437 Chronic Myelogenous Leukemia: A Review and Update of Therapeutic Strategies Guillermo Garcia-Manero, M.D.1 Stefan Faderl, M.D.1 Susan O’Brien, M.D.1 Jorge Cortes, M.D.1 Moshe Talpaz, M.D.2 Hagop M. Kantarjian, 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. Address for reprints: Hagop M. Kantarjian, M.D., Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 428, Houston, TX 77030; Fax: (713) 792-2031; E-mail: [email protected] Received February 13, 2003; revision received March 28, 2003; accepted April 9, 2003 © 2003 American Cancer Society DOI 10.1002/cncr.11520 C hronic myelogenous leukemia (CML) is a myeloproliferative disorder of pluripotent hematopoietic stem cells.1 The growth advantage of the leukemic cells over normal hematopoietic cells is due to both excessive proliferation and failure of programmed cell death (apoptosis) of the CML cells.2– 6 Patients with CML may present with signs or symptoms related to leukocytosis, splenomegaly, or anemia. However, the presenting features of CML have changed over time, and in 30 – 40% of cases it often is diagnosed accidentally by a routine blood test or physical examination (Table 1). The Philadelphia chromosome (Ph), the hallmark cytogenetic abnormality of CML, is identiﬁed in the bone marrow cells of ⬎ 90% of patients with the clinical and laboratory features of CML (Fig. 1).7,8 The Ph abnormality, which represents a balanced translocation involving the long arms of chromosomes 9 and 22, t(9; 22)(q34;q11), produces the BCR-ABL fusion gene. BCR-ABL gives rise to a chimeric protein, p210BCR-ABL, which is characterized by constitutive activation of its tyrosine kinase activity. Increased autophosphorylation and abnormal phosphorylation of various cytosolic protein targets then induces activation of multiple downstream signaling pathways that are responsible for the phenotype of CML.9 –13 The course of CML follows a biphasic or triphasic course with a chronic, accelerated, and blastic phase. Survival from the time of diagnosis of each phase is shown in Figure 2. The majority of patients (85%) present in chronic phase but, if left untreated, the disease will progress into the accelerated and blastic phases. The median survival of patients with CML has improved from 3– 4 years when treated with busulfan or hydroxyurea to 6 – 8 years in the era of interferon-␣ (IFN-␣) therapy. The introduction of newer therapies such as imatinib mesylate (Gleevec™ [STI571]; Novartis Pharmaceutical Corporation, East Hanover, NJ), a BCR-ABL-speciﬁc tyrosine kinase inhibitor, may further improve the outcome of patients with CML (Fig. 3). Allogeneic stem cell transplantation (SCT) can produce long-term event-free survival rates of 40 – 80%, depending on several factors such as disease stage, patient age, and degree of host-donor matching. CML provides a prime example of a disease characterized by a well deﬁned cytogenetic-molecular abnormality that is capable of transforming hematopoietic progenitor cells, thus inducing the clinical manifestations of the disease. Therefore, CML has become a paradigm for our understanding of leukemogenesis, for targeted drug development in recent years (of which imatinib mesylate is one example), and for the signiﬁcance of the evaluation of minimal residual disease in the setting of SCT and other treatment approaches. 438 CANCER August 1, 2003 / Volume 98 / Number 3 TABLE 1 Presentation of Chronic Myelogenous Leukemia in Newly Diagnosed Patients by Time Period Percent of patients Parameter No. referred Age (yrs) Splenomegaly Hepatomegaly Lymphadenopathy Symptoms at presentation Hemoglobin (g/dL) Platelets (⫻ 109/L) Leukocytes (⫻ 109/L) Peripheral blasts % bone marrow blasts % peripheral basophils % bone marrow basophils Prognostic group (Hasford score69) Category 1965–1980 1981–1989 1990–2000 2001 Onward ⱖ 60 Yes Yes Yes Yes ⬍ 12 ⬎ 700 ⬎ 100 Yes ⱖ5 ⱖ7 ⱖ4 Good Intermediate Poor 215 19 75 44 22 16 61 27 71 66 11 15 25 40 38 22 409 12 57 23 9 40 50 20 56 55 7 12 21 59 34 7 1073 17 46 8 4 40 46 14 51 57 7 14 19 55 37 8 230 26 36 6 3 32 34 16 43 54 7 11 29 49 45 7 P value ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 0.03 0.16 0.54 0.01 ⬍ 0.001 FIGURE 1. The Philadelphia chromo- some. ETIOLOGY The cause of CML is unknown. Leukemogenesis is a multistep phenomenon that is divided into initiation, promotion, and progression phases. The initiation phase involves acquisition of a genetic defect that confers cell survival advantage. What triggers the generation of the initiation step in CML is unknown. In experiments in which leukemic cell lines were exposed to gamma irradiation, fusion genes characteristic of different forms of leukemias were induced, although these defects were also detected at a low level in untreated cells.14 The generation of the BCRABL gene is now recognized as the key molecular event leading to CML. What induces this molecular rearrangement is unknown. Using highly sensitive polymerase chain reaction (PCR) techniques, BCR- ABL transcripts could be detected in the bone marrow cells of 25–30% of healthy volunteers and in 5% of infants, but not in cord blood cells.15,16 Because clinical CML is reported to develop in only 1–2 of 100,000 individuals, it follows that in most of these individuals, those cells expressing BCR-ABL do not produce overt CML disease. This observation suggests that immune regulatory processes or additional molecular events contribute to the development of CML. There is no evidence supporting hereditary or genetic factors. BCR-ABL is found only in hematopoietic cells, and there is no increased incidence of CML in monozygotic twins or in the relatives of patients with CML. No chemical or infectious exposures have been linked to CML. The incidence of CML is reported to be higher in survi- Chronic Myelogenous Leukemia/Garcia-Manero et al. 439 FIGURE 2. Survival of patients in the chronic, accelerated, or blastic phases of chronic myelogenous leukemia. FIGURE 3. Survival of patients with chronic myelogenous leukemia who were referred in early chronic phase by year of therapy (M. D. Anderson patient data obtained between 1965–2002). vors of the atomic bomb or nuclear exposures, as well as after ionizing radiation. INCIDENCE Every year, approximately 5000 –7000 individuals are diagnosed with CML in the U.S. The annual incidence is 1–2 cases per 100,000 individuals. CML accounts for approximately 15% of all leukemias and 7–20% of adult leukemias. The incidence has not changed over the last 50 years. CML affects males more often than females (ratio of 1.3–2.2 to 1). The incidence of CML increases with age. The median age at presentation reported from large cohort studies is 45–55 years.17–19 The median age reported in the Surveillance, Epide- 440 CANCER August 1, 2003 / Volume 98 / Number 3 miology, and End Results (SEER) program data is 67 years, suggesting either a referral bias of younger patients to investigational studies and tertiary centers, or a different coding reporting of the SEER data.20,21 In the trials of imatinib mesylate, 30% of patients were age ⬎ 60 years,22 although this incidence was only 12% in studies of IFN-␣ regimens, perhaps reﬂecting a referral bias because older patients tend not to tolerate IFN as well as their younger counterparts.23 CML comprises ⬍ 5% of pediatric leukemia cases. BIOLOGY CML is deﬁned by the Ph chromosome or the presence of the BCR-ABL transcript in the leukemic cells.24 –27 The Ph chromosome is detectable in 90% of patients with a clinical and laboratory picture of CML (Ph-positive CML). In the remaining 10% of Ph-negative patients, BCR-ABL transcripts can be found in approximately 30 –50%. These Ph-negative, BCR-ABLpositive CML cases have clinicopathologic features and prognosis identical to Ph-positive CML patients, and respond similarly to therapy.28 –30 The truly Phnegative and BCR-ABL-negative patients are a heterogeneous group with an inferior prognosis