Erythropoietin Is Effective in Improving the AnemiaInduced by Imatinib Mesylate Therapy in Patientswith Chronic Myeloid Leukemia in Chronic Phase

Jorge Cortes, M.D.

Susan O’Brien, M.D.

Alfonso Quintas, M.D.

Francis Giles, M.D.

Jianquin Shan, Ph.D.

Mary Beth Rios, R.N.

Moshe Talpaz, M.D.

Hagop Kantarjian, M.D.

Department of Leukemia, The University of Texas,M. D. Anderson Cancer Center, Houston, Texas.

Dr. Cortes is a Clinical Research Scholar for theLeukemia and Lymphoma Society

Address for reprints: Jorge Cortes, M.D., Depart-ment of Leukemia, M. D. Anderson Cancer Center,1515 Holcombe Boulevard, Unit 428, Houston, TX77030; Fax: (713) 794-4297; E-mail: jcortes@mdanderson.org

Received February 6, 2004; revision receivedMarch 19, 2004; accepted March 23, 2004.

BACKGROUND. Myelosuppression occurs in up to 50% of patients with chronic

myeloid leukemia (CML) who are treated with imatinib and � Grade 3 myelosup-

pression is reported in approximately 10% of patients.

METHODS. The authors investigated the prognostic significance of anemia occur-

ring during therapy with imatinib in patients with CML in chronic phase.

RESULTS. Of 338 patients treated with imatinib (150 patients after interferon failure

and 188 patients with newly diagnosed CML), 230 (68%) developed anemia. In a

multivariate analysis, factors associated with an increased probability of develop-

ing anemia were a starting hemoglobin level � 12 g/dL, age � 60 years, female

gender, higher imatinib dose, and intermediate or high Sokal risk group. Of these

230 patients, 102 patients received treatment with 40,000 U of recombinant human

erythropoietin administered subcutaneously once weekly. An increase in the he-

moglobin level of � 2 g/dL was achieved in 69 patients (68%) and 22 patients (22%)

had an increase of 1–1.9 g/dL. Patients who developed anemia had a trend toward

a lower probability of complete cytogenetic remission compared with patients

without anemia (68% vs. 77%; P � 0.14), as well as a trend for inferior survival.

Patients with anemia and other manifestations of myelosuppression were found to

have a significantly worse outcome than those with isolated anemia.

CONCLUSIONS. The authors concluded that erythropoietin is safe and effective in

patients in chronic-phase CML who develop anemia with imatinib therapy. Cancer

2004;100:2396 – 402. © 2004 American Cancer Society.

KEYWORDS: erythropoietin, imatinib, chronic myeloid leukemia, anemia.

Imatinib mesylate (STI571), a specific Bcr-Abl tyrosine kinase inhib-itor,1,2 has shown positive results in Philadelphia chromosome (Ph)-

positive chronic myeloid leukemia (CML).3–10 Overall, imatinib ther-apy is well tolerated, but severe and dose-limiting side effects arereported to occur in 2–5% of patients. These include fatigue, skinrashes, bone aches, muscle cramps, fluid retention, edema, and liverdysfunction.3–10 Myelosuppression is the most common Grade � 3adverse event, reportedly occurring in 35– 45% of patients. The result-ing anemia, neutropenia, and thrombocytopenia lead to treatmentinterruptions that may be prolonged and/or to dose reductions ofimatinib.11 Myelosuppression occurs in patients with CML, but de-velops less frequently in patients with newly diagnosed CML com-pared with patients treated for chronic-phase CML after interferon-alpha (IFN-�) failure and patients in the transformed phases of CML.The incidence of Grade 3 (hemoglobin [Hb] level 6.5– 8 g/dL) or Grade4 (Hb level � 6.5 g/dL) anemia was reported to be 3% with imatinibtherapy for newly diagnosed CML and 7% for chronic-phase CML

2396

© 2004 American Cancer SocietyDOI 10.1002/cncr.20292Published online 3 May 2004 in Wiley InterScience (www.interscience.wiley.com).

after IFN-� failure.5,10 This may be related to the de-gree of preservation of the normal hematopoietic stemcell pool, which has been suppressed by the Ph-posi-tive clones. Myelosuppression during imatinib ther-apy for CML has been associated with a worse re-sponse to therapy and with worse prognosis.12,13

