we found no difference in the
erythropoietin response to anemia in allogeneic versus autologous trans-
plants at our center. Within the allogeneic bone marrow transplant pa-
tients, the erythropoietin response to anemia was more severely de-
pressed in patients with acute graft-versus-host disease as compared
with patients without acute graft-versus-host disease.
This depressed erythropoietin response to anemia persisted up to 1

1000

:::J
l'
::::>
S
a;
>
Q)
....J
t:
• ... Figure 2. The erythropoietin he-
moglobin relationship week 4 and
"-ai
·0 a· •• 5 after bone marrow transplant
c.
e
.<::
E-
Q)
•
•
..••..• compared with erythropoietin he-
moglobin relationship in iron-defi-
cient patients represented by the
OJ shaded area. (From Miller CB,
0
....J Jones RJ, Burns WH, et al: Im-
10 paired erythropoietin (EPO) re-
•
sponse after bone marrow trans-
5
8 9 10 11 plantation (BMT) [abstract]. Exp
Hematol 18:700, 1990; with per-
Hemoglobin (g/dL) mission.)
 ERYTHROPOIETIN AFTER BONE MARROW TRANSPLANTATION 979

after bone marrow seen at

6-month visit remained anemic below 11 g/
dL). Allogeneic bone marrow transplant patients were more likely to be
anemic at the 6-month visit than were autologous bone marrow trans-
plant patients (20 of 28 versus 4 of 13, P = 0.01). The erythropoietin
response to anemia in the anemic patients remained markedly depressed
as compared with iron-deficiency controls (Fig. 3). Although only a small
percentage of patients were anemic at the 12-month visit, anemic patients
continued to have an inappropriately low erythropoietin response for
the degree of anemia.
These data, in conjunction with those of others,9' 14, 26, 52 show that at
the time of erythroid recovery, there is inadequate stimulation of ery-
throid progenitors owing to inappropriately low endogenous erythro-
poietin levels. The cause of the inadequate erythropoietin response to
anemia is not known, but it may be related to a toxic effect on erythro-
poietin-producing cells owing to drugs or infection, or it may be related
to direct suppression of erythropoietin production by cytokines. Tumor
necrosis factor and other cytokine levels are often elevated after bone
marrow transplant19 and can suppress erythropoietin production in the
Hep3B cell line. 18
Regardless of the etiology, the inadequate erythropoietin response
to anemia after bone marrow transplant suggests that exogenous recom-

1000

::::J
E
:3
E-
O)
>
(])
....J 100
C
~
'0
0.
2
.c
~
(])
0)
0
....J

10
III

5
7 8 9 10 11
Hemoglobin (g/dL)

Figure 3. The erythropoietin hemoglobin relationship in anemic patients at the 6 month

(circ/es) and 12 month (squares) follow-up visits compared with the erythropoietin hemoglo-
bin relationship in iron-deficient patients represented by the shaded area. (From Miller CB,
Jones RJ, Burns WH, et al: Impaired erythropoietin (EPO) response after bone marrow
transplantation (BMT) [abstract]. Exp Hematol18:700, 1990; with permission.)
980 MILLER & MILLS

binant human erythropoietin treatment may be beneficial in patients

after bone marrow transplant.
Recombinant human erythropoietin (rHuEPO) has been effective in
improving erythroid recovery and decreasing transfusion requirements
in patients receiving conventional-dose chemotherapy. 1, 2, 17,43,47 As well,
rHuEPO is effective in the treatment of the anemias associated with other
chronic diseases such as HIV infection21 and rheumatoid arthritisP' 46
Data on the use of rHuEPO after bone marrow transplantation will be
summarized.