that is variably referred to as Ph-negative CML, atypical CML, proliferative variants of myelodysplastic syndromes, or chronic myelomonocytic leukemia (CMML).31,32 The Ph chromosome was ﬁrst described in 1960 as a shortened chromosome 22.7 It was later characterized as a balanced translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11).8 The Ph has been identiﬁed in myeloid, erythroid, megakaryocytic, and B-lymphoid precursor cells; rarely in T-lymphoid precursor cells; and not at all in bone marrow ﬁbroblasts, indicating that CML originates in a pluripotent hematopoietic stem cell. Variant chromosomal abnormalities have been described in CML, including simple and complex Ph translocations and “masked” Ph (translocations between chromosomes 9;22 and other chromosomes), depending on the number and particular chromosomes involved. C-ABL has 11 exons and expands over 230 kilobases (kb). It is located on chromosome 9q34 and encodes a 140-kilodalton (kD) protein with weak tyrosine kinase activity. C-ABL has two alternate exon I sequences that are transcribed differentially from two different promoters (Fig. 1). These exons are designated Ib and Ia and their respective promoters are Pb and Pa. Exon Ib is located at the 5⬘ end of the gene and is 150 –200 kb upstream of exon Ia. The ﬁrst common exon of C-ABL is exon 2. The proximal promoter (Pa) and the distal promoter (Pb) are separated by 175 kb. They direct the synthesis of 2 different mRNA species of 6 kb and 7 kb, respectively. In approximately 90% of Ph translocations, the proximal promoter, Pa, is nested within the BCR-ABL transcriptional unit. In the majority of cases of CML, the translocation breakpoint occurs between exons Ib and Ia; therefore, the Ph chromosome contains the entire coding sequence of C-ABL (exons 2-11) and an intact exon Ia and its promoter. It should be noted that the C-ABL promoter is usually silenced and has no regulatory effect on BCR-ABL transcription.33 In t(9;22), this 3⬘ end of CABL is transposed from chromosome 9 into the major breakpoint cluster region of BCR (M-BCR) on chromosome 22. This region is located between exons 12 and 16 (also known as b1– b5) of BCR on chromosome 22 and extends over 5.8 kb. Usually, the breakpoints in BCR are located between introns b2 and b3 or b3 and b4. As a consequence, a BCR-ABL fusion gene is generated with either a b2a2 or b3a2 junction (denoting the exons in BCR and ABL involved). This hybrid gene is transcribed into an 8.5-kb mRNA that is translated into a chimeric protein of 210 kD, p210BCR-ABL.24 A second breakpoint cluster region of BCR is referred to as the minor breakpoint cluster region or m-BCR, and is located 5⬘ of M-BCR. It reportedly is involved in 50 – 80% of Ph-positive acute lymphoblastic leukemia (ALL) cases,34 but only rarely occurs in CML.35 Although several investigators have reported low levels of this transcript in patients with CML,36,37 the m-BCR breakpoint is within a long intron separating alternative exon e2⬘ from exon 2. Secondary splicing of alternative exons e1⬘ and e2⬘ generates an e1a2 junction between BCR (e1) and ABL (a2). Because of the proximal location of m-BCR, the BCR-ABL fusion gene generated is smaller, resulting in a fusion protein of only 190 kD, p190BCR-ABL. A third breakpoint cluster region, -BCR, located more distally at the 3⬘ end of M-BCR, has recently been described. It is located between exons e19 and e20, creating an e19a2 junction. The fusion protein generated has a molecular weight of 230 kD and is known as p230BCR-ABL. p230BCR-ABL has been described in cases of chronic neutrophilic leukemia, a rare disorder marked by sustained mature neutrophilic expansion, thrombocytosis, and a more indolent clinical behavior with a lower likelihood to transform than p210BCR-ABL-positive CML. The p230ABL-BCR oncoprotein is usually expressed at low levels in the leukemic cells, which may explain the less aggressive course of this disease variant.38 Transfection of bone marrow-derived cell lines with a retroviral vector-encoding BCR-ABL resulted in growth factor independency and malignant transformation. The N-terminus of ABL contains three Srchomology (SH) domains (SH1–SH3 domains), a catalytic domain, and a myristorylation sequence that allows the binding of BCR-ABL to plasma membrane Chronic Myelogenous Leukemia/Garcia-Manero et al. proteins. The C-terminus is comprised of a DNA-binding domain, nuclear localization signals, and an actinbinding site. Interactions of BCR with functional domains of ABL are believed to be responsible for the leukemogenic activity of BCR-ABL. The coiled-coil dimerization motif of the N-terminal segment of BCR inﬂuences the activity of ABL domains so that the tyrosine kinase activity of the fusion protein is increased. BCR also interferes with the SH3 domain of ABL. Because the SH3 domain has a negative regulatory effect on the tyrosine kinase activity of ABL, this interference constitutively activates the phosphotyrosine kinase activity of ABL. The C-ABL sequences deleted in p210BCR-ABL share homology with several nonreceptor tyrosine kinases including SRC. Deletion of these sequences activates the transforming capacity of C-ABL. The transforming activity of BCR-ABL is also regulated by the ﬁrst exon of BCR. This ﬁrst exon of BCR binds to the SRC Homology 2 (SH2) domain of ABL. This binding is essential for the transforming capacity of BCR-ABL.9,10 Signal Transduction Cascades of CML BCR-ABL oncoproteins are constitutively active tyrosine kinases. They exert their leukemogenic effect via autophosphorylation and phosphorylation of several signal transduction pathways including RAS, RAF, ERK, JNK, MYC, JAK/STAT, PI3Kinase-AKT, and NF-B pathways.39 – 48 Multiple adapter proteins such as CRKL, p62Dok, paxillin, CBL, RIN, SHC, and GRB2 link BCR-ABL to its downstream targets. GRB2 is fundamental in connecting p210BCR-ABL with RAS. GRB2 is a 26-kD protein comprised of 1 SH2 domain and 2 SH3 domains. It couples BCR-ABL to SOS, a RAS activator. GRB2 performs its docking function by binding with its SH2 domain to phosphorylated tyrosine kinases such as BCR-ABL, and with its SH3 domains to SOS. GRB2 cannot bind to either BCR or ABL alone. It speciﬁcally binds to the amino acid residue Y177F in the ﬁrst exon of BCR. This interaction is essential for RAS signaling. Mutation of Y177F inhibits the transforming capacity of BCR-ABL, implicating the RAS pathway at the core of the transforming signals generated by BCR-ABL. BCR-ABL also activates ubiquitindependent degradation of targeted proteins. BCR-ABL may also induce the proteasomal degradation of cyclin-dependent kinase inhibitors, such as p27, and thus may promote cell cycle progression. BCR-ABL has also been reported to have antiapoptotic activity. Expression of BCR-ABL protects growth factor-dependent cells from apoptotic cell death after cytokine withdrawal, and up-regulates bcl-2 and bcl-XL. The causal association between the BCR-ABL molecular abnormalities and the development of CML 441 has been proven in several animal models.11–13 Transfection of BCR-ABL into hematopoietic stem cells, which were then reinfused into irradiated mice, mirrored the pathophysiology of a CML-like disease in humans; a CML-like proliferative disease was noted in 50% of engrafted mice, whereas others developed lymphoblastic-like disease or monocytic tumors. The ﬁnding that expression of BCR-ABL itself can imitate the clinical manifestations of CML, including progression from chronic to blastic phase, has encouraged the development of BCR-ABL-speciﬁc tyrosine kinase inhibitors such as imatinib mesylate. Molecular Events in Transformed CML Additional nonrandom cytogenetic abnormalities are found in 50 – 80% of patients with advanced stage CML. These include the presence of a double Ph, trisomy 8, isochromosome 17 or other chromosome 17 abnormalities, additional chromosomes 19 and 21, monosomies of chromosome 