Results of imatinib mesylate therapy in patients ... - Wiley Online Library

2760

Results of Imatinib Mesylate Therapy in Patients with Refractory or Recurrent Acute Myeloid Leukemia, High-Risk Myelodysplastic Syndrome, and Myeloproliferative 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, Stefan Faderl, M.D.1 Laurie Letvak, M.D.3 August Salvado, M.D.3 Hagop Kantarjian, M.D.1

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 expressed in most patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) and PDGF has been implicated in the pathogenesis of myeloproliferative disorders (MPD). METHODS. The authors investigated the efficacy of imatinib in patients with these M.D.

1

1

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

2

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

3

Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.

Dr. Armand Keating served as guest editor on this article. Dr. Cortes is a clinical research scholar for The Leukemia and Lymphoma Society, White Plains, New York. Address for reprints: Jorge Cortes, M.D., Department of Leukemia, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., P.O. Box 428, Houston, TX 77030; Fax: (713) 794-4297; E-mail: jcortes@ mdanderson.org Received December 13, 2002; revision received February 24, 2003; accepted February 27, 2003. © 2003 American Cancer Society

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 imatinib 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.

I

matinib mesylate (STI571; Gleevec, East Hanover, NJ) is a potent and selective tyrosine kinase inhibitor with significant in vitro activity against c-abl and bcr-abl.1,2 This selective activity has translated into remarkable response efficacy in patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML).3–9 Sixty percent of patients with CML who do not respond to interferon-alpha (IFN-␣) therapy achieved a major cytogenetic response with imatinib.3,4 Significant responses have also been reported in CML pa-

Imatinib Mesylate Therapy/Cortes et al.

tients in accelerated7,10 and blastic phases.4,8,9 Therapy was well tolerated. Only 2% of patients discontinued therapy because of toxicity.3 In addition to its inhibitory activity against c-abl and bcr-abl, imatinib also inhibits two other tyrosine kinases, c-kit and platelet-derived growth factor-receptor (PDGF-R).1,11,12 In vitro inhibition of these kinases was achieved at concentrations similar to those required to inhibit bcr-abl, whereas minimal if any inhibition of other tyrosine kinases (e.g., epidermal growth factor receptor, JAK-2, c-erbB2) was obtained at these concentrations.1 C-kit (CD117) is expressed in greater than 80% of patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), including refractory anemia with excess of blasts (RAEB) and RAEB in transformation (RAEBT).13,14 Elevated plasma levels of PDGF have been found in patients with essential thrombocythemia, myelofibrosis (MF), polycythemia vera (PV), and other myeloproliferative disorders (MPD)15,16 and may play a role in the pathogenesis of fibrosis associated with MPD. In addition, some patients with chronic myelomonocytic leukemia (CMML) present with reciprocal translocations involving the PDGF-RB gene.17 Most patients with AML and high-risk MDS die of their disease. There is no effective standard therapy for MPD that can change significantly the course of the disease. Therefore, there is a great need for novel therapies for these patients. We investigated whether imatinib has antileukemic activity in patients with AML, MDS, and MPD.

MATERIALS AND METHODS Patients with AML or high-risk MDS (i.e., RAEB or RAEB-T) were eligible if they had failed to respond to previous chemotherapy regimens (defined as failure to achieve disease remission or recurrence after chemotherapy). Also eligible were previously untreated older patients (age, ⱖ 60 years) who were not candidates for intensive induction chemotherapy because of concomitant medical problems or their refusal to receive chemotherapy. In addition, patients were required to express c-kit (CD117) in at least 10% of the bone marrow blasts by flow cytometry. Patients with low-risk MDS or one of the following MPDs were eligible regardless of their treatment history: CMML, MF, PV, and atypical chronic myeloid leukemia (CML). Atypical CML was defined as CML without the Ph chromosome or the BCR/ABL fusion gene and was associated with dysplasia.18 All patients, regardless of diagnosis, were also required to have an Eastern Cooperative Oncology Group performance status score of 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

2761

addition, all other treatment regimens were to be discontinued for all eligible patients. Patients signed an informed consent as per institutional guidelines. Patients were treated with a single daily oral dose of 400 mg imatinib. The guidelines for administration, interruption of therapy, and dose adjustments were identical to those used for patients with Ph-positive CML.3,4 All patients were given a physical examination before the start of therapy that included a complete blood count with a differential and platelet count, blood chemistry that comprised the concentrations of total protein, albumin, calcium, phosphorus, glucose, uric acid, blood urea nitrogen, creatinine, total bilirubin, alkaline phosphatase, lactate dehydrogenase and alanine aminotransferase, and a bone marrow aspiration and biopsy with cytogenetic analysis. Patients were followed for the duration of therapy with periodic physical examinations, CBC, SMA-12, and bone marrow aspirations.