Whether this is a manifestation of an intrinsicallyworse disease or of inadequate delivery of imatinib isdifficult to ascertain. Nevertheless, if the myelosup-pression-associated worse outcome is due to treat-ment interruptions, averting such situations may im-prove treatment efficacy and prognosis. Erythro-poietin and granulocyte– colony-stimulating factorsare easily delivered therapeutic modalities that couldimprove the anemia and neutropenia associated withimatinib therapy, and allow for the continuation ofeffective dose schedules of imatinib (i.e., � 300 mgdaily).

Erythropoietin improves anemia associated withchemotherapy in patients with solid tumors.14 It isalso moderately active in patients with anemia asso-ciated with myelodysplastic syndrome, and its efficacyis inversely related to the intrinsic erythropoietin lev-els.15 Despite the common use of erythropoietin incommunity practice, there is reluctance toward its usein patients with myeloid leukemias because of the lackof studies and the hypothetical risk of stimulating theleukemic clones.16,17

In the current study, we report that erythropoietinis safe and effective in most patients with Ph-positiveCML who experienced anemia associated with ima-tinib therapy.

MATERIALS AND METHODSStudy GroupAdults with a diagnosis of Ph-positive CML in chronicphase who were receiving imatinib in protocols in-volving CML after IFN-� failure (Novartis 110) ornewly diagnosed CML (ID01-015, ID01-151, andDM00-163) were evaluated. Entry criteria, treatmentdose schedules and adjustments, pretreatment andfollow-up evaluations, and response criteria havebeen detailed in previous studies.5,7,10 Briefly, a com-plete hematologic response required normalization,for � 4 weeks, of the bone marrow (� 5% blasts) andperipheral blood with a leukocyte count � 10 � 109/L,without peripheral blasts, promyelocytes, or myelo-cytes, in addition to the disappearance of all signs andsymptoms of CML. This was classified further accord-ing to cytogenetic response (suppression of Ph-posi-tive cells) as follows: no cytogenetic response, Ph pos-itive 100%; minor cytogenetic response, Ph positive35–90%; partial cytogenetic response, Ph positive1–34%; and complete cytogenetic response, Ph posi-

tive 0%. A major cytogenetic response included com-plete and partial cytogenetic responses (i.e., Ph posi-tive � 35%).

Treatment of AnemiaAnemia was classified as mild (Hb level of 10.0 –11g/dL), moderate (Hb level of 8.0 to � 10 g/dL), orsevere (Hb level of � 8.0 g/dL) for the purpose oftreatment evaluation. These levels correspond toGrades 1, 2, and � 3 of the National Cancer Institute(NCI) Common Toxicity Criteria, respectively. Patientswere treated for anemia with weekly doses of 40,000 Uerythropoietin subcutaneously until the Hb level in-creased to 11–13 g/dL, at which time the erythropoi-etin dose schedule was reduced to 40,000 U every 2– 4weeks and discontinued if the Hb levels remainedstable at 11–12 g/dL or higher. In addition, all patientsreceived iron and multivitamin supplementation asneeded. For patients with suspected iron-deficientanemia (based on clinical history and red blood cell[RBC] parameters), levels of serum iron, iron-bindingcapacity, and serum ferritin were evaluated, as wasany possible cause of blood loss, before erythropoietinwas considered. Erythropoietin levels were notscreened before the initiation of erythropoietin ther-apy in most patients. For the purpose of the currentanalysis, a favorable response to erythropoietin wasconsidered as a sustained (i.e., lasting � 4 weeks)increase in the Hb level � 2 g/dL from the pretreat-ment values.

Dose reductions of imatinib for nonhematologicor hematologic toxic effects were initiated for a varietyof reasons. Imitinib therapy was discontinued in pa-tients who developed persistent Grade 2 nonhemato-logic toxicity until toxicity improved to Grade � 1.Imatinib was then resumed at a lower dose, but neverreduced to � 300 mg daily. If Grade � 3 nonhemato-logic toxicity occurred at any time, the same proce-dure was followed. Treatment was interrupted for pa-tients who developed Grade � 3 neutropenia orthrombocytopenia until the neutrophil count recov-ered to � 1 � 109/L and/or the platelet count recov-ered to � 50 � 109/L. Imatinib was then resumed atthe same dose if the counts recovered within 2 weeks,but the dose was reduced if myelosuppression per-sisted for � 2 weeks. No dose reductions were allowedbelow 300 mg daily. No dose interruptions or reduc-tions were indicated for anemia alone.