7, and t(3;21)(q26;q22). Isochromosome 17 is typically associated with myeloid blastic phase.49 –51 Molecular abnormalities include clonal immunoglobulin and T-cell receptor rearrangements in patients with lymphoid transformation; mutations of RAS; and abnormalities of p53, RB1, CMYC, p16INK4, and AML-EVI-1. The majority of these abnormalities have a cytogenetic counterpart and are associated with particular phenotypic characteristics. p53 abnormalities are frequently associated with myeloid blastic phase and at times are linked to isochromosome 17, whereas RB1 abnormalities are usually found in lymphoid blastic phase. Mutations in p53 have been observed in transformed phases but not in chronic-phase CML, suggesting that functional loss of p53 may be involved in disease evolution. SYMPTOMS AND SIGNS: NATURAL HISTORY CML typically evolves along three clinical phases. The initial chronic phase is followed by an accelerated phase that eventually transforms into the blastic phase. Approximately 85% of patients present in chronic phase and nearly 80% of cases progress into the accelerated phase before development of the blastic phase. Presenting features are changing in time because of earlier diagnosis, a result of routine physical examinations and blood testing (Table 1). The incidence of asymptomatic presentation in the chronic phase has increased from 15% to approximately 40 –50%. Features of increased tumor burden or aggressive disease (splenomegaly, basophilia, highrisk presentation) are also reportedly decreasing. Symptoms at the time of presentation are often the result of anemia or splenomegaly, and include fatigue and left upper abdominal pain or mass.52 Less com- 442 CANCER August 1, 2003 / Volume 98 / Number 3 mon presentations are related to a hypermetabolic state with fever, anorexia, weight loss, or gout, or to consequences of platelet dysfunction such as hemorrhage, ecchymosis, hematomas, or thromboembolic events. Findings of hyperleukocytosis and hyperviscosity include priapism, tinnitus, stupor, retinal hemorrhages, and cerebrovascular accidents. On physical examination, splenomegaly is reported in 40 – 60%, of cases and hepatomegaly in 10 –20%. Manifestations of extramedullary hematopoiesis such as subcutaneous lesions or lymphadenopathy are rare, and identify a subgroup of patients with poor prognosis. Features of accelerated phase are evidence of progressive maturation arrest with increased blasts and basophils, resistance to therapy, increased constitutional symptoms, progressive splenomegaly, cytogenetic clonal evolution, leukocytosis, and thrombocytosis or thrombocytopenia.52,53 Approximately 10 –20% of patients die in accelerated phase, which is reported to have a median survival time of 1– 1.5 years. Patients who develop blastic phase often are symptomatic with weight loss, fever, night sweats, and bone pain, as well as infections and bleeding.54 – 61 Extramedullary hematopoiesis is also frequent and involves the lymph nodes, skin, subcutaneous tissues, bone, and central nervous system (30% of lymphoid blastic-phase disease).62,63 Lymphoid blastic phase is more frequent in younger patients (40% in patients age ⬍ 40 years).61,62 Deﬁnitions of accelerated and blastic-phase CML are summarized in Table 2.53,55 LABORATORY FINDINGS The most common feature in chronic-phase CML is leukocytosis; approximately 50 –70% of patients present with a leukocyte count ⬎ 100 ⫻ 109/L. Cyclic variations in the leukocyte count have been described in 10 –20% of patients. Thrombocytosis is observed in 30 –50% of patients and may exceed 1000 ⫻ 109 /L. Platelet aggregation abnormalities are frequent. Anemia (hemoglobin level ⬍ 10 g/dL) is observed in 20% of patients. The peripheral blood differential shows myeloid cells in all stages of maturation. Basophils and eosinophils may be increased. The leukocyte alkaline phosphatase (LAP) score, although rarely used now, is low and may help to differentiate CML from other myeloproliferative disorders or secondary leukemoid reactions. The bone marrow is hypercellular with an elevated myeloid to erythroid ratio of 10:1 to 30:1. Megakaryocytes are frequently increased, and Gaucher-like cells and sea-blue histiocytes are observed in 10% of cases. Grade 3-4 reticulin stain-measured myeloﬁbrosis is reported in 40% of cases and has been associated with a worse prognosis.64 More stringent accelerated phase criteria derived TABLE 2 Features and Deﬁnitions of Accelerated and Blastic-Phase CML Accelerated phase CML A. Multivariate analysis-derived criteria: Peripheral blasts ⱖ 15% Peripheral blasts ⫹ promyelocytes ⱖ 30% Peripheral basophils ⱖ 20% Platelets ⬍ 100 ⫻ 109/L unrelated to therapy Cytogenetic clonal evolution B. Criteria used in common practice: Bone marrow or peripheral blasts ⱖ 10% Bone marrow or peripheral basophils and eosinophils ⱖ 20% Frequent Peger-Huët-like neutrophils, nucleated red cells, or megakaryocytic nuclear fragments Increased bone marrow reticulin or collagen ﬁbrosis Leukocytosis (⬎ 50 ⫻ 109/L), anemia (hematocrit ⬍ 25%), and thrombocytopenia (⬎ 100 ⫻ 109/L) not responsive to antileukemic therapy Marked thrombocytosis (⬎ 1000 ⫻ 109/L) Progressive splenomegaly unresponsive to therapy Unexplained fever or bone pain Requirement of increased doses of medication Blastic-phase CML – ⱖ 30% bone marrow or peripheral blasts – Extramedullary hematopoiesis with immature blasts CML: chronic myelogenous leukemia. from a multivariate analysis are shown in Table 2. Increased number of blasts (ⱖ 15%) or blasts and promyelocytes (ⱖ 30%), basophilia (ⱖ 20%) in the blood or bone marrow, thrombocytopenia ⬍ 100 ⫻ 109/L is unrelated to therapy, and clonal evolution have been deﬁned by multivariate analysis to be predictive of a survival of ⱕ 1.5 years.53 The blastic phase of CML is deﬁned by the presence of ⱖ 30% blasts, or extramedullary blastic inﬁltrates.55 Approximately 50% of patients have the myeloid phenotype, 25% have the lymphoid phenotype, and 25% of patients have undifferentiated or other rare blastic phenotypes (megakaryocytic, erythroid, promyelocytic, or basophilic).55–59 Lymphoid blastic origin is deﬁned by a negative peroxidase (MPO) stain; positive terminal deoxynucleotidyl transferase (TdT); and the expression of pre-B cell markers including CD19, CD20, and the common acute lymphoid leukemia antigen (CALLA, CD10).60,61 Myeloid marker coexpression in lymphoid blastic phase is common. Few patients with lymphoid blast-phase CML express low levels of peroxidase positivity (⬍ 5%).60 PROGNOSTIC FACTORS The clinical course of CML is heterogeneous. With hydroxyurea or busulfan therapy, the median survival Chronic Myelogenous Leukemia/Garcia-Manero et al. is reported to be 3– 4 years. The expected annual mortality rate is 5–10% in the ﬁrst 2 years and 15–25% subsequently. Pretreatment poor prognostic factors for survival include the presence of splenomegaly, older age, leukocytosis, increased blast or basophil counts, thrombocytosis or thrombocytopenia, and cytogenetic clonal evolution.65 Several multivariate-derived prognostic models and staging systems have been proposed.65–70 These models are helpful in deﬁning individual prognosis, assigning patients to different strategies based on risk, evaluating the effects of newer therapies, and comparing the relative beneﬁts of existing therapies within risk groups. The percentages of patients in good (30 –50%), intermediate (30 – 40%), and poor (10 –20%) risk categories have varied in different studies. Median survival times with chemotherapy ranged from 50 – 60 months, 36 – 40 months, and 24 –30 months, respectively. With IFN-␣ the median survival times were reported to be 102 months, 80 –95 months, and 45– 60 months, respectively, in the 3 risk groups. The European Collaborative CML Prognostic Factors Project Group developed a prognostic score (also known as the Euro score or Hasford score) that included age, spleen