Results of Imatinib Mesylate Therapy in Patients withRefractory or Recurrent Acute Myeloid Leukemia,High-Risk Myelodysplastic Syndrome, andMyeloproliferative Disorders

Jorge Cortes, M.D.1

Francis Giles, M.D.1

Susan O’Brien, M.D.1

Deborah Thomas, M.D.1

Maher Albitar, M.D.1

Mary Beth Rios, M.D.1

Moshe Talpaz, M.D.2

Guillermo Garcia-Manero, M.D.1

Stefan Faderl, M.D.1

Laurie Letvak, M.D.3

August Salvado, M.D.3

Hagop Kantarjian, M.D.1

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

2 Department of Bioimmunotherapy, The Universityof Texas, M. D. Anderson Cancer Center, Houston,Texas.

3 Novartis Pharmaceuticals Corporation, EastHanover, New Jersey.

Dr. Armand Keating served as guest editor on thisarticle.

Dr. Cortes is a clinical research scholar for TheLeukemia and Lymphoma Society, White Plains,New York.

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

Received December 13, 2002; revision receivedFebruary 24, 2003; accepted February 27, 2003.

BACKGROUND. Imatinib mesylate is a selective tyrosine kinase inhibitor of c-abl,

bcr/abl, c-kit, and platelet-derived growth factor-receptor (PDGF-R). c-kit is ex-

pressed in most patients with acute myeloid leukemia (AML) and myelodysplastic

syndrome (MDS) and PDGF has been implicated in the pathogenesis of myelo-

proliferative disorders (MPD).

METHODS. The authors investigated the efficacy of imatinib in patients with these

disorders. Forty-eight patients with AML (n � 10), MDS (n � 8), myelofibrosis (n

� 18), atypical chronic myeloid leukemia (CML; n � 7), chronic myelomonocytic

leukemia (CMML; n � 3), or polycythemia vera (n � 2) were treated with imatinib

400 mg daily.

RESULTS. None of the patients with AML or MDS responded. Among patients with

myelofibrosis, 10 of 14 patients with splenomegaly (71%) had a 30% or greater

reduction in spleen size, 1 patient had trilineage hematologic improvement, 2 had

erythroid hematologic improvement, and 1 had improvement in platelet count.

One patient with atypical CML had erythroid hematologic improvement. Both

patients with polycythemia vera needed fewer phlebotomies (from 2–3 per year to

none during the 8 months of therapy and from 3– 6 per year to 1 during 9 months

of therapy). None of the three patients with CMML responded. Treatment was well

tolerated. The side effects were similar to those observed in patients with CML.

CONCLUSIONS. Within these small subgroups of disease types, single-agent ima-

tinib did not achieve a significant clinical response among patients with AML,

MDS, atypical CML, or CMML without PDGF-R fusion genes. Preliminary data on

polycythemia vera are promising and deserve further investigation. Responses

among myelofibrosis patients were minor. Therefore, a combination treatment

regimen including imatinib may be more effective. Cancer 2003;97:2760 – 6.

© 2003 American Cancer Society.

DOI 10.1002/cncr.11416

KEYWORDS: imatinib mesylate, acute myeloid leukemia, myelodysplastic syndrome,platelet-derived growth factor, myelofibrosis, polythemia vera.

Imatinib mesylate (STI571; Gleevec, East Hanover, NJ) is a potentand selective tyrosine kinase inhibitor with significant in vitro ac-

tivity against c-abl and bcr-abl.1,2 This selective activity has translatedinto remarkable response efficacy in patients with Philadelphia chro-mosome (Ph)-positive chronic myeloid leukemia (CML).3–9 Sixty per-cent of patients with CML who do not respond to interferon-alpha(IFN-�) therapy achieved a major cytogenetic response with ima-tinib.3,4 Significant responses have also been reported in CML pa-

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© 2003 American Cancer Society

tients in accelerated7,10 and blastic phases.4,8,9 Ther-apy was well tolerated. Only 2% of patientsdiscontinued therapy because of toxicity.3

In addition to its inhibitory activity against c-abland bcr-abl, imatinib also inhibits two other tyrosinekinases, c-kit and platelet-derived growth factor-re-ceptor (PDGF-R).1,11,12 In vitro inhibition of these ki-nases was achieved at concentrations similar to thoserequired to inhibit bcr-abl, whereas minimal if anyinhibition of other tyrosine kinases (e.g., epidermalgrowth factor receptor, JAK-2, c-erbB2) was obtainedat these concentrations.1 C-kit (CD117) is expressed ingreater than 80% of patients with acute myeloid leu-kemia (AML) and high-risk myelodysplastic syndrome(MDS), including refractory anemia with excess ofblasts (RAEB) and RAEB in transformation (RAEB-T).13,14 Elevated plasma levels of PDGF have beenfound in patients with essential thrombocythemia,myelofibrosis (MF), polycythemia vera (PV), and othermyeloproliferative disorders (MPD)15,16 and may playa role in the pathogenesis of fibrosis associated withMPD. In addition, some patients with chronic my-elomonocytic leukemia (CMML) present with recipro-cal translocations involving the PDGF-RB gene.17