A proportion of patients with anemia did not re-ceive erythropoietin because of physician–patientchoice or for financial/insurance reasons. For thesepatients, anemia was managed with supportive care,packed RBC transfusions when needed, and/or withimatinib dose adjustments or interruptions.

Erythropoietin in CML/Cortes et al. 2397

Patients were followed with complete bloodcounts (CBC) weekly during the first 4 weeks of ther-apy with imatinib and then every 2– 4 weeks. Patientswho developed myelosuppression had a CBC per-formed every 1–2 weeks.

Statistical ConsiderationsSurvival was calculated from the date of the initiationof therapy to death from any cause or last follow-up.Survival curves were plotted using the Kaplan–Meiermethod.18 Univariate and multivariate analyses with alogistic regression model were performed to identifypotential prognostic factors and their association withthe onset of anemia.19

RESULTSStudy GroupIn the current study, 338 patients receiving imatinibtherapy were evaluated. The sample included 150 pa-tients with chronic-phase CML after IFN-� failure(Novartis 110) and 188 patients with newly diagnosedCML (ID01-015 [n � 50 patients], ID01-151 [n � 115patients], and DM00-163 [n � 23 patients]). Of these,230 patients (68%) developed anemia (Hb level � 11g/dL). The clinical characteristics of patients who de-veloped anemia are compared with the patients with-out anemia in Table 1. A multivariate analysis identi-fied the following pretreatment factors to beindependently associated with a higher risk of devel-oping anemia during therapy with imatinib: baselineHb level � 12 (P � 0.00001), age � 60 years (P � 0.01),female gender (P � 0.00001), higher initial imatinibdose (P � 0.001), and intermediate or high Sokal riskgroup (P � 0.04). A total of 102 of the 230 patients whodeveloped anemia (44%) were treated with erythropoi-etin. The median time from the initiation of imatinibtherapy to initiation of erythropoietin therapy was 1.9months (range, 1– 41 months). The median age of thepatients treated with erythropoietin was 58 years(range, 17–79 years).

Response to Treatment of Anemia with ErythropoietinTable 2 summarizes the response to erythropoietintherapy according to three parameters: 1) CML status(chronic post–IFN-� failure or chronic newly diag-nosed), 2) the dose of imatinib at the time erythropoi-etin was initiated, and 3) the severity of anemia.

Of the 102 patients receiving erythropoietin, 69(68%) had an increase in Hb levels of � 2 g/dL. Of 48patients in early chronic phase treated for anemia, 36patients (75%) had such an increase and 10 otherpatients (21%) had an Hb increase of 1–1.9 g/dL.Therefore, only 2 of 48 patients treated had no re-sponse at all to erythropoietin therapy.

Of 54 patients with chronic-phase CML afterIFN-� who were treated for anemia, 33 (61%) re-sponded to erythropoietin with a Hb increase of � 2g/dL. Twelve (22%) additional patients had an Hbincrease of 1–1.9 g/dL. Therefore, patients in earlychronic phase appeared to have a higher response rateto erythropoietin treatment for severe anemia com-pared with patients with chronic-phase CML afterIFN-� failure (96% vs. 83%; P � 0.06). Forty-three ofthe102 patients who received erythropoietin hadsymptomatic anemia and 37 (86%) improved in terms

TABLE 1Characteristics of Patients Who Did or Did Not Develop Anemia

Pretreatment characteristics

No. of patients withsubsequent anemia (%)

P valueYes (n � 230) No (n � 108)

Age (yrs)� 60 86 (37) 23 (21) 0.005

GenderFemale 125 (54) 20 (19) � 0.0001

SplenomegalyYes 53 (23) 15 (14) 0.06

Hemoglobin (g/dL)� 12 124 (54) 18 (17) � 0.0001

Leukocyte count (� 109/L)50–99 41 (18) 9 (8) 0.08� 100 16 (7) 9 (8)