size, percent of blasts, percent of eosinophils plus basophils, and platelet counts as variables. Using this model, 42% of patients were found to have low-risk, 45% to have intermediate-risk, and 13% to have high-risk disease. The 10-year survival rates were 42%, 18%, and 5%, respectively.69 Response to treatment with IFN-␣ and imatinib mesylate were also powerful treatment-associated prognostic factors. The 10-year survival rates of patients achieving a complete cytogenetic response with IFN-␣ were reported to be between 70 – 80%.71–74 Cytogenetic clonal evolution remains a poor prognostic factor in CML65,66,70 in the era of IFN-␣, as well as with imatinib mesylate therapy.22,75,76 However, its prognostic signiﬁcance depends on several factors including the speciﬁc abnormality, its prevalence, onset time, association with other variables, and therapy.65,77 Clonal evolution as the only sign of disease acceleration is associated with favorable prognosis after allogeneic SCT.78 Several molecular markers have been investigated for their prognostic signiﬁcance. Large deletions of derivative chromosome 9 were observed in a subgroup of patients (15%) and were associated with poor prognosis (median survival of 38 months vs. 88 months; P ⬍ 0.01).79 DNA methylation of the Pa promoter of C-ABL was associated with late chronic phase and with transformation.80,81 Telomere shortening in chronic-phase disease was associated with faster progression to accelerated phase and with increased risk of blastic transformation within 2 years.82 Expression 443 of proteins of the IFN regulatory family (IRF), in particular IRF 4, were down-regulated in T cells from patients with CML, and were found to predict for response to IFN-␣ treatment.83,84 DIAGNOSTIC EVALUATION The diagnostic workup includes a complete blood count with differential and platelet count to evaluate blastosis, basophilia, thrombocytosis, and thrombocytopenia; and bone marrow aspiration and biopsy to quantify the percentage of blasts and basophils, degree of ﬁbrosis, and for cytogenetic analysis. Cytogenetic analysis remains the gold standard in the diagnosis of CML. The major advantage of conventional chromosome studies is the detection of other cytogenetic abnormalities (i.e., clonal evolution as a marker of disease progression). Conventional cytogenetic analysis is limited by the number of metaphases analyzed (approximately 20 –25 with a good harvest), and is time-consuming. Patients occasionally may present with thrombocytosis alone and are erroneously labeled as having essential thrombocytosis. Thus, all patients with the clinical and laboratory picture of essential thrombocytosis should also undergo cytogenetic analysis to identify the rare Ph-positive cases. Genomic polymerase chain reaction (PCR) and Southern blot analysis can delineate the exact BCR breakpoints. Reverse transcriptase (RT)-PCR and Northern blot analysis are able to detect BCR-ABL transcripts, and antibodies against BCR or ABL detect the BCRABL protein. Occasionally, patients present with p190BCR-ABL-positive disease that can be detected by PCR but not by Southern blot analysis.35 Another rare entity, p230BCR-ABL CML, may manifest as Ph-positive, BCR-ABL-negative CML. Speciﬁc PCR studies and protein analysis will conﬁrm the diagnosis of p230BCR-ABL CML.38 The differential diagnosis in CML includes leukemoid reactions (typical leukocyte counts of ⬍ 50 ⫻ 109/L and the presence of toxic granulation and vacuolation, as well as Döhle bodies in the granulocytes, the absence of basophilia, and a normal or increased LAP score), use of corticosteroids (which rarely cause extreme neutrophilia and left shift, selflimited), and other myelodysplastic or myeloproliferative syndromes. Patients with agnogenic myeloid metaplasia with or without myeloﬁbrosis often have splenomegaly and may present with neutrophilia and thrombocytosis. Patients with polycythemia rubra vera associated with iron deﬁciency may present with a normal hemoglobin and hematocrit values and elevated neutrophil and platelet counts. Documentation of the Ph abnormality is virtually diagnostic for CML and helps to exclude other conditions. 444 CANCER August 1, 2003 / Volume 98 / Number 3 Laboratory Monitoring of Response and Evaluation of Minimal Residual Disease Response to therapy is evaluated by the disappearance of the Ph chromosome or the BCR-ABL transcripts. Cytogenetic analysis has a limited role in the detection and follow-up of minimal residual disease, which is better evaluated with other techniques.85–100 Fluorescent in situ hybridization (FISH) is typically performed by cohybridization of a BCR and ABL probe to denatured metaphase chromosomes or interphase nuclei. FISH techniques allow rapid evaluation of several hundred cells in a time-efﬁcient manner. Several molecular techniques are used to detect the BCR-ABL gene. Southern blot analysis is limited by the amount of DNA required. False-positive or false-negative results with Southern blot analysis are rare, but can occur due to changes in the size of the rearranged band. Southern blot analysis measures the level of BCR-ABL and these results usually correspond with cytogenetic results. Southern blot analysis has a low sensitivity and cannot be used to assess minimal residual disease. It is best used in patients who are Ph negative to detect Ph-negative, BCR-ABL-positive CML. BCR-ABL protein detection and quantiﬁcation can be performed by Western blot analysis, through probing protein lysates, from blood or bone marrow with an antibody against ABL, thus allowing the detection of the three BCR-ABL protein isoforms.96 PCR, the most sensitive molecular technique, is particularly well suited for the evaluation of minimal residual disease.90 –100 It can detect 1 Ph-positive cell among 104 to 108 normal cells. Qualitative RT-PCR studies are useful in monitoring residual disease in cytogenetic complete responders. Original studies involved patients after allogeneic SCT.98 Positivity as detected by nested PCR at 6 months and 12 months after transplantation was found to correlate signiﬁcantly with disease recurrence.98 RT-PCR negativity in patients who achieved a complete cytogenetic response in the nontransplantation setting also has been found to be predictive of long-term event-free survival.74,93 Quantitative real-time RT-PCR and competitive RT-PCR studies are currently being evaluated for their predictive value for achieving rapid response in patients with active disease, and for long-term event-free survival in patients achieving a complete cytogenetic response while receiving imatinib mesylate therapy.99 –102 A practical approach to monitoring patients is shown in Table 3. The occurrence of additional chromosomal abnormalities has been described in Ph-positive as well as Ph-negative cells of patients treated with imatinib mesylate.103,104 This ﬁnding also had been reported previously with IFN-␣ therapy.105 TABLE 3 Monitoring of Patients with Ph-Positive CML Receiving Imatinib Time receiving therapy Tests Pretherapy On therapy Cytogenetics; FISH-PB; QPCR-PB FISH every 2–3 months; cytogenetics every 6–12 months; once FISH ⬍ 10%, conﬁrm CR by cytogenetic studies QPCR every 2–3 months Cytogenetics every 6–12 months In CR Ph: Philadelphia chromosome; Cml: chronic myelogenous Leukemia, FISH: ﬂuorescent in situ hybridization; PB: peripheral blood; QPCR: quantitative polymerase chain reaction; CR: complete response. These abnormalities have included trisomy 8 and chromosome 5 or 7 abnormalities. Because the prognostic signiﬁcance of these abnormalities is unknown, it would be appropriate to continue monitoring patients with additional bone marrow cytogenetic studies at least once a year. TREATMENT Treatment decisions in patients with CML are based on the patient’s age and phase of the disease.106 –108 Busulfan was the ﬁrst agent shown to provide effective hematologic control in patients