ALLOGENEIC BONE MARROW TRANSPLANT

The first report of the use of rHuEPO after bone marrow transplant
was published in 1992. Link et aP2 reported preliminary data showing
an increased reticulocyte count and decreased time of red blood cell
transfusion support in 12 patients treated with rHuEPO after allogeneic
bone marrow transplant as compared with 44 historical controls. Two
dose schedules were used in this trial: 150 units per kilogram two times
a week, and 100 units per kilogram by continuous infusion.
We began a pilot trial of rHuEPO in patients after allogeneic bone
marrow transplant from an HLA-identical sibling donor for chronic my-
elogenous leukemia, acute lymphocytic leukemia, and acute myeloge-
nous leukemia?9 The trial was discontinued after 18 patients were
entered because of a patent dispute. We compared transfusion require-
ments in patients treated with rHuEPO with the 50 consecutive adult
allogeneic bone marrow transplant patients transplanted for the same
diseases in the preceding 18 months. rHuEPO was given intravenously
five times a week at a dose of 100 U /kg starting day 5 after bone marrow
transplant. Dosing was changed to 150 U /kg three times a week after 4
weeks and was continued for a maximum of 10 weeks or until the
hematocrit was greater than 35% for a week without blood transfusion.
rHuEPO was restarted if hematocrit fell below 30%. After 12 patients
were treated, a planned dose escalation to 200 U /kg for the first 4 weeks
followed by 300 U /kg three times a week was done. Six patients were
treated at this dose level. Study patients were transfused according to
the same guidelines used in the historical controls by an independent
transfusion service. Generally, patients were transfused to maintain a
hematocrit of approximately 30% while aplastic and 25% after WBe
recovery. With use of these transfusion guidelines, the median number
of red blood cell transfusions in the historical controls during the study
period (day 5 to day 82 post transplant) was 18 units.
All patients engrafted promptly. The median time to 500 granulo-
cytes was not different in the treated group versus the controls (17 days
versus 17.5 days, P = 0.43, Wilcoxon rank sum test). Interestingly, the
median time to 1000 leukocytes was less in the rHuEPO patients as
compared with controls (13.5 days versus 17 days, P = 0.03).
The time course of corrected reticulocyte recovery is shown for all
 ERYTHROPOIETIN AFTER BONE MARROW TRANSPLANTATION 981

with historical controls in 4. The median time

to corrected count of greater than was 19 in the
rHuEPO-treated group as compared with 31 in the control
(P = 0.005, Wilcoxon rank sum test).
Although there was evidence of enhanced erythropoiesis, there was
no significant differences in either the mean (15.8 versus 18.7, P = .42,
Student's T-test) or median (14 versus 18, P = 0.22, Wilcoxon rank sum
test) red blood cell transfusion requirement at day 5 to day 82 after trans-
plant (study period) between the rHuEPO-treated patients and controls.
Three randomized trials of rHuEPO after allogeneic bone marrow
transplant have been completed. The first randomized trial was reported
by Steegman et aP3 in 1992. Twenty-eight patients undergoing allogeneic
bone marrow transplant for hematologic malignancies were randomly
assigned to rHuEPO (100 U /kg day 0 to 7, 150 U /kg day 7 to 30) or
placebo. Thirteen rHuEPO and 11 placebo patients received greater than
14 days of treatment and were considered evaluable. There was a signif-
icant improvement in time to a reticulocyte count of 1%, 5%, and 20%
related to rHuEPO, as well as an increase in bone marrow erythroid
cellularity. This improvement in erythropoiesis led to a significant de-
crease in red blood cell transfusion requirements from a mean of 12 units
to 4 units (P < 0.05) during the first 30 days. There was also a significant
improvement in the time to an untransfused platelet count of greater
than 25,000/mm3 (19 days versus 31 days, P < 0.05) in the rHuEPO

7
~
~
C 6
:::l
0
0
(J) 5
:;,
u
..Q
:::l
U
~
0:
"0
{!J 2
~
0
0

10 20 30 40 50 60 70 80 90
Day After BMT

Figure 4. Mean ± standard deviation corrected reticulocyte count for the first 50 days after
bone marrow transplantation in rHuEPO treated allogeneic bone marrow transplant pa-
tients '8 compared with non-rHuEPO treated historical controls (narrow line = control; heavy
line rHuEPO). (From Rowley SO, Zuehisdorf M, Braine HG, et al: CFU-GM content of
bone marrow graft correlates with time to hematologic reconstitution following autologous
bone marrow transplantation with 4-hydroperoxycyclophosphamide-purged bone marrow.
Blood 70:271-275, 1987; with permission.)
982 MILLER & MILLS