Statistical Analysis Data are presented as median (range) unless otherwise specified. The Mann–Whitney U test was used to compare values between groups.

RESULTS From June 2001 to September 2001, 48 patients were recruited and included in this study (Table 1). The median age of the cohort was 66 years (range, 23– 83 years). Their distribution by disease category was as follows: AML (n ⫽ 10), MDS (n ⫽ 8; refractory anemia with 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 MDS Eighteen 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 of 2 previous treatment regimens (range, 1– 4 regimens), including 6 patients who did not respond to high-dose cytosine arabinoside– containing regimens. Six patients 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 expression in less than 20% of blasts and 10 (56%) had c-kit expression in 80% or greater of blasts. The median blast count in the bone marrow was 18.5% (range, 0 – 65%) and 11 patients had blasts present in the peripheral blood (PB; median, 5%; range, 1–38%). Among patients with MDS, 2 were classified as RAEB I according to the World Health Organization (WHO) criteria (i.e., ⬍ 5% blasts in the PB, 5–9% in the bone marrow), and 5 were categorized as RAEB II (i.e.,

2762

CANCER June 1, 2003 / Volume 97 / Number 11

TABLE 1 Patient Characteristics by Disease Group No. (median) Characteristic

AML/MDS

Myelofibrosis

Ph-CML

PVa

CMML

No. Age (yrs) WBC (⫻ 109/L) Platelets (⫻ 109/L) Hemoglobin level (g/dL) No. of patients with splenomegaly Spleen size (cm BCM) No. of patients previously treated (%)

18 70 (23–83) 2.4 (0.9–12.1) 48 (5–164) 8.8 (6.7–11) 4 4 (1–10) 12 (67)

18 61 (28–77) 12.25 (1.5–123.3) 340 (7–762) 10.1 (7.8–13.3) 14 13 (4–25) 16 (89)

7 67 (48–73) 10.2 (5.4–47.1) 144 (47–287) 11.1 (9.5–11.9) 4 3 (1–10) 6 (86)

2 48, 59 9.3, 7.9 654, 235 15.5, 14.6 1 17 2 (100)

3 65 (56–67) 31.3 (10–59.8) 173 (60–230) 9.6 (8.8–13.9) 1 9 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.

5–19% blasts in PB or 10 –19% in the bone marrow).18 Eight patients (44%) had no cytogenetic abnormalities. Cytogenetic abnormalities in the other 10 patients (56%) included trisomy 8 (n ⫽ 4), chromosome 5 or 7 abnormalities (n ⫽ 3), complex abnormalities (n ⫽ 2), and dup (1) (n ⫽ 1). Patients received therapy for a median of 60.5 days (range, 20 –174 days). None of these patients had a complete or partial response to therapy by standard criteria.19,20 There was no significant change (increase or decrease) in the white blood cell count (WBC) throughout the course of therapy except for 2 patients whose WBC doubled and to more than 20 ⫻ 109/L. This occurred over a period of more than 90 days in both instances. Detailed review of the blast counts during therapy did not demonstrate any significant change during therapy except for 1 patient who had a transient decrease in bone marrow blast count to 3%, which increased to 37% 3 weeks later. Two patients had a significant but transient increase in platelet count from 67 to 108 ⫻109/L and from 63 to 332 ⫻109/L, respectively. The two patients with MDS who presented with splenomegaly had a significant reduction in spleen size. Spleen size decreased from 10 cm below the costal margin (BCM) to undetectable and from 7 cm to 1 cm BCM, respectively. Among 6 previously untreated patients, 1 later received chemotherapy and achieved a complete remission of disease that lasted 28 weeks. The median survival for the 18 patients with AML or MDS was 15 weeks.