Platelet count (%)� 450 74 (32) 28 (26) 0.30

Blasts (%)Blood

Yes 66 (29) 28 (26) 0.69Bone marrow

� 5 20 (9) 11 (10) 0.69Basophils (%)

Blood� 7 45 (20) 13 (12) 0.09

Bone marrow� 4 62 (27) 27 (25) 0.84

Additional chromosomal abnormalitiesYes 19/228 (8) 10 (9) 0.84

Risk group (Sokal model)Low 56/155 (36) 50/84 (60) 0.002Intermediate 66 (43) 21 (25)High 33 (21) 13 (15)

Duration of CML (mos)0–12 135 (59) 69 (64) 0.76� 12–36 51 (22) 22 (20)� 36 44 (19) 17 (16)

Initial imatinib dose (mg/day)400 141 (61) 86 (76) 0.01800 89 (39) 26 (24)

CML phasePost–IFN-� failure 106 (46) 44 (41) 0.42Early chronic phase 124 (54) 64 (59)

CML: chronic myeloid leukemia; IFN-�: interferon-alpha.

2398 CANCER June 1, 2004 / Volume 100 / Number 11

of performance status (Eastern Cooperative OncologyGroup) and fatigue (graded according to the NCICommon Toxicity Criteria).

To better define the effect of erythropoietin, wecompared the frequency of an improvement in Hblevels of � 2 g/dL between patients receiving erythro-poietin and those not receiving this drug. Becauseimatinib dose reductions/interruptions usually resultin improvement of myelosuppression, this is betterevaluated among patients who had no such imatinibtreatment interruptions. Among 75 such patients whoreceived erythropoietin, 48 (64%) responded, com-pared with 32 of 79 patients (41%) who did not receiveerythropoietin (P � 0.006). The difference was partic-ularly noticeable among patients with moderate orsevere anemia. Twenty-nine of 44 patients receivingerythropoietin responded (66%) compared with 8 of28 patients not receiving erythropoietin (29%) (P� 0.003).

Outcome of Patients Who Did or Did Not Develop AnemiaIn addition to the 102 patients who developed anemiaand received erythropoietin, 79 patients developedanemia (mild in 50 patients, moderate in 28 patients,and severe in 1 patient) but did not receive erythro-poietin therapy by patient or physician choice or be-cause of financial or insurance problems, and did not

have any imatinib dose interruptions or reductions.Patients receiving erythropoietin were more often fe-males (P � 0.02), had a longer duration of chronic-phase CML (P � 0.005), and were more often in theintermediate to high-risk Sokal groups (P � 0.03).Other characteristics were similar. Thirty-five patients(mild in 12 patients and moderate in 23 patients) hadimatinib dose reductions and/or treatment interrup-tions for myelosuppression (neutropenia or thrombo-cytopenia) or nonhematologic toxicity. There was atrend toward a higher percentage of patients requiringdose reductions or treatment interruptions because ofmyelosuppression or nonhematologic toxicity amongpatients who did not receive erythropoietin (35 of 114[31%]) compared with those who did (20 of 102 [20%])(P � 0.08).

The outcome of the 108 patients who never hadanemia was compared with the outcome for patientswho had anemia and who did or did not receive eryth-ropoietin therapy (Table 3; Fig. 1). The development ofanemia with imatinib was associated with a trend to-ward worse complete cytogenetic response rates (68%vs. 77%; P � 0.14) and a trend toward worse survival (P� 0.16). The trend also was observed between patientswith anemia who did or did not receive erythropoietintherapy (Table 4; Fig. 1). The rate of complete cytoge-netic response was significantly lower for patients (n� 116) who had anemia accompanied by other myelo-suppression compared with patients with isolated ane-mia (59% vs. 77%; P � 0.01). There was no statisticaldifference noted in survival between these two groups.