with CML,109 but its use should be discouraged outside the setting of preparative regimens for allogeneic SCT.110 The use of busulfan outside the setting of preparative allogeneic SCT regimens has been associated with signiﬁcantly worse survival, with worse outcome after allogeneic SCT, and with potentially serious side effects including delayed myelosuppression and organ damage.111,112 Hydroxyurea is an excellent debulking agent and allows for the rapid control of the blood count, inducing hematological responses in 50 – 80% of patients.113 Cytogenetic responses are rare, and hydroxyurea does not appear to change the natural history of CML. Hydroxyurea is very effective in initial cytoreduction as an adjunct to other more deﬁnitive therapies, and to control disease in preparation for allogeneic SCT. However, it should not be considered deﬁnitive therapy for CML. Other palliative strategies include 6-mercaptopurine, 6-thioguanine, cytarabine, melphalan, other chemotherapies, and anagrelide (for thrombocytosis). Deﬁnitive Therapy for Patients with CML is Divided into Transplant and NonTransplant Alternatives. Allogeneic SCT Allogeneic SCT is curative in selected patients with CML, and is most effective when performed during the chronic phase of disease. In chronic-phase CML, allogeneic SCT is associated with 3–5-year survival rates of Chronic Myelogenous Leukemia/Garcia-Manero et al. 40 – 80%, and 10-year survival rates of 30 – 60%. Transplantation-related mortality (TRM) ranges from 5–50%, depending on patient age, donor origin (related vs. unrelated) and degree of matching, patient and host cytomegalovirus status, adequate use of antiinfective prophylaxis, preparative regimens, and institutional expertise, among other factors.114 –122 Recurrence rates are 20% and the risk of disease recurrence is reported to plateau at 5 –7 years after transplantation. The two most signiﬁcant factors reported to inﬂuence transplantation outcome are patient age and phase of disease. Disease-free survival (DFS) rates with matched-related allogeneic SCT are 40 – 80% in chronic phase, 15– 40% in accelerated phase, and 5–20% in blastic phase. In chronic phase CML, patients age ⬍ 30 – 40 years are reported to have DFS rates of 60 – 80%, 1-year TRM rates of ⬍ 5% to 20%, and recurrence rates of 20%. Outcome worsens with older age. Large series have reported 5-year survival rates of 30 – 40% in patients age ⬎ 50 years. The European Bone Marrow Transplantation Registry (EBMTR) reported a TRM of 47% and a 5-year DFS of 25% in patients age ⬎ 45 years.115 The optimal timing of transplantation is controversial; the majority of transplantation centers recommend transplantation in early chronic-phase CML within 1 year from diagnosis. Several recent updates have shown little difference in long-term outcome among patients transplanted in the ﬁrst 12 months after diagnosis compared with those transplanted during the ﬁrst 24 months.123 The use of IFN-␣ prior to transplantation has not been shown to negatively inﬂuence the outcome of matched related allogeneic SCT nor the outcome of unrelated allogeneic SCT, provided IFN-␣ is discontinued at least 3 months prior to the transplant procedure.106,124 –126 Toxicity from preparative regimens is observed in 100% of patients. Acute graft-versus-host disease (GVHD) occurs in 10 – 60% of patients and is the cause of death in 10 –15%. Chronic GVHD occurs in 75% of patients and its associated mortality is 10%. Strategies to minimize GVHD include the use of T-cell depletion, which improves TRM but increases recurrence rates and the occurrence of secondary lymphoproliferative disorders. The most common causes of death after transplantation are acute GVHD (2–13%), chronic GVHD (8 –10%), interstitial pneumonitis (4 –32%), opportunistic infections (3–24%), venoocclusive disease (1– 4%), and resistant disease recurrence (5–10%). Longterm complications of allogeneic SCT include sterility, cataracts, hip necrosis, secondary tumors (5–10%), chronic GVHD complications, and worse quality of life. One limitation of allogeneic SCT is the availability of related donors. Human leukocyte antigen (HLA)- 445 compatible unrelated donors are found in 50% of patients. Patients of white origin have an 85% chance of identiﬁcation of a perfect match. The median time from donor search to transplantation is approximately 3– 6 months.120,121,127 The use of unrelated donors is associated with higher morbidity and mortality rates. Recent single institutional studies have reported similar outcomes with unrelated SCT compared with related SCT when the transplant is provided by a molecularly perfectly matched donor.122 Greater than 50% of the mortality associated with unrelated allogeneic SCT is secondary to acute and chronic GVHD. Nonablative preparative regimens (mini-transplants, reduced intensity transplants) have attempted to expand the indications of allogeneic SCT to older patients, and to reduce transplant mortality and complications. Preparative regimens rely on immunosuppressive (rather than ablative) therapy to allow for donor cell engraftment. Early results of nonablative regimens in patients not considered to be eligible for standard transplantation demonstrate acceptable degrees of engraftment, less mortality, more persistent residual disease, and perhaps similar degrees of GVHD.128 The improved results from reduced morbidity and mortality may be offset by the higher incidence of persistent or recurrent disease, which could be approached with post-SCT maneuvers such as donor lymphocyte infusions (DLI), IFN-␣, or imatinib mesylate. Patients who develop disease recurrence after allogeneic SCT may be reinduced into a second longterm DFS with multiple modalities including DLI, imatinib mesylate, IFN-␣, or second allogeneic SCT.129 –135 RT-PCR studies predict for the probability of disease recurrence occurring after allogeneic SCT; patients who remain RT-PCR-positive 12 months after allogeneic SCT are reported to have a 30 – 40% recurrence probability compared with a probability of ⬍ 5% among RT-PCR-negative patients.98 DLI induce longterm DFS in 60% of patients who develop disease recurrence during the chronic phase of disease, but in only 10 –30% of those who develop disease recurrence during the accelerated or blastic phase.133 It also is associated with recurrent GVHD (20 –30%), severe myelosuppression (20 –30%), and mortality (10 –20%). Imatinib is effective in inducing complete cytogenetic and molecular disease remissions in patients whose disease recurs molecularly, cytogenetically, or in chronic phase after allogeneic SCT.135 Imatinib may soon precede DLI as the treatment of choice for this condition, particularly in patients with GVHD. Its results in patients who develop a disease recurrence during the accelerated or blastic phase of disease are poor. In such patients, combinations of imatinib with chemotherapy and DLIs should be considered, al- 446 CANCER August 1, 2003 / Volume 98 / Number 3 though patients should be monitored for the development of GVHD. IFN-␣ achieves responses in 30 – 40% of patients who develop disease recurrence in the chronic phase after allogeneic SCT.131,132 A second allogeneic SCT can be considered in patients who are ⬎ 12 months from a previous transplantation (to reduce complications and mortality), most likely after failure to respond to some of the above measures.134 Patients with a high predicted risk of disease recurrence (e.g., transplantation in accelerated-blastic phase) after allogeneic SCT may beneﬁt from preventive postallogeneic SCT maintenance measures such as imatinib or IFN-␣. Nontransplantation Therapies Interferon-␣-based therapies Single-agent IFN-␣ is active in CML. IFN-␣ doses used have ranged from 3–5 MU 3 times a week to 5 MU/m2 daily or the maximally tolerated daily dose.17–19 There is a dose-response effect, but side effects appear to increase with higher doses. Response