patients, and a significant decrease in platelet units required (36 versus

138, P < 0.05). rHuEPO was well tolerated without significant side ef-
fects.
Klaesson et aF9 treated 50 patients with hematologic malignancies in
a randomized, blinded trial. Patients were treated with rHuEPO (200 U /
kg) or placebo daily for 4 weeks followed by twice weekly for 4 weeks
starting the day of bone marrow transplant. The dose was decreased to
100 U /kg when the hemoglobin was greater than 10 g/ dL and discontin-
ued when the hemoglobin was greater than 12 g/ dL. Baseline character-
istics were not different between rHuEPO-treated patients and placebo
patients. Five patients (three rHuEPO and two controls) died before day
28 and were not considered evaluable. Red blood cells were transfused
to maintain hemoglobin of greater than 7.0 g/ dL, and platelets were
transfused to maintain a count of greater than 30,000/mm3 • Engraftment
parameters and transfusion requirement are summarized in Table 2.
Despite no significant improvement in reticulocyte recovery, there was a
significantly higher mean hemoglobin at month 2 in the rHuEPO-treated
patients as compared with placebo patients and a 50% decrease in red
blood cell transfusion requirement. There was no effect on platelet trans-
fusion requirement or neutrophil recovery.
Cost analysis was performed. The estimated cost of rHuEPO was
$5,405 per patient. Each unit of red blood cells is estimated to cost $175
(excluding cost of infusion). Total red blood cell cost savings was $725 if
all units were given on an inpatient basis without a separate infusion
cost. Quality of life measurements related to improved hematocrit were
not evaluated.
Ninety-one consecutive adult patients receiving a matched related
allogeneic bone marrow transplant for acute and chronic leukemia or
aplastic anemia were randomized by Biggs et apa, 11 to either placebo or

Table 2. ENGRAFTMENT AND TRANSFUSION SUMMARY29

rHuEPO Placebo
(n=22) (n=23) PVa!ue

Days to WBC > 200/mm 3 16 (10-23) 17 (10-23) ns

Days to neutrophils > 500/mm3 20 (15-34) 20 (14-32) ns
Reticulocytes (%)
at day of BMT 0.2 0.6
mean month 1 1.0 1.1 ns
mean month 2 2.7 2.9
Days to reticulocytes > 2% 15 17 ns
Mean hemoglobin (g/dL)
at day of BMT 8.3 8.7 ns
mean month 1 8.7 8.4 ns
mean month 2 10.0 9.0 0.02
Mean RBC transfusions 5 ± 5 10 ± 9 0.04
Days to RBC independence 17 30 0.03
Mean platelet transfusions 16 ± 12 17 ± 15 ns
Days to platelet independence 24 29 ns

ns = not significant
 ERYTHROPOIETIN AFTER BONE MARROW TRANSPLANTATION 983

rHuEPO (300 U /kg) three times a week from 0 to day

42. The study was held if rose to greater than 12 g/ dL
and was reinstituted at a 50% dose reduction when hemoglobin fell
below 12 g/ dL. Four patients died prior to day 28 and were not evalua-
ble for engraftment. Neutrophil and platelet engraftment and days of
hospitalization were the same between the two groups (Table 3). Median
hemoglobin levels and reticulocyte counts were not different between
the two groups before day 14; however, at all other time points, hemo-
globin and reticulocyte counts were significantly higher in the rHuEPO
group. Marrow cellularity was evaluated blindly, and the myeloid/ ery-
throid ratio was significantly reversed in the rHuEPO-treated patients by
day 21. Despite this significant enhancement of erythroid activity, red
blood cell transfusion requirement was not improved over the study
period (see Table 3). This may be in part related to the short length of
follow-up and the time it takes to see a response to rHuEPO. There was
also no effect on platelet transfusion requirement or blood pressure.
Although serum iron and transferrin were not different in the two
groups, median ferritin level at day 42 was significantly lower in the
rHuEPO-treated patients than in controls (1740 versus 3419, P = 0.0005).
It was concluded that although rHuEPO had a real effect on erythropoi-
esis, it may be most effective given later after neutrophil and platelet
recovery. A study looking at delayed erythropoiesis will be summarized
later in this review.
Two studies evaluated the effect of rHuEPO on homologous blood
requirement. Mitus et al44 studied 11 donor recipient pairs in a pilot trial.
Donors were treated with rHuEPO at a dose of 300 U /kg subcutaneously
five times a week starting 3 weeks before bone marrow harvest and
continuing until 2 weeks after harvest, for a total of 25 doses. One unit
of red blood cells was collected on the first day of the study and then
two times a week for the duration of the study, provided that the he-
matocrit was greater than 33%. The recipients were treated with rHuEPO
(200 U /kg) daily for 28 days starting on day 1 after bone marrow trans-
plant.
Two donors withdrew from the study after 15 and 19 doses of
Table 3. ENGRAFTMENT AND TRANSFUSION SUMMARY"
rHuEPO Placebo
(n=48) (n = 43) PValue