Most patients with AML and high-risk MDS die oftheir disease. There is no effective standard therapyfor MPD that can change significantly the course ofthe disease. Therefore, there is a great need for noveltherapies for these patients. We investigated whetherimatinib has antileukemic activity in patients withAML, MDS, and MPD.

MATERIALS AND METHODSPatients with AML or high-risk MDS (i.e., RAEB orRAEB-T) were eligible if they had failed to respond toprevious chemotherapy regimens (defined as failureto achieve disease remission or recurrence after che-motherapy). Also eligible were previously untreatedolder patients (age, � 60 years) who were not candi-dates for intensive induction chemotherapy becauseof concomitant medical problems or their refusal toreceive chemotherapy. In addition, patients were re-quired to express c-kit (CD117) in at least 10% of thebone marrow blasts by flow cytometry. Patients withlow-risk MDS or one of the following MPDs wereeligible regardless of their treatment history: CMML,MF, PV, and atypical chronic myeloid leukemia (CML).Atypical CML was defined as CML without the Phchromosome or the BCR/ABL fusion gene and wasassociated with dysplasia.18 All patients, regardless ofdiagnosis, were also required to have an Eastern Co-operative Oncology Group performance status scoreof 2 or lower, a creatinine level of 1.5 mg/dL or lower,and a total bilirubin level of 1.5 mg/dL or lower. In

addition, all other treatment regimens were to be dis-continued for all eligible patients. Patients signed aninformed consent as per institutional guidelines.

Patients were treated with a single daily oral doseof 400 mg imatinib. The guidelines for administration,interruption of therapy, and dose adjustments wereidentical to those used for patients with Ph-positiveCML.3,4 All patients were given a physical examinationbefore the start of therapy that included a completeblood count with a differential and platelet count,blood chemistry that comprised the concentrations oftotal protein, albumin, calcium, phosphorus, glucose,uric acid, blood urea nitrogen, creatinine, total biliru-bin, alkaline phosphatase, lactate dehydrogenase andalanine aminotransferase, and a bone marrow aspira-tion and biopsy with cytogenetic analysis. Patientswere followed for the duration of therapy with peri-odic physical examinations, CBC, SMA-12, and bonemarrow aspirations.

Statistical AnalysisData are presented as median (range) unless other-wise specified. The Mann–Whitney U test was used tocompare values between groups.

RESULTSFrom June 2001 to September 2001, 48 patients wererecruited and included in this study (Table 1). Themedian age of the cohort was 66 years (range, 23– 83years). Their distribution by disease category was asfollows: AML (n � 10), MDS (n � 8; refractory anemiawith ringed sideroblasts [RARS; n � 1] and RAEB [n� 7]), MF (n � 18), Ph-negative CML (n � 7), CMML(n � 3), and PV (n � 2).

AML and MDSEighteen patients with AML and MDS were treated.Their median age was 70 years (range, 23– 83 years).Twelve patients (67%) did not respond to a median of2 previous treatment regimens (range, 1– 4 regimens),including 6 patients who did not respond to high-dosecytosine arabinoside– containing regimens. Six pa-tients did not receive previous therapy for AML (n � 3)or MDS (n � 3). Their median age was 68 years (range,57– 83 years). Only 1 patient (RARS) had c-kit expres-sion in less than 20% of blasts and 10 (56%) had c-kitexpression in 80% or greater of blasts. The medianblast count in the bone marrow was 18.5% (range,0 – 65%) and 11 patients had blasts present in theperipheral blood (PB; median, 5%; range, 1–38%).Among patients with MDS, 2 were classified as RAEB Iaccording to the World Health Organization (WHO)criteria (i.e., � 5% blasts in the PB, 5–9% in the bonemarrow), and 5 were categorized as RAEB II (i.e.,

Imatinib Mesylate Therapy/Cortes et al. 2761

5–19% blasts in PB or 10 –19% in the bone marrow).18

Eight patients (44%) had no cytogenetic abnormali-ties. Cytogenetic abnormalities in the other 10 pa-tients (56%) included trisomy 8 (n � 4), chromosome5 or 7 abnormalities (n � 3), complex abnormalities (n� 2), and dup (1) (n � 1).