rates with single-agent IFN-␣ include a complete hematologic response (CHR) of 40 – 80%, a cytogenetic response of 15–58%, a major cytogenetic response (Ph ⬍ 35%) of 30 –50%, and a complete cytogenetic response (Ph of 0%) of 5–25%. The median survivals ranged from 60 –90 months.136 –143 Achieving a complete cytogenetic response was associated with 10-year survival rates of 70 – 80%.71–74 Several randomized studies have compared IFN-␣ therapy with hydroxyurea or busulfan. In the majority of studies, IFN-␣ was associated with signiﬁcantly higher response rates and longer survivals.138 –143 A meta-analysis conﬁrmed the beneﬁt of IFN-␣ on survival, mainly in a low-risk group of patients.142 IFN-␣ has been combined with low doses of cytosine arabinoside (Ara-C). Several single-arm and randomized studies of IFN-␣ plus Ara-C compared with IFN-␣ alone have been conducted to date.144 –149 When IFN-␣ was given at a dose of 5 MU/m2 daily and Ara-C was given at a dose of 10 mg subcutaneously daily, a CHR was achieved in 92% of patients and a cytogenetic response was noted in 74%. The rates of major cytogenetic response were higher with IFN-␣ and daily Ara-C compared with IFN-␣ and intermittent Ara-C or IFN-␣ alone.147 Two randomized trials comparing IFN-␣ plus Ara-C with IFN-␣ have been reported to date.148,149 In a French multicenter trial conducted in patients with CML, IFN-␣ plus AraC was associated with a signiﬁcantly higher CHR rate at 6 months (66% vs. 55%; P ⬍ 0.01), a higher cytogenetic response rate at 12 months (61%vs. 50%; major in 38%vs. 26% [P ⬍ 0.01]), and signiﬁcantly better survival (5-year survival rate of 70% vs. 60%; P ⫽ 0.02). A landmark analysis at 2 years demonstrated an asso- ciation between cytogenetic response and survival; the 7-year survival rate was 85% with a complete or partial cytogenetic response, 62% with a minor cytogenetic response, and 25% for others.148 In the experience of the Italian Cooperative Study Group on CML (ICSG-CML), the combination of IFN-␣ plus Ara-C demonstrated better major cytogenetic response rates than IFN-␣ alone, but not better survival. However, the median duration of Ara-C therapy was only 7 months, and the drug was often discontinued because of side effects.149 Imatinib Mesylate Imatinib has revolutionized the treatment and prognosis of CML.150 –163 Several studies in patients with chronic-phase CML have shown high rates of complete cytogenetic responses. The impact of such therapy on long-term prognosis awaits further maturation of the data. However, if the early results continue to persist with long-term follow-up in relation to high rates of complete and durable cytogenetic responses, as well as low transformation and mortality rates and no new unexpected frequent long-term imatinib toxicities, then imatinib will soon be established as the most effective treatment for CML. Imatinib was identiﬁed as a lead compound in a high-throughput in vitro screen for tyrosine kinase inhibitors, and then was optimized for its activity for speciﬁc kinases.152 After the preclinical studies, and after overcoming several hurdles related to animal toxicities, oral formulation, and market economic considerations, imatinib entered Phase I trials in 1998155,156 and was approved by the Food and Drug Administration (FDA) in 2001 for the treatment of patients with chronic-phase CML after IFN-␣ failure, those with accelerated phase, and those with blastic phase.157,158 Imatinib is a small molecule 2-phenylaminopyrimidine that acts as an ATP mimic thus occupying the binding site for ATP within BCR-ABL, which then leads to inhibition of the phosphorylation of tyrosine residues on substrate proteins and BCRABL itself.152 Consequently, imatinib prevents activation of signal transduction pathways that are crucial for CML leukemogenesis. In addition to p210BCR-ABL, imatinib inhibits several other tyrosine kinases including p190BCR-ABL, v-ABL, c-ABL, c-Kit, and platelet-derived growth factor-receptor (PDGF-R). Phase I studies. In a Phase I study of patients with late chronic-phase and blastic-phase CML, including Phpositive ALL, the dose of imatinib was escalated from 25 mg to 1000 mg orally daily.155,156 Common but rarely serious side effects included nausea and emesis, diarrhea, skin rash, muscle cramps, bone or joint Chronic Myelogenous Leukemia/Garcia-Manero et al. aches, myelosuppression, and weight gain. Less common side effects reported to occur at higher doses were ﬂuid retention, periorbital and peripheral edema, fever, occasional liver dysfunction, and decreased skin pigmentation. No maximum tolerated dose or dose-limiting toxicities were deﬁned, but toxicities were more signiﬁcant at doses of ⱖ 800 mg daily. In the Phase I chronic-phase study, 83 patients were treated. Among 54 patients who received imatinib at doses of ⱖ 300 mg, the CHR rate was 98% and the cytogenetic response rate was 31% (complete in 13%).155 In blastic-phase CML, the bone marrow complete remission rate (bone marrow blasts ⬍ 5% with or without peripheral count recovery) was 32% in myeloid blastic phase and 55% in lymphoid blastic phase; responses were transient.156 Phase II studies. Three multiinstitutional, multinational pivotal studies of imatinib in late chronic phase after IFN-␣ failure, accelerated phase, and blastic phase were completed. The Phase II study in 532 patients in chronic phase CML and IFN-␣ failure utilized a dose of 400 mg of imatinib orally daily. Major cytogenetic responses were observed in 65% of patients and were complete in 48%. The estimated 24-month transformation rate was 13%; the estimated 24-month survival rate was 92%.22,164 A lower incidence of major cytogenetic response was observed in patients with splenomegaly, thrombocytopenia, anemia, a longer duration of the chronic phase, active disease, clonal evolution, and 100% Ph positivity at the initiation of therapy.159 The updated results of this trial164 and of the M. D. Anderson experience159 in patients treated on this study and on the expanded access study are summarized in Table 4. The Phase II study of imatinib in patients with accelerated phase disease accrued 235 patients (181 with a conﬁrmed diagnosis of accelerated phase disease). Patients received imatinib 400 mg or 600 mg daily. Overall, 82% of patients achieved a hematologic response, which lasted for at least 4 weeks in 69% (CHR in 34%). A major cytogenetic response was observed in 33% of patients (complete in 24%). The estimated 24-month progression-free survival and survival rates were 49% and 63%, respectively.157,165 Compared with 400 mg, imatinib 600 mg orally daily was associated with better cytogenetic responses and a longer median time to transformation and survival.157 The updated results of the FDA pivotal trial165 and the M. D. Anderson experience of patients treated on this study and the expanded access study160 are shown in Table 5. In the Phase II study in patients with blastic phase disease, the imatinib daily doses were 400 – 600 mg. 447 TABLE 4 Updated Results of Imatinib Therapy in Patients with Chronic Phase CML after Interferon-␣ Failure Parameter No. treated CHR (%) Cytogenetic response (%) Major Complete Progression-free survival (mos) (%) Survival (mos) (%) FDA pivotal trial M. D. Anderson experience 532 95 261 98 65 48 87 (24) 92 (24) 62 45 98 (18) 96 (18) CML: Chronic myelogenous leukemia; FDA: Food and Drug Administration; CHR: Complete hematologic response. TABLE 5 Updated Results of Imatinib Therapy in Patients with Accelerated Phase CML Parameter No. evaluable CHR (%) Cytogenetic response (%) Major Complete Progression-free survival (mos) (%) Survival (mos) (%) FDA pivotal trial M. D. Anderson experience 181 37 237 80 33 24 49 (24) 63 (24) 35 24 68 (18) 73 (18) CML: Chronic myelogenous leukemia; FDA: Food and Drug Administration; CHR: complete hematologic response. The overall response rates were 40 –50% (CHR in 7–20%), but the