Days to platelets> 50,000/mm 3 26 29 ns

Days to neutrophils > 500/mm3 20 20 ns
Mean RBC transfusions 6 ± 5 7 ± 5 ns
Mean platelet transfusions 11 ± 9 11 ± 7 ns
Median ferritin (mg/mL)
pretransplant 873 741 ns
day 21 2052 2423 ns
day 42 1740 3419 0.005
Hemoglobin level day 21 (g/dL) 10.35 9.75 0.025
Absolute reticulocyte count day 21 (x 109 ) 63.1 24 0.005

ns = not significant
984 MILLER & MILLS

rHuEPO. All 11 donors were able to donate blood, with a median of six
units donated (range, 4 to 11). Five of the 11 donors required one or two
units after the harvest, and 5 of the 11 recipients received only donor-
derived transfusions. Total red blood cell requirement during the 28-day
study period was not different between the rHuEPO patients and
matched historical controls (8.3 versus 8.1 units, respectively). However,
there was a trend to a decrease in homologous units (4.5 versus 8.1 units)
in the rHuEPO patients. There was improvement in time to reticulocyte
recovery in the rHuEPO patients; however, there was no effect on plate-
let or neutrophil recovery or number of platelet units required.
York et aP8 treated 10 marrow donors (two children and eight
adults) with 100 U/kg of rHuEPO daily prior to harvest. Patients were
selected for the protocol if they weighed less than 30 kg and did not
have a unit of autologous blood stored prior to harvest, or if they were
anemic (hematocrit less than 37%) with one stored unit, or if a high
blood loss was expected. Donors were treated after harvest with rHuEPO
150 U /kg three times a week for 2 weeks or until the hematocrit reached
40%. Each rHuEPO-treated patient was compared with two computer-
generated matched controls. Seven of the 10 patients completed the pre-
scribed course of rHuEPO. No attempt was made to collect autologous
units for transfusion to the recipient. Table 4 shows the effect of rHuEPO
on hematocrit and blood transfusion. Although there was a marked
improvement in hematocrit in donors who were treated with rHuEPO,
and there was no homologous blood use in this high-risk group of
patients, none of the adult control donors required homologous blood
either. However, in the children, neither of the rHuEPO-treated donors
required blood, whereas two of the four controls did. In the adult donor
population, where one unit of blood can be stored, the risk of homolo-
gous blood use is small, and rHuEPO is not indicated in these patients
unless blood products for recipient use after harvest are required. How-
ever, rHuEPO may be useful in children, who generally do not bank
autologous blood, or in adults who are unable to bank autologous units.

AUTOLOGOUS BONE MARROW TRANSPLANTATION

Ayash et aF have completed a pilot trial of rHuEPO after unpurged
autologous bone marrow transplantation for solid tumors. Eleven pa-

Table 4. EFFECT OF rHuEPO ON HEMATOCRIT AND NEED FOR BLOOD

TRANSFUSION IN RECIPIENT-DONOR PAIRS5s
Historical
rHuEPO Controls PValue

Percent change hematocrit initial to + 18% - 6% 0.0001

preoperative
Percent change hematocrit initial to - 4% - 26% 0.0003
postoperative
Number requiring allogeneic blood none 2/4 children
0/16 adults
 ERYTHROPOIETIN AFTER BONE MARROW TRANSPLANTATION 985