Patients received therapy for a median of 60.5days (range, 20 –174 days). None of these patients hada complete or partial response to therapy by standardcriteria.19,20 There was no significant change (increaseor decrease) in the white blood cell count (WBC)throughout the course of therapy except for 2 patientswhose WBC doubled and to more than 20 � 109/L.This occurred over a period of more than 90 days inboth instances. Detailed review of the blast countsduring therapy did not demonstrate any significantchange during therapy except for 1 patient who had atransient decrease in bone marrow blast count to 3%,which increased to 37% 3 weeks later. Two patientshad a significant but transient increase in plateletcount from 67 to 108 �109/L and from 63 to 332�109/L, respectively. The two patients with MDS whopresented with splenomegaly had a significant reduc-tion in spleen size. Spleen size decreased from 10 cmbelow the costal margin (BCM) to undetectable andfrom 7 cm to 1 cm BCM, respectively. Among 6 pre-viously untreated patients, 1 later received chemo-therapy and achieved a complete remission of diseasethat lasted 28 weeks. The median survival for the 18patients with AML or MDS was 15 weeks.

MPDsThirty patients with various MPDs were included. Lev-els of PDGF-AB and PDGF-BB were measured in 25patients (83%) and found to be significantly highercompared with normal controls (data not shown).

MFEighteen patients with MF were treated. Their medianage was 61 years (range, 28 –77 years). Sixteen patients(89%) had received a median of 2 previous treatmentsfor MF (range, 1–5 treatments), including thalidomide(n � 12), IFN-� (n � 4), etanercept (n � 5), and otherinvestigational agents (n � 6). The initial WBC was lessthan 4 � 109/L in 2 patients (11%) and greater than 30� 109/L in 3 patients (17%). Eight patients (17%) hada hemoglobin level less than 10 g/dL and 5 patients(28%) were transfusion dependent. Two patients re-ceived erythropoietin. The platelet count was less than50 � 109/L in 3 patients (17%; 1 patient was transfu-sion dependent) and greater than 500 � 109/L in 5patients (28%). Eight patients (44%) had cytogeneticabnormalities. Fourteen patients had splenomegaly atthe start of therapy, with a median of 13 cm BCM(range, 4 –22 cm BCM) and 1 patient underwent asplenectomy for symptomatic splenomegaly.

Ten of 14 patients (71%) with splenomegaly had areduction in spleen size of at least 30% (median re-duction, 46%; range, 30 –100%) to a median spleen sizeof 6.5 cm BCM (range, 0 –15 cm BCM). Four patients(29%) had complete resolution of splenomegaly (pre-treatment spleen size, 9.5, 7, 5, and 4 cm BCM). He-matologic improvement was noted in some patients.Three patients had minor hematologic improvementin erythroid series. For example, 1 patient had agreater than 50% decrease in transfusion require-ments from 1 transfusion per week to 1 transfusionevery 3– 4 weeks (Fig. 1) and 2 patients had an im-provement of hemoglobin levels by 1.8 and 2.1 g/dL,respectively (from 11.8 to 13.9 g/dL and from 11.6 to13.4 g/dL). Two of 3 patients with a platelet count lessthan 50 � 109/L at the start of therapy had an im-

TABLE 1Patient Characteristics by Disease Group

Characteristic

No. (median)

AML/MDS Myelofibrosis Ph-CML PVa CMML

No. 18 18 7 2 3Age (yrs) 70 (23–83) 61 (28–77) 67 (48–73) 48, 59 65 (56–67)WBC (� 109/L) 2.4 (0.9–12.1) 12.25 (1.5–123.3) 10.2 (5.4–47.1) 9.3, 7.9 31.3 (10–59.8)Platelets (� 109/L) 48 (5–164) 340 (7–762) 144 (47–287) 654, 235 173 (60–230)Hemoglobin level (g/dL) 8.8 (6.7–11) 10.1 (7.8–13.3) 11.1 (9.5–11.9) 15.5, 14.6 9.6 (8.8–13.9)No. of patients with splenomegaly 4 14 4 1 1Spleen size (cm BCM) 4 (1–10) 13 (4–25) 3 (1–10) 17 9No. of patients previously treated (%) 12 (67) 16 (89) 6 (86) 2 (100) 1 (33)

AML: acute myeloid leukemia; MDS: myelodysplastic syndrome; Ph-CML: Philadelphia chromosome-negative chronic myeloid leukemia; PV: polycythemia vera; CMML: chronic myelomonocytic leukemia; BCM:

below costal margin.a Individual values for each patient.