DISCUSSIONThe development of myelosuppression with imatinibtherapy has been associated with poor outcome bymultivariate analysis in patients with Ph-positivechronic-phase CML.12,13 It is difficult to ascertainwhether this is due to an intrinsically worse diseaseassociated with a poor normal hematopoietic stemcell pool or to inadequate dose intensity with imatinibbecause of treatment interruptions and dose adjust-ments. If the decreased dose intensity was at leastpartially the cause, it would be reasonable to assumethat the use of hematopoietic growth factors (e.g.,filgrastim, erythropoietin) might improve myelosup-pression and allow effective imatinib dose scheduledelivery. To our knowledge, erythropoietin has notbeen systematically studied in the context of anemiaand myeloid disorders other than myelodysplasticsyndrome. Its use is considered to carry the hypothet-ical risk of stimulation of the myeloid leukemiacells.16,17

In our study of erythropoietin for imatinib-asso-ciated anemia in patients with chronic-phase CML, we

TABLE 2Response to Erythropoietin by CML Phase, Imatinib Dose, andSeverity of Anemia before Erythropoietin Treatment

Imatinib dose(mg/day)

Degree ofanemia

No. ofpatients

No. of patients withan Hb increase of> 2 g/dL (%)

Chronic-phase IFN-�failure (n � 54)

300–400 Severe 3 1 (33)300–400 Mild to moderate 35 23 (66)600 Severe — —600 Mild to moderate 4 2 (50)800 Severe 1 1 (100)800 Mild to moderate 11 6 (55)Total Severe 4 2 (50)Total Mild to moderate 50 31 (62)

Early chronic phase(n � 48)

400 Severe 1 1 (100)400 Mild to moderate 10 8 (80)600 Severe 1 1 (100)600 Mild to moderate 6 3 (50)800 Severe 6 6 (100)800 Mild to moderate 24 17 (71)Total Severe 8 8 (100)Total Mild to moderate 40 28 (70)

CML: chronic myeloid leukemia; IFN-�: interferon-alpha; Hb: hemoglobin.

Erythropoietin in CML/Cortes et al. 2399

observed a very high rate of improvement of anemiawith the use of erythropoietin. As expected, imatinib-induced anemia was more frequent in late chronic-phase CML patients compared with early chronic-phase CML patients (36% vs. 9% with imatinib given ata dose of 400 mg daily) and was more frequent in earlychronic-phase patients treated with high-dose versusthose treated with conventional-dose imatinib (i.e.,800 mg vs. 400 mg daily, respectively). A major re-sponse to erythropoietin therapy (i.e., � 2 g/dL im-provement in Hb levels) occurred in the majority ofpatients (e.g., 61% of patients in chronic-phase CMLafter IFN-� failure and 75% of patients in early chron-ic-phase CML). As patients respond to imatinib, he-matopoiesis improves and some patients recover frommyelosuppression without intervention.20 Indeed,myelosuppression is reported to occur more fre-quently during the first 2 or 3 months of therapy.Nevertheless, significantly more patients treated witherythropoietin had a � 2 g/dL improvement in Hblevel compared with patients who were not treated.This suggests that erythropoietin therapy is beneficialfor improving anemia induced by imatinib.

The current study had several limitations, includingthe lack of measurement of erythropoietin levels, as wellas the lack of systematic studies of iron levels, iron-

binding capacity, and serum ferritin levels. However, thetemporal relation between the initiation of imatinibtherapy and the development of anemia, the cost of suchstudies, and the high rates of response in the initialcohort of patients suggested that the benefit of erythro-poietin therapy occurred regardless of the erythropoietinlevels, and that iron deficiency did not, in most cases,cause the anemia. However, it is possible that the pa-tients with a poor response to erythropoietin may havehigher erythropoietin levels than the responders or thatthey may have had iron or other deficiency anemia. Twoof the nonresponders were investigated (one female andone male with recurrent gastrointestinal bleeding fromgastric arteriovenous malformations) and were found tohave iron deficiency anemia despite appropriate oraliron therapy. They both responded to intravenous irontherapy and continuation of erythropoietin. It also ispossible that imatinib may, by some unknown mecha-nism, suppress endogenous erythropoietin simulation,as it suppressed testosterone production in one study.21

We are currently investigating systematically the levels oferythropoietin and iron-related parameters in our pa-tients.