tients with solid tumors received rHuEPO. One was not evalua-
ble owing to mycoplasma-induced hemolysis. were treated with
rHuEPO at a dose of 200 U /kg daily intravenously beginning day 1 after
transplant with iron supplementation. rHuEPO was continued for 28
days or until the hematocrit was greater than 35% without transfusion.
Red blood cells were given for a hematocrit of less than 25%. Preparative
regimens either ifosfamide, etoposide, and carboplatin (n = 5); cyclo-
phosphamide, BCNU, and cisplatin (n = 3); or cyclophosphamide, thio-
tepa, and carboplatin (n = 2). The median number of prior chemother-
apy regimens in these patients was 4.5.
Compared with 37 historical controls treated with the same prepar-
ative regimens without rHuEPO, erythroid recovery was faster in the
rHuEPO-treated patients. The median day to hematocrit greater than
30% without red blood cell transfusion was 24 days in the rHuEPO
group as compared with day 57 in the historical controls (P = 0.001).
Three patients achieved a hematocrit of greater than 35% without trans-
fusion within 1 month after marrow reinfusion (days 19, 19, and 29)
associated with a significant reticulocytosis (median reticulocyte peak,
0.37 X 109 /L). In the five patients treated with the ifosfamide regimen,
where the median number of red blood cell transfusions was nine (range,
4 to 22), the median number of red blood cell units transfused in the
rHuEPO group was 8.5 (range, 4 to 12). The median day to hematocrit
greater than 30 percent was 24, with a median duration of rHuEPO
treatment of 26 days (range, 14 to 31). Engraftment was prompt, with a
median day to greater than 500 granulocytes of 24 (in historical controls
the median day to 500 granulocytes was 22 days), and the median day
to a platelet count of greater than 20,OOO/mm3 was day 21. These data
suggest a trend toward earlier engraftment and the use of fewer units of
red blood cells in patients treated with rHuEPO after autologous bone
marrow transplants.
Preliminary analysis of two randomized trials of rHuEPO after au-
tologous bone marrow transplant is available in abstract form. Miller et
aps randomized patients into three groups: (1) to receive placebo; (2) to
receive placebo for the first 3 doses, followed by rHuEPO (200 U /kg); or
(3) rHuEPO throughout the study. The study drug was given every other
day for a total of 14 doses. Fifteen patients were randomized, five to a
group. Despite a heterogenous population, there was a trend to faster
erythroid recovery. Bone marrow progenitor assays did not demonstrate
any evidence of negative impact on myeloid or mixed progenitor colo-
nies.
We completed a randomized trial of rHuEPO in patients with non-
Hodgkin's lymphoma or acute myelogenous leukemia who received au-
tologous marrow grafts purged with 4HC. 42 Patients received either
rHuEPO (200 U /kg) or placebo intravenously daily for 28 days, then
three times a week until day 50 or hematocrit was greater than 40%.
Patients were transfused to maintain a hematocrit of greater than 30%
when febrile and 30% otherwise. Randomization was stratified for dis-
ease (leukemia versus lymphoma). Twenty-six patients (five leukemia,
21 lymphoma) received rHuEPO, and 24 patients (five leukemia, 19
986 MILLER & MILLS

lymphoma) received placebo. Two patients (one rHuEPO and one pla-
cebo) did not receive 3 weeks of therapy and were not evaluable. There
was no difference in any of the engraftment parameters measured (Table
5) or the red blood cell or platelet transfusion requirement. These results
were similar to the results seen with myeloid growth factors after chem-
ically purged autografts and may reflect inadequate progenitors early
after reinfusion of purged bone marrow.

COMPARISON OF THE RESPONSE TO rHuEPO IN

ALLOGENEIC AND AUTOLOGOUS TRANSPLANTS

Locatelli et aP4 evaluated the response to rHuEPO in children. Ten

allogeneic bone marrow transplant patients and 10 mafosphamide-
purged autologous bone marrow transplant patients treated with
rHuEPO were compared with historical controls. rHuEPO was given
intravenously at a dose of 75 U /kg daily for 30 days after marrow
infusion. In the historical controls, erythropoietin response was sup-
pressed after allogeneic bone marrow transplant, but normal after autolo-
gous transplant. Erythroid reconstitution was enhanced in the rHuEPO
allogeneic patients as compared with historical controls; however, no
effect was seen in the autologous patients (Table 6). There was an in-
crease in transferrin receptor early in the allogeneic patients; however, at
15 days there was no difference in the reticulocyte count. There was a
decrease in red blood cell units transfused before transfusion indepen-
dence in the rHuEPO-treated allogeneic patients as compared with the
historical controls (1.7 ± 1.3 versus 5.0 ± 3.0, P < 0.05). A decrease in
platelet transfusions prior to independence was also seen (4.0 ± 2.3
versus 8.4 ± 6.8, P < 0.05). There was no effect on red cell or platelet
transfusions in the autologous patients. In both autologous and alloge-
neic transplants, there was no significant difference in cost of transfusion
therapy versus transfusion therapy plus rHuEPO.