2762 CANCER June 1, 2003 / Volume 97 / Number 11

provement in platelet count. One patient had signifi-cant improvement (from 7 � 109 to 63 � 109/L; Fig. 1),and 1 had a less substantial improvement (from 40� 109 to 68 � 109/L). One additional patient whostarted with a platelet count of 104 � 109/L had anincrease in platelet count to 256 � 109/L. One patient(Fig. 1) had a dramatic improvement in absolute neu-trophil count (from 0.12 � 109 to 2.1 � 109/L). Thus,one patient (Fig. 1) had a significant trilineage re-sponse. This patient required a dose reduction of ima-tinib to 300 mg daily because of Grade 3 bone pain.She stopped responding after 16 weeks of therapy. Inaddition, all 3 patients who started with a WBC greaterthan 10 � 109/L had a significant reduction of WBC (�25% reduction). Their WBC decreased from 193 � 109

to 24 � 109/L, from 41 � 109 to 29 � 109/L, and from35 � 109 to 23 � 109/L, respectively. Fourteen patientsdiscontinued therapy after a median of 15 weeks(range, 5–31 weeks). Two patients discontinued ther-apy because of toxicity while still showing a responseand 12 discontinued because of lack of response orthere was no further hematologic improvement. Fourpatients (22%) continued with therapy a median of 53weeks form the start of therapy (range, 48 –58 weeks).Overall, 13 of 18 patients had an objective improve-ment in clinical or hematologic features.

Atypical CMLSeven atypical CML patients with a median age of 67years (range, 48 –73 years) were treated. Six patientshad received previous therapy with hydroxyurea and 2had failed previous therapy with R115777, a farnesyl-transferase inhibitor. One patient did not receive pre-vious treatment. Two patients had a pretreatment he-moglobin level of less than 10 g/dL and 5 patients had

a WBC geater than 10 � 109/L. Four patients hadsplenomegaly of a median 3 cm BCM (range, 1–10 cmBCM).

One patient had a major hematologic improve-ment in hemoglobin level (from 9.5 to 13.7 g/dL).There were no other hematologic improvements.Three patients had minor improvement in spleno-megaly (from 1, 2, and 4 cm BCM to 0, 0, and 2 cmBCM, respectively). Patients received therapy for amedian of 14 weeks (range, 6 – 42 weeks).

PVTwo PV patients were treated. One patient had beendiagnosed 15 years before treatment was initiated withimatinib and had received 2–3 phlebotomies per year.This patient had splenomegaly 17 cm BCM and pre-treatment hematocrit value was 44.8%. Since the startof treatment, this patient did not require any phlebot-omies. However, therapy was discontinued after 32weeks because of persistent splenomegaly with nochange from pretreatment size. The second patienthad been diagnosed for with PV for 8 years, required 1phlebothomy every 2– 4 months, and had no spleno-megaly. The starting hematocrit value was 49.5%. Thispatient received therapy for more than 63 weeks andrequired only 1 phlebotomy 9 months after the start oftherapy for a hematocrit value of 49.7%. The currenthematocrit value is 42.6%. Neither patient had bleed-ing or thrombotic events during the course of therapywith imatinib.

CMMLThree patients with CMML were treated. One patienthad received previous treatment with hydroxyureaand R115777, and 2 patients had not received previoustreatment. Two had diploid cytogenetics and 1 hadtrisomy 21. Two patients had CMML 1 and 1 patienthad CMML 2 according to the WHO classification18

and 2 patients had a WBC greater than 12 � 109/L.None of these patients responded to treatment. Onepatient had stable disease for 33 weeks, 1 did not havea hematologic response after 4 weeks on therapy al-though there was evident reduction in spleen size(from 9 to 5 cm BCM), and 1 patient had a rapid blastictransformation after 1 week of therapy.

ToxicityTreatment was well tolerated. Fatigue was a commonside effect (n � 30 [63%]), although only 1 patient (2%)had Grade 3 toxicity. Other toxicities (� Grade 3)included bone pain in 2 patients (4%), fluid retentionin 2 patients (4%), nausea in 1 patient (2%), and dys-pepsia in 1 patient (2%).

FIGURE 1. Response to imatinib in a patient with myelofibrosis. HGB:

hemoglobin; WBC: white blood cell; ANC: absolute neutrophil count; PLT:

platelet; RBC: red blood cell.