MPDs Thirty patients with various MPDs were included. Levels of PDGF-AB and PDGF-BB were measured in 25 patients (83%) and found to be significantly higher compared with normal controls (data not shown).

MF Eighteen patients with MF were treated. Their median age was 61 years (range, 28 –77 years). Sixteen patients (89%) had received a median of 2 previous treatments for MF (range, 1–5 treatments), including thalidomide (n ⫽ 12), IFN-␣ (n ⫽ 4), etanercept (n ⫽ 5), and other investigational agents (n ⫽ 6). The initial WBC was less than 4 ⫻ 109/L in 2 patients (11%) and greater than 30 ⫻ 109/L in 3 patients (17%). Eight patients (17%) had a hemoglobin level less than 10 g/dL and 5 patients (28%) were transfusion dependent. Two patients received erythropoietin. The platelet count was less than 50 ⫻ 109/L in 3 patients (17%; 1 patient was transfusion dependent) and greater than 500 ⫻ 109/L in 5 patients (28%). Eight patients (44%) had cytogenetic abnormalities. Fourteen patients had splenomegaly at the start of therapy, with a median of 13 cm BCM (range, 4 –22 cm BCM) and 1 patient underwent a splenectomy for symptomatic splenomegaly. Ten of 14 patients (71%) with splenomegaly had a reduction in spleen size of at least 30% (median reduction, 46%; range, 30 –100%) to a median spleen size of 6.5 cm BCM (range, 0 –15 cm BCM). Four patients (29%) had complete resolution of splenomegaly (pretreatment spleen size, 9.5, 7, 5, and 4 cm BCM). Hematologic improvement was noted in some patients. Three patients had minor hematologic improvement in erythroid series. For example, 1 patient had a greater than 50% decrease in transfusion requirements from 1 transfusion per week to 1 transfusion every 3– 4 weeks (Fig. 1) and 2 patients had an improvement of hemoglobin levels by 1.8 and 2.1 g/dL, respectively (from 11.8 to 13.9 g/dL and from 11.6 to 13.4 g/dL). Two of 3 patients with a platelet count less than 50 ⫻ 109/L at the start of therapy had an im-

Imatinib Mesylate Therapy/Cortes et al.

2763

a WBC geater than 10 ⫻ 109/L. Four patients had splenomegaly of a median 3 cm BCM (range, 1–10 cm BCM). One patient had a major hematologic improvement in hemoglobin level (from 9.5 to 13.7 g/dL). There were no other hematologic improvements. Three patients had minor improvement in splenomegaly (from 1, 2, and 4 cm BCM to 0, 0, and 2 cm BCM, respectively). Patients received therapy for a median of 14 weeks (range, 6 – 42 weeks).

PV 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.

provement in platelet count. One patient had significant 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 who started with a platelet count of 104 ⫻ 109/L had an increase in platelet count to 256 ⫻ 109/L. One patient (Fig. 1) had a dramatic improvement in absolute neutrophil count (from 0.12 ⫻ 109 to 2.1 ⫻ 109/L). Thus, one patient (Fig. 1) had a significant trilineage response. This patient required a dose reduction of imatinib to 300 mg daily because of Grade 3 bone pain. She stopped responding after 16 weeks of therapy. In addition, all 3 patients who started with a WBC greater than 10 ⫻ 109/L had a significant reduction of WBC (ⱖ 25% reduction). Their WBC decreased from 193 ⫻ 109 to 24 ⫻ 109/L, from 41 ⫻ 109 to 29 ⫻ 109/L, and from 35 ⫻ 109 to 23 ⫻ 109/L, respectively. Fourteen patients discontinued therapy after a median of 15 weeks (range, 5–31 weeks). Two patients discontinued therapy because of toxicity while still showing a response and 12 discontinued because of lack of response or there was no further hematologic improvement. Four patients (22%) continued with therapy a median of 53 weeks form the start of therapy (range, 48 –58 weeks). Overall, 13 of 18 patients had an objective improvement in clinical or hematologic features.