Table 5. ENGRAFTMENT AFTER 4HC PURGED AUTOGRAFTS42

Median rHuEPO Placebo PValue

Days to platelets> 50,000/mm 3 46 48 ns

(23->50) (26->50)
Days to neutrophils > 500/mm3 31 32 ns
(20->50) (21->50)
Days to reticulocyte> 2% 38 35 ns
(22->50) (22->50)
Hemoglobin day 50 (g/dL) 10.5 9.5 0.02
(7.9-14.8) (7.3-13.9)
Platelet units transfused 176 168 ns
(57-584) (72-970)
RBC units transfused 13 15 ns
(8-50) (6-87)

ns = not significant; 4HC = 4-hydroperoxycyclophosphamide

 ERYTHROPOIETIN AFTER BONE MARROW TRANSPLANTATION 987

Table 6. COMPARISON OF RESPONSE TO rHuEPO IN ALLOGENEIC VERSUS

AUTOLOGOUS BONE MARROW TRANSPLANT PATIENTS34
Historical
rHuEPO Controls PValue

ALLOGENEIC 10 Patients 15 Patients

Days to neutrophils > 500/mm 3 14 ± 4 16 ± 5 ns
Days to platelets> 50,000/mm 3 28 ± 9 38 ± 20 ns
Reticulocytes day 15 (x 109 /L) 63 ± 36 56 ± 46 ns
Reticulocytes day 30 (x 10 9 /L) 187 ± 51 107 ± 63 0.05
Transferrin receptor d + 15 (mg/dL) 4300 ± 1500 2800 ± 900 0.05
Transferrin receptor d + 30 (mg/dL) 8300 ± 5100 4500 ± 2200 0.05
Total RBC transfusions 17 ± 1.3 5.1 ± 3 0.001
Total platelet transfusions 4.0 ± 2.3 8.4 ± 6.8 0.05
Total cost (US) (transfusions and 2490 ± 1337 3734 ± 2594 ns
rHuEPO)
AUTOLOGOUS 10 Patients 10 Patients
Days to neutrophils > 500/mm 3 24.8 ± 7.6 24.8 ± 8.0 ns
Days to platelets> 50,000/mm 3 60.8 ± 34.4 89.8 ± 857 ns
Reticulocytes day 15 (x 10 9 /L) 10.9 ± 6.3 11.3 ± 7.0 ns
Reticulocytes day 30 (x 10 9 /L) 42 ± 26.5 40 ± 24 ns
Transferrin receptor d + 15 (mg/dL) 1900 ± 300 300 ± 1000 ns
Transferrin receptor d + 30 (mg/dL) 2400 ± 900 2900 ± 1400 ns
Total RBC transfusions 4.8 ± 2.3 6.1 ± 3.9 ns
Total platelet transfusion 7.8 ± 4.4 11 ± 9.1 ns
Total cost (US) (transfusion and 4265 ± 1629 3687 ± 2369 ns
rHuEPO)

ns = not significant

This difference in response to rHuEPO in allogeneic versus autolo-

gous bone marrow transplant has been confirmed in a randomized, mul-
ticenter study.33 Two hundred fifteen allogeneic and 114 autologous pa-
tients were randomized to receive either 150 U /kg rHuEPO or placebo
daily starting the day of bone marrow infusion until red blood cell
transfusion independence or day 42. In the autologous transplant pa-
tients, there was no effect on any of the parameters tested. However,
there was a significant improvement in erythroid recovery in the
rHuEPO-treated allogeneic patients, with a higher median reticulocyte
count from day 21 to day 42 and a decrease in time to red cell indepen-
dence from 29 in the placebo patients to 19 in the rHuEPO patients (P =
0.02). Despite the marked improvement in time to red cell independence,
there was no significant decrease in red blood cell transfusion require-
ment (8.0 ± 6.1 versus 8.7 ± 6.6). This suggests that the majority of
blood is used early (within the first 3 weeks) after bone marrow reinfu-
sion, at which time there is not a significant rHuEPO effect.