Imatinib Mesylate Therapy/Cortes et al. 2763

DISCUSSIONThe preclinical development of imatinib, and the suc-cessful clinical experience in Ph-positive CML pa-tients, have boosted the interest in the search fortargeted therapies.21 The first obstacle to the develop-ment of such therapies is the identification of valid‘targets’. Ideally, these targets would be universallypresent in malignant cells (and absent in normal cells)in all patients with a certain type of malignancy. Inaddition, they would be relevant to the disease patho-physiology (e.g., through inhibition, stimulation, andbinding) so that targeting would lead to death of theaffected cells. Imatinib inhibits the tyrosine kinaseactivity not only of c-abl and bcr-abl, but also of c-kitand PDGF-R.1,11,12 Because of the presence and pos-sible biologic significance of these kinases in patientswith AML, MDS, and MPD, we investigated the possiblevalue of imatinib to treat patients with these diseases.

Our results did not show a significant activity ofimatinib in patients with AML and MDS, althoughc-kit was expressed in greater than 80% of blasts inmost patients. These results support the idea that theexpression (or overexpression) of c-kit is not by itselfsufficient to support expectations of a response toimatinib. A significant response to imatinib was dem-onstrated in gastrointestinal stromal tumors (GIST),22

a malignancy with frequent expression of c-kit. How-ever, c-kit frequently carries a mutation that confersconstitutional activation in GIST patients.23 Mastocy-tosis also frequently expresses mutated c-kit, whichconfers constitutive activation. However, this muta-tion occurs in codon 816, resulting in residue substi-tutions in the activation loop,24 and is insensitive toimatinib in vitro.25 Despite the frequent expression ofc-kit in AML and MDS patients, mutations are re-ported rarely.26 –29 Furthermore, expression of c-kithas no prognostic implications in AML patients.30 Thelack of response to imatinib suggests that it is ineffec-tive in inhibiting the tyrosine kinase activity of c-kit invivo or that inhibition of the tyrosine kinase activity ofc-kit by itself has no significant effect on the survivaland/or proliferation of leukemic cells. Whether ima-tinib may have activity in combination with otheragents remains to be determined.

Several reports have suggested the participation ofPDGF and activation of PDGF-R in myeloproliferativedisorders.15–17,31 In this regard, the activity observed inpatients with MF is noteworthy. Most patients had asignificant decrease in spleen size. This response wasobserved also in some patients with atypical CML andwith MDS. Tefferi et al.32 reported on 23 patients withMF who were treated with imatinib. Two patients(10%) had a greater than 50% reduction in spleen size.

In the current study, 10 patients had a greater than30% reduction in spleen size, including 1 partial re-sponse (� 50% reduction) and 4 complete responses.In both studies, the most significant reductions inspleen size occurred in patients with modest spleno-megaly, i.e., 4 and 7 cm BCM in the Tefferi et al. studyand 12 (partial), 9.5, 7, 5, and 4 cm BCM in the currentstudy. Transient improvement in hematopoiesis wasobserved in some patients. One patient had a signifi-cant trilineage response (Fig. 1). However, most otherresponses occurred in patients with mild cytopenias.These patients had pretreatment hemoglobin levels of11.6 and 11.8 g/dL and platelet counts of 48 � 109 and104 � 109/L, respectively. This was also the case in theseries by Tefferi et al. In their study, 11 patients (48%)experienced increases in platelet counts, but there wasno improvement in patients with pretreatment plate-let counts less than 100 � 109/L. Thus, earlier treat-ment with imatinib and/or the use of imatinib incombination with other agents (e.g., thalidomide33–35)might be more effective.

The two patients with PV did not need as manyphlebotomies. This observation requires further inves-tigation and we continue to explore the efficacy ofimatinib in PV patients. There were no responses inpatients with CMML. Tyrosine kinase fusion geneshave been identified in CMML and atypical CML pa-tients.17 These typically fuse PDGF-RB with one of atleast four different genes described to date.36 –39 Thesepatients usually have chromosomal translocations in-volving chromosome 5q33. Patients with these fusiongenes have been reported to achieve rapid hemato-logic, cytogenetic, and molecular responses with ima-tinib therapy.40,41 However, none of our patients hadany abnormality involving chromosome 5q33 and nonehad eosinophilia, a common feature among patientswith these fusion genes. Similar results were reported byRaza et al.42 in patients without PDGF-R fusion genes.

We conclude that imatinib, as administered in thisstudy, had no significant clinical activity against c-kit–positive AML or high-risk MDS patients. Minor activitywas seen in some patients with MF, which was man-ifested as a reduction in spleen size. The possible roleof imatinib earlier in the treatment of MF or in com-bination with other agents with reported activity inthis disease, such as thalidomide and farnesyltrans-ferase inhibitors, deserves further investigation. In ad-dition, the possible role of imatinib in the treatment ofPV patients deserves further investigation.

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