complete cytogenetic response rate was only 7%.158 The median survival was 7 months. Compared with Ara-C-based chemotherapy, imatinib produced similar response rates in patients with nonlymphoid blastic phase, and was associated with lower toxicity and induction mortality rates, and with better survival.161 However, the results still were poor, and combinations of imatinib and chemotherapy should be investigated further. The results of imatinib in cases of blastic phase have been updated and compared with intensive chemotherapy in Table 6. Phase III studies. A multinational study (IRIS) randomized 1106 patients to received either imatinib at a dose of 400 mg orally daily (n ⫽ 553) or a combination of IFN-␣ at a dose of 5 MU/m2 daily with Ara-C at a dose of 20 mg/m2 subcutaneously daily for 10 days every month (n ⫽ 553).163 The median follow-up time was 19 months. After 18 months of therapy, imatinib was associated with signiﬁcantly higher rates of major cytogenetic responses (87% vs. 35%) and complete cyto- 448 CANCER August 1, 2003 / Volume 98 / Number 3 TABLE 6 Results of Imatinib Therapy in Patients with blastic phase CML and Comparison of Results with Ara-C-Based Chemotherapy Combinations Parameter No. treated CHR plus other objective response (%) Cytogenetic response (%) Major Complete Survival Median (mos) 12-mos. (%) 4-week mortality (%) Imatinib; FDA pivotal trial Imatinib; M. D. Anderson Intensive chemotherapy, M.D. Anderson 229 75 133 8 ⫹ 22 (31%) 23 ⫹ 29 (52%) 29 16 7 12 7 Not available 7 28 7 23 4 4 15 15 P value 0.001 0.04 0.07 CML: chronic myelogenous leukemia; Ara-C: Cytosine arabinoside; FDA: Food and Drug Administration; CHR: Complete hematologic response. TABLE 7 Comparison of Imatinib Versus Interferon-␣ plus Low-Dose Ara-C in Newly Diagnosed Patients with Ph-Positive CML 18-month response parameter CHR (%) Cytogenetic response (%) Major Complete 18-mos progression-free survival (%) 18-mos transformation (%) 18-mos survival (%) Imatinib Interferon ⴙ Ara-C P value 97 69 0.001 87 76 35 14 0.001 0.001 92 3 97 73 9 95 0.001 0.001 0.16 Ara-C: cytosine arabinoside; Ph: Philadelphia Chromosome; CML: chronic myelogenous leukemia; CHR: Chronic hematologic response. genetic responses (76% vs. 14%) and with lower rates of disease progression (8% vs. 27%), transformation (3% vs. 9%), and intolerance (1% vs. 19%) (Table 7). These results illustrate that, whereas at the time of diagnosis, practically 100% of the bone marrow cells in patients with CML contain the Ph chromosome, a healthy but suppressed normal stem cell pool must exist in nearly all patients in the early chronic phase of the disease that can be reactivated by the suppression or elimination of Ph-containing leukemic bone marrow cells. Survival rates were 97% versus 95% (p ⫽ 0.16). However, the median duration of IFN-␣ plus Ara-C therapy was only 8 months and at the time of last follow-up, 89% of patients had either crossed over to imatinib therapy (58%) or elected to be taken off therapy and treated with commercially available imatinib. Thus, although a survival advantage for imatinib may not be detectable in this randomized trial, it could be inferred from comparisons with historical data (Fig. 1). Based on these results, imatinib should be considered the new frontline standard of care for CML patients with early chronic-phase disease. The incidence of qualitative or quantitative RT-PCR negativity is currently approximately 10% in patients with chronic-phase disease after IFN-␣ failure (median follow-up of 3 years), 10% in newly diagnosed patients after 12 months of imatinib at a dose of 400 mg daily, and about 30% in similar patients treated with imatinib at a dose of 800 mg daily.162,166 Recently, the emergence of resistance to imatinib has become the focus of intense research, especially in patients with acute leukemia and those previously treated with IFN. Several mechanisms have been identiﬁed, including mutations in the catalytic domain of the protein and, less frequently, ampliﬁcation of BCR-ABL.167 At the current time, this is a rare event in patients treated with imatinib initially. A practical approach to the management of the side effects occurring with imatinib is shown in Table 8. Special therapeutic considerations Patients with severe signs and symptoms related to hyperleukocytosis should undergo leukapheresis. These symptoms include evidence of cardiopulmonary compromise, alterations to the central nervous system, and priapism. Severe thrombocytosis may respond to anagrelide, thiotepa, IFN-␣, or pheresis. Pregnant women with CML may have their disease controlled with pheresis during the ﬁrst trimester, and later with hydroxyurea until delivery, although the long-term sequelae of this intervention are unknown. The use of IFN-␣ during pregnancy has been reported to be safe anecdotally in patients with essential thrombocytosis and in those with CML. However, little experience exists regarding the use of imatinib during Chronic Myelogenous Leukemia/Garcia-Manero et al. TABLE 8 Management of Side Effects from Imatinib Side effect Management Nausea and/or emesis Avoid taking imatinib on an empty stomach Diarrhea Skin rashes Muscle cramps Bone aches Liver function abnormalities Antiemetics (e.g., ondansetron at a dose of 8 mg orally or prochlorperazine at a dose of 10 mg orally 30 minutes prior to intake of imatinib) Adequate ﬂuid intake Loperamide at a dose of 2 mg orally after each loose bowel movement (up to 16 mg daily) or diphenoxylate atropine at a dose of 20 mg orally daily in 3–4 divided doses avoid sun exposure topical steroids (e.g., 0.1% triamcinolone cream topically as needed) Systemic steroids (e.g., prednisone at a dose of 20 mg orally daily for 3–5 days) Electrolyte substitution Tonic water (quinine) Ca2⫹ replacements Cox-2 inhibitors (e.g. celecoxib at a dose of 200 mg orally daily or rofecoxib at a dose of 25 mg orally daily) Hold imatinib Resume within 1–2 weeks Consider decreasing the dose (no less than 300 mg orally daily) Myelosuppression Anemia Neutropenia Thrombocytopenia Erythropoietin as needed G-CSF as needed Hold for platelets ⱕ 40 ⫻ 109/L High-dose folic acid Interleukin-11 as needed Resume at lower dose level (no less than 300 mg orally daily) G-CSF: granulocyte–colony-stimulating factor. pregnancy. Splenectomy may provide palliation in patients with CML in transformation. Experimental therapies for CML Other agents currently are being developed that may have enhanced activity in combination with imatinib. Polyethylene glycol (PEG) IFNs are a modiﬁed formulation of IFN-␣ attached to polyethylene glycol. This prolongs the half-life of IFN-␣ from minutes to days, allowing once-a-week administration, and may reduce toxicity and improve efﬁcacy.168 In a randomized study in patients with early chronic-phase CML, 144 patients received either PEG-IFN-␣-2a (PEG Roferon [Hoffman-La Roche, Nutley, NJ]; Pegasys) or IFN-␣2a.169 After 12 months of therapy, PEG-IFN-␣-2a was associated with signiﬁcantly higher CHR rates (69% vs. 41%; P ⫽ 0.0008), major cytogenetic response rates (35% vs. 18%; P ⫽ 0.016), and a lower incidence of 449 withdrawal for side effects (8.5% vs. 22%). When combined with Ara-C, PEG-IFN-␣-2b (PEG Intron; Schering-Plough, Kenilworth, NJ) demonstrated encouraging results.170 YNK01 is an oral Ara-C precursor metabolized to Ara-C in the liver. YNK01 combined with IFN-␣ in patients with newly diagnosed CML resulted in a CHR rate of 78%, a major cytogenetic response of 39%, and a toxicity rate of 30%.171,172 Homoharringtonine (HHT) is a semisynthetic plant alkaloid. In late chronic-phase CML, a low-dose continuous infusion schedule of HHT (2.5 mg/m2 intravenously daily every 7–14 days) induced a CHR in 65% of patients and cytogenetic responses in approximately 30%.173 Survival was longer with the combination of HHT plus Ara-C versus HHT alone (4-year survival rate of 58% vs. 38%; P ⫽ 0.02).174 Favorable