Two PV patients were treated. One patient had been diagnosed 15 years before treatment was initiated with imatinib and had received 2–3 phlebotomies per year. This patient had splenomegaly 17 cm BCM and pretreatment hematocrit value was 44.8%. Since the start of treatment, this patient did not require any phlebotomies. However, therapy was discontinued after 32 weeks because of persistent splenomegaly with no change from pretreatment size. The second patient had been diagnosed for with PV for 8 years, required 1 phlebothomy every 2– 4 months, and had no splenomegaly. The starting hematocrit value was 49.5%. This patient received therapy for more than 63 weeks and required only 1 phlebotomy 9 months after the start of therapy for a hematocrit value of 49.7%. The current hematocrit value is 42.6%. Neither patient had bleeding or thrombotic events during the course of therapy with imatinib.

CMML Three patients with CMML were treated. One patient had received previous treatment with hydroxyurea and R115777, and 2 patients had not received previous treatment. Two had diploid cytogenetics and 1 had trisomy 21. Two patients had CMML 1 and 1 patient had 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. One patient had stable disease for 33 weeks, 1 did not have a hematologic response after 4 weeks on therapy although there was evident reduction in spleen size (from 9 to 5 cm BCM), and 1 patient had a rapid blastic transformation after 1 week of therapy.

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

Toxicity Treatment was well tolerated. Fatigue was a common side effect (n ⫽ 30 [63%]), although only 1 patient (2%) had Grade 3 toxicity. Other toxicities (ⱖ Grade 3) included bone pain in 2 patients (4%), fluid retention in 2 patients (4%), nausea in 1 patient (2%), and dyspepsia in 1 patient (2%).

2764


DISCUSSION The preclinical development of imatinib, and the successful clinical experience in Ph-positive CML patients, have boosted the interest in the search for targeted therapies.21 The first obstacle to the development of such therapies is the identification of valid ‘targets’. Ideally, these targets would be universally present in malignant cells (and absent in normal cells) in all patients with a certain type of malignancy. In addition, they would be relevant to the disease pathophysiology (e.g., through inhibition, stimulation, and binding) so that targeting would lead to death of the affected cells. Imatinib inhibits the tyrosine kinase activity not only of c-abl and bcr-abl, but also of c-kit and PDGF-R.1,11,12 Because of the presence and possible biologic significance of these kinases in patients with AML, MDS, and MPD, we investigated the possible value of imatinib to treat patients with these diseases. Our results did not show a significant activity of imatinib in patients with AML and MDS, although c-kit was expressed in greater than 80% of blasts in most patients. These results support the idea that the expression (or overexpression) of c-kit is not by itself sufficient to support expectations of a response to imatinib. A significant response to imatinib was demonstrated in gastrointestinal stromal tumors (GIST),22 a malignancy with frequent expression of c-kit. However, c-kit frequently carries a mutation that confers constitutional activation in GIST patients.23 Mastocytosis also frequently expresses mutated c-kit, which confers constitutive activation. However, this mutation occurs in codon 816, resulting in residue substitutions in the activation loop,24 and is insensitive to imatinib in vitro.25 Despite the frequent expression of c-kit in AML and MDS patients, mutations are reported rarely.26 –29 Furthermore, expression of c-kit has no prognostic implications in AML patients.30 The lack of response to imatinib suggests that it is ineffective in inhibiting the tyrosine kinase activity of c-kit in vivo or that inhibition of the tyrosine kinase activity of c-kit by itself has no significant effect on the survival and/or proliferation of leukemic cells. Whether imatinib may have activity in combination with other agents remains to be determined. Several reports have suggested the participation of PDGF and activation of PDGF-R in myeloproliferative disorders.15–17,31 In this regard, the activity observed in patients with MF is noteworthy. Most patients had a significant decrease in spleen size. This response was observed also in some patients with atypical CML and with MDS. Tefferi et al.32 reported on 23 patients with MF 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 than 30% reduction in spleen size, including 1 partial response (⬎ 50% reduction) and 4 complete responses. In both studies, the most significant reductions in spleen size occurred in patients with modest splenomegaly, i.e., 4 and 7 cm BCM in the Tefferi et al. study and 12 (partial), 9.5, 7, 5, and 4 cm BCM in the current study. Transient improvement in hematopoiesis was observed in some patients. One patient had a significant trilineage response (Fig. 1). However, most other responses occurred in patients with mild cytopenias. These patients had pretreatment hemoglobin levels of 11.6 and 11.8 g/dL and platelet counts of 48 ⫻ 109 and 104 ⫻ 109/L, respectively. This was also the case in the series by Tefferi et al. In their study, 11 patients (48%) experienced increases in platelet counts, but there was no improvement in patients with pretreatment platelet counts less than 100 ⫻ 109/L. Thus, earlier treatment with imatinib and/or the use of imatinib in combination with other agents (e.g., thalidomide33–35) might be more effective. The two patients with PV did not need as many phlebotomies. This observation requires further investigation and we continue to explore the efficacy of imatinib in PV patients. There were no responses in patients with CMML. Tyrosine kinase fusion genes have been identified in CMML and atypical CML patients.17 These typically fuse PDGF-RB with one of at least four different genes described to date.36 –39 These patients usually have chromosomal translocations involving chromosome 5q33. Patients with these fusion genes have been reported to achieve rapid hematologic, cytogenetic, and molecular responses with imatinib therapy.40,41 However, none of our patients had any abnormality involving chromosome 5q33 and none had eosinophilia, a common feature among patients with these fusion genes. Similar results were reported by Raza et al.42 in patients without PDGF-R fusion genes. We conclude that imatinib, as administered in this study, had no significant clinical activity against c-kit– positive AML or high-risk MDS patients. Minor activity was seen in some patients with MF, which was manifested as a reduction in spleen size. The possible role of imatinib earlier in the treatment of MF or in combination with other agents with reported activity in this disease, such as thalidomide and farnesyltransferase inhibitors, deserves further investigation. In addition, the possible role of imatinib in the treatment of PV patients deserves further investigation.