Another consideration is whether the develop-ment of anemia with imatinib therapy was a manifes-tation of an intrinsically worse CML condition and/ora poorly preserved normal hematopoietic stem cellpool. In the current study, patients with anemia dem-onstrated a trend toward worse complete cytogeneticresponse rates and worse survival. This effect was notas marked as that observed with other lineage myelo-suppression (neutropenia, thrombocytopenia). Pa-tients with Grade � 3 neutropenia or thrombocytope-nia have been reported to have a significantly lowerprobability of achieving a major and complete cyto-genetic response12 and inferior probability of surviv-al.13 The use of filgrastim has been reported to im-prove neutropenia and the probability of achieving amajor cytogenetic response in a small series of pa-tients.22,23 Erythropoietin therapy did not clearly im-pact the prognosis of patients reported in the currentseries, although the number of events (failures) mostlikely was too small to define such differences. In

TABLE 3Outcome of Patients by Development of Anemia with Imatinib Therapy

Parameters No anemia (n � 108) Anemia (n � 230) P value

No. of patients with a complete hematologic response (%) 104 (96) 225 (98) 0.65No. of patients with a cytogenetic response (%) 99 (92) 200 (87) 0.28

Major 93 (86) 188 (82) 0.40Complete 83 (77) 157 (68) 0.14

Estimated 3-yr survival (%) 96 90 0.16

FIGURE 1. Survival of patients without (A) or with anemia who received

imatinib therapy and who did (B) or did not receive erythropoietin therapy (C).

2400 CANCER June 1, 2004 / Volume 100 / Number 11

addition, patients who developed isolated anemia didnot usually have their therapy withheld. Indeed, pa-tients with isolated anemia had a better probability ofresponding to imatinib compared with patients withanemia and other manifestations of myelosuppres-sion. However, 86% of patients with symptomatic ane-mia improved with imatinib therapy.

One hypothetical consideration with the use oferythropoietin for patients with myeloid disorders iswhether, by stimulating the growth of the leukemic pro-genitors, it may worsen response and long-term progno-sis. This is based on observations that erythropoietin,when used together with phytohemagglutinin-stimu-lated leukocyte-conditioned medium, may promote theclonogenic growth of acute myeloid leukemia (AML)cells.16,17 We did not observe any adverse effect of eryth-ropoietin on response to therapy with imatinib. The rateof major, and particularly complete, cytogenetic re-sponses was higher (although not statistically signifi-cant) for patients who received erythropoietin. The sur-vival for patients with anemia was similar regardless ofwhether they received erythropoietin. However, becausea complete cytogenetic response is associated with pro-longed survival, it is possible that, if there is a differencewith longer-term follow-up, it might be in favor of pa-tients treated with erythropoietin. This lack of an adverseeffect with the use of erythropoietin is not unexpected.Both filgrastim and granulocyte-macrophage–colony-stimulating factor can stimulate the growth of myeloidleukemia progenitors in vitro, most likely more potentlythan erythropoietin.24 When used after chemotherapyfor AML, they have been shown to improve the durationof neutropenia and reduce the number of hospitaliza-tions and infections, without adversely affecting the out-come (and in some instances, possibly even improvingthe outcome) of AML.25,26 The use of these growth fac-tors after induction chemotherapy in patients with AMLis similar to their use after imatinib in patients with CML.

The results of the current study indicate thaterythropoietin is safe and effective for the treatment ofanemia associated with imatinib therapy in patients

with chronic-phase CML. Further studies investigatingthe impact on other measures, such as quality of lifeand fatigue, are needed to measure other dimensionsof the use of this cytokine.

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TABLE 4Outcome of Patients by Development of Anemia with Erythropoietin Therapy

ParametersNo anemia(n � 108)

Anemia,erythropoietintherapy (n � 102)

Anemia, noerythropoietintherapy(n � 114) P value

No. of patients with a complete hematologic response (%) 104 (96) 100 (98) 111 (97) 0.74No. of patients with a cytogenetic response (%) 99 (92) 89 (87) 97 (85) 0.31

Major 93 (86) 83 (81) 92 (81) 0.52Complete 83 (77) 74 (73) 72 (63) 0.07

Estimated 3-yr survival (%) 96 86 89 0.36

Erythropoietin in CML/Cortes et al. 2401

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