rHuEPO IN DELAYED ERYTHROPOIESIS AFTER BONE

MARROW TRANSPLANTATION
As discussed previously, red blood cell recovery often lags behind
platelet and neutrophil recovery associated with an inadequate erythro-
988 MILLER & MILLS

20r-----------------------------~ 12

• •• • • • ••
10
15

8
c C
::J
:0 0
o ()
&10 6 ()
E i=
Ql w
I a:
4
5

~----------------------------~ 0
56 66 76 86 96 106 116 126
BMT (day)

Figure 5. Patient who received an allogeneic bone marrow transplant for acute myelogenous
leukemia in first CR with baseline erythropoietin level of 16 mU/mL (solid circle = RETIC;
open square = HGB; open circle = RBC; solid square = EPO).

poietin response to anemia. This delayed erythropoiesis may be espe-

cially important, because the anemia may have a significant negative
impact on patient recovery and ability to return to normal activities after
a long hospitalization. Also, in the outpatient setting, red blood cell
transfusion is a significant inconvenience owing to the time in clinic
required to receive the transfusions and the costs related to the infusion.
The efficacy of rHuEPO in patients with delayed erythropoiesis (defined
as hemoglobin less than 9 g/ dL greater than 21 days after bone marrow
transplantation) was evaluated in a pilot trial. 45 Patients were treated
initially with rHuEPO (150 U /kg) three times a week subcutaneously for
3 weeks. If hemoglobin increased by 1 g/ dL over the 3 weeks without
transfusion, rHuEPO was held. If hemoglobin fell during the subsequent
3 weeks, rHuEPO was restarted. If the hemoglobin failed to increase by
1 g/ dL during the initial 3 weeks, the dose was doubled for an additional
3 to 6 weeks. Twenty patients were entered (13 allogeneic, seven autolo-
gous) at a median day 44 after bone marrow transplant. Two patients
withdrew early (one early death due to CMV pneumonia, one patient
request). Eleven of the 18 remaining patients received only the 150 U /kg
dose level. Fifteen of 18 patients (83%) responded with an increase in
hemoglobin of 1 g/ dL or decrease in transfusion requirement. Nine
patients had a complete response (hemoglobin increase of greater than 2
g/ dL or 100% decrease in transfusion requirement). Bone marrow cellular-
 ERYTHROPOIETIN AFTER BONE MARROW TRANSPLANTATION 989

ity increased from 4% to 32% in the nine who were evaluated.

Response correlated with baseline erythropoietin level, with a
response being achieved in seven of eight patients with a baseline eryth-
ropoietin level of less than 50 mU /mL but only two of nine with a
baseline level of greater than 50 mU/mL. The response in a patient
treated on this protocol is shown in Figure 5. These data suggest that
rHuEPO may be helpful in ameliorating anemia and decreasing the
transfusion requirement in patients with delayed erythropoiesis after
bone marrow transplant.

CONCLUSIONS

Bone marrow transplantation, both allogeneic and autologous, is

associated with a significant need for red blood cell transfusions. The
anemia after transplantation is complicated by a relative erythropoietin
deficiency for the degree of anemia. Studies suggest that rHuEPO is safe
after bone marrow transplantation. The data summarized in this article
suggest no significant role for rHuEPO early after autologous bone mar-
row transplant, especially if purged marrows are used. The data in the
allogeneic studies are more promising. Two randomized studies did
show a decrease in transfusion requirement when given early after allo-
geneic bone marrow transplant. Further studies should look at the cost
effectiveness of rHuEPO given early after bone marrow transplantation.
The use of rHuEPO in chromc anemia associated with bone marrow
transplantation is of great interest and should be studied in a random-
ized fashion to evaluate the effect on quality of life and cost in this
patient population.

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Address reprint requests to

Carole B. Miller, MD
The Johns Hopkins Oncology Center
600 N. Wolfe Street, Room 167
Baltimore, MD 21287-8985