REFERENCES 1.

Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561–566.

Imatinib Mesylate Therapy/Cortes et al. 2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17. 18.

Beran M, Cao X, Estrov Z, et al. Selective inhibition of cell proliferation and BCR-ABL phosphorylation in acute lymphoblastic leukemia cells expressing Mr 190,000 BCR-ABL protein by a tyrosine kinase inhibitor (CGP-57148). Clin Cancer Res. 1998;4:1661–1672. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645– 652. Kantarjian HM, Cortes J, O’Brien S, et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood. 2002; 99:3547–3553. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038 –1042. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031–1037. Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood. 2002;99:1928 –1937. Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 2002;99:3530 –3539. Ottmann OG, Druker BJ, Sawyers CL, et al. A Phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood. 2002;100:1965–1971. Kantarjian HM, O’Brien S, Cortes JE, et al. Treatment of Philadelphia chromosome–positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Cancer Res. 2002;8:2167–2176. Carroll M, Ohno-Jones S, Tamura S, et al. CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood. 1997;90:4947– 4952. Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000;96: 925–932. Bene MC, Bernier M, Casasnovas RO, et al. The reliability and specificity of c-kit for the diagnosis of acute myeloid leukemias and undifferentiated leukemias. The European Group for the Immunological Classification of Leukemias (EGIL). Blood. 1998;92:596 –599. Wells SJ, Bray RA, Stempora LL, Farhi DC. CD117/CD34 expression in leukemic blasts. Am J Clin Pathol. 1996;106: 192–195. Gersuk GM, Carmel R, Pattengale PK. Platelet-derived growth factor concentrations in platelet-poor plasma and urine from patients with myeloproliferative disorders. Blood. 1989;74:2330 –2334. Rueda F, Pinol G, Marti F, Pujol-Moix N. Abnormal levels of platelet-specific proteins and mitogenic activity in myeloproliferative disease. Acta Haematol. 1991;85:12–15. Cross NC, Reiter A. Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Leukemia. 2002;16:1207–1212. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100:2292–2302.

2765

19. Cheson BD, Bennett JM, Kantarjian H, et al. Myelodysplastic syndromes standardized response criteria: further definition. Blood. 2001;98:1985. 20. Cheson BD, Cassileth PA, Head DR, et al. Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol. 1990;8:813– 819. 21. Mauro MJ, O’Dwyer M, Heinrich MC, Druker BJ. STI571: a paradigm of new agents for cancer therapeutics. J Clin Oncol. 2002;20:325–334. 22. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472– 480. 23. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577–580. 24. Ma Y, Longley BJ, Wang X, Blount JL, Langley K, Caughey GH. Clustering of activating mutations in c-KIT’s juxtamembrane coding region in canine mast cell neoplasms. J Invest Dermatol. 1999;112:165–170. 25. Ma Y, Zeng S, Metcalfe DD, et al. The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations. Blood. 2002;99:1741–1744. 26. Ning ZQ, Li J, Arceci RJ. Signal transducer and activator of transcription 3 activation is required for Asp(816) mutant c-Kit-mediated cytokine-independent survival and proliferation in human leukemia cells. Blood. 2001;97:3559 –3567. 27. Ashman LK, Ferrao P, Cole SR, Cambareri AC. Effects of mutant c-kit in early myeloid cells. Leuk Lymphoma. 2000; 37:233–243. 28. Broudy VC, Smith FO, Lin N, Zsebo KM, Egrie J, Bernstein ID. Blasts from patients with acute myelogenous leukemia express functional receptors for stem cell factor. Blood. 1992;80:60 – 67. 29. Tajima F, Kawatani T, Ishiga K, Nanba E, Kawasaki H. Serum soluble c-kit receptor and expression of c-kit protein and mRNA in acute myeloid leukemia. Eur J Haematol. 1998;60: 289 –296. 30. Schwartz S, Heinecke A, Zimmermann M, et al. Expression of the C-kit receptor (CD117) is a feature of almost all subtypes of de novo acute myeloblastic leukemia (AML), including cytogenetically good-risk AML, and lacks prognostic significance. Leuk Lymphoma. 1999;34:85–94. 31. Reilly JT. Pathogenesis and management of idiopathic myelofibrosis. Baillieres Clin Haematol. 1998;11:751–767. 32. Tefferi A, Mesa RA, Gray LA, et al. Phase 2 trial of imatinib mesylate in myelofibrosis with myeloid metaplasia. Blood. 2002;99:3854 –3856. 33. Barosi G, Grossi A, Comotti B, Musto P, Gamba G, Marchetti M. Safety and efficacy of thalidomide in patients with myelofibrosis with myeloid metaplasia. Br J Haematol. 2001; 114:78 – 83. 34. Elliott MA, Mesa RA, Li CY, et al. Thalidomide treatment in myelofibrosis with myeloid metaplasia. Br J Haematol. 2002; 117:288 –296. 35. Piccaluga PP, Visani G, Pileri SA, et al. Clinical efficacy and antiangiogenic activity of thalidomide in myelofibrosis with myeloid metaplasia. A pilot study. Leukemia. 2002;16:1609 – 1614.

2766


36. Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell. 1994;77:307–316. 37. Ross TS, Bernard OA, Berger R, Gilliland DG. Fusion of Huntingtin interacting protein 1 to platelet-derived growth factor beta receptor (PDGFbetaR) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2). Blood. 1998;91:4419 – 4426. 38. Schwaller J, Anastasiadou E, Cain D, et al. H4(D10S170), a gene frequently rearranged in papillary thyroid carcinoma, is fused to the platelet-derived growth factor receptor beta gene in atypical chronic myeloid leukemia with t(5;10)(q33; q22). Blood. 2001;97:3910 –3918. 39. Magnusson MK, Meade KE, Brown KE, et al. Rabaptin-5 is a

novel fusion partner to platelet-derived growth factor beta receptor in chronic myelomonocytic leukemia. Blood. 2001; 98:2518 –2525. 40. Magnusson MK, Meade KE, Nakamura R, Barrett J, Dunbar CE. Activity of STI571 in chronic myelomonocytic leukemia with a platelet-derived growth factor beta receptor fusion oncogene. Blood. 2002;100:1088 –1091. 41. Apperley JF, Gardembas M, Melo JV, et al. Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med. 2002;347:481– 487. 42. Raza A, Lisak L, Dutt D, et al. Gleevec (imatinib mesylate) in 16 patients with chronic myelomonocytic leukemia (CMMoL) [abstract]. Blood. 2001;98:273b.