results have been observed in patients with early chronic-phase CML treated with HHT alone and in combinations.175,176 Current investigations include combinations of HHT, IFN-␣, and Ara-C; subcutaneous routes of HHT delivery; and possible future combination with imatinib mesylate.177 5-aza-2⬘-deoxycytidine (decitabine) is a cytidine analogue that inhibits DNA methyltransferase. Decitabine therapy produced response rates of 28% in patients with blastic phase CML and of 50 – 60% in patients with accelerated phase CML.178 –180 Decitabine is currently under investigation in imatinib-resistant CML phases. Activation of the RAS signal transduction pathway is a central event in BCR-ABL-induced malignant transformation. Farnesyl transferase inhibitors (FTI) inhibit the enzyme farnesyl protein transferase, disrupt RAS prenylation, alter proper subcellular localization, and result in inhibition of RAS-dependent cellular transformation. FTIs have demonstrated anti-CML activity in preclinical murine animal models injected with STI-resistant CML lines.181 FTIs have also been evaluated with some success in patients with acute myeloid leukemia and those with CML.182,183 Immunotherapy to treat CML has been tested in the context of minimal residual disease after transplantation. One patient with accelerated phase CML achieved a complete disease remission after therapy with in vitro selected, expanded, leukemia-reactive, cytotoxic T-lymphocytes.184 Vaccination of CML patients with BCR-ABL fusion peptides has been demonstrated to be safe and to elicit speciﬁc immune responses.185,186 Other strategies include T-cell-depleted allogeneic SCT to reduce transplant toxicity, followed by infusions of incremental doses of T-cells to eradicate minimal residual disease. The addition of granulocyte-macrophage colony- 450 CANCER August 1, 2003 / Volume 98 / Number 3 stimulating factor (GM-CSF) therapy to IFN-␣-sensitive patients was reported to induce signiﬁcant cytogenetic responses.187 Smith et al. reported that the combination of GM-CSF and IFN-␣ induced rapid cytogenetic responses in 78% of 38 patients with CML.188 The rationale for this approach was that both GM-CSF and IFN-␣ induced cell differentiation of CML progenitors in vitro. GM-CSF also induced increased expression of HLA-DR, facilitating recognition of CML cells by natural killer lymphocytes. Current and future studies of interest include combinations of imatinib (regular or high-dose)166,189,190 with IFNs, hematopoietic growth factors, Ara-C, HHT, decitabine, FTIs, SRC inhibitors, and others.191 The use of imatinib in the setting of allogeneic or autologous SCT is being actively explored.135 Choice of Initial Therapy for Patients with Chronic-Phase CML Ongoing studies of imatinib as frontline therapy in patients with newly diagnosed chronic phase CML, and as salvage therapy, are maturing with continued positive results. Patients with newly diagnosed chronic phase CML who are treated outside the setting of a clinical trial may be offered therapy either with imatinib or allogeneic SCT. The choice of therapy is based on 1) the beneﬁt:risk ratio of allogeneic SCT versus imatinib, 2) patient risk group, and 3) patient preference. Although the standard of care remains controversial and is updated continuously, treatment algorithms are based on the following principles: 1) Postponing allogeneic SCT for up to 24 months and the pretransplantation use of imatinib do not appear to inﬂuence transplantation outcome adversely123; 2) The 1-year TRM is age-related and may deﬁne what is a reasonably acceptable risk of transplantation in exchange for long-term outcome; 3) The median survival with IFN-␣-based regimens is reported to be 6 –7 years, for good risk patients the median survival is 9 years, and for patients who achieve a complete cytogenetic response the 10- year survival rate is between 70 – 80%71–74; and 4) Because imatinib induces complete cytogenetic response rates of ⱖ 60%,162,163 the median survival in CML patients may exceed 10 years if the signiﬁcance of a complete cytogenetic response is similar when achieved with imatinib as when achieved with IFN-␣ therapy. Arguments favoring upfront allogeneic SCT include: 1) it is the only proven curative modality; and 2) delaying allogeneic SCT may worsen patient outcome. Long-term follow-up results with imatinib are not currently available. Therefore: A) it could have a transient beneﬁt, B) it may not have the same association of cytogenetic response with survival, C) it may have unexpected long-term toxicities, and D) it may adversely affect allogeneic SCT results. Arguments in favor of imatinib as frontline CML therapy include: 1) the potential of long-term eventfree survival outside the setting of allogeneic SCT (10% at 10 years with IFN-␣); 2) comparing imatinib with IFN-␣, the complete cytogenetic response rates (76% vs. 14%) and major cytogenetics response rates (87% vs. 35%) (surrogate endpoints for better survival) appear to be much higher with imatinib; 3) in addition to allogeneic SCT mortality (approximately 5–20% in some series and 10 –50% in others), there are considerable toxicities associated with allogeneic SCT (e.g., cataracts, sterility, second tumors, hip necrosis, decreased quality of life, and GVHD); and 4) the followup studies with imatinib have not demonstrated signiﬁcant unusual or unexpected side effects, or high rates of resistance in patients with chronic phase disease. Thus, with currently available knowledge, and until data further mature for imatinib and for allogeneicrelated and unrelated transplantation, patients may be offered the options of allogeneic SCT or imatinib as initial therapies, after a detailed discussion of updated results has taken place. Treatment of Accelerated and Blastic-Phase Disease Response rates to chemotherapy combinations are reported to be 20% in patients with nonlymphoid blastic phase and 60% in patients with lymphoid blastic phase (with anti-ALL therapy). The median survivals are 3– 6 months and 9 –12 months, respectively. Allogeneic SCT is the only proven curative therapy for accelerated and blastic phase disease. Cure rates are in the range of 15– 40%, and 5–20%, respectively. Patients with cytogenetic clonal evolution as the only accelerated phase criterion appear to fare better, with long-term event-free survival rates of 60% after allogeneic SCT. However, reinduction of a second chronic phase or a disease remission before allogeneic SCT may improve the outcome of allogeneic SCT in patients who achieve such remissions. Outside the context of allogeneic SCT, imatinib is the only approved treatment for accelerated or blastic phase CML. Although single-agent imatinib is the most active agent in accelerated phase, and still has activity in the blastic phase, results are far less favorable than in chronic phase CML, and it appears the majority of patients will develop a disease recurrence (Table 6). Thus, combinations of imatinib with IFN-␣, Ara-C, other chemotherapy, or investigational agents (e.g., HHT, decitabine, or FTIs) are indicated in patients with advanced phases of CML. In those patients with lymphoid blastic phase and Ph-positive ALL, combinations of Chronic Myelogenous Leukemia/Garcia-Manero et al. imatinib with anti-ALL therapy (e.g., hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, and dexamethasone]) currently are being investigated. Similarly, patients with nonlymphoid blastic-phase disease should be treated with combinations of imatinib and anti-acute myeloid leukemia (AML) chemotherapy (e.g., Ara-C plus anthracyclines) or investigational regimens (e.g., decitabine or FTIs). In general, patients with disease in the accelerated or blastic phases should be encouraged to participate in clinical trials to attempt to determine the optimal treatment strategy. Splenectomy is useful as a palliative measure in patients with massive painful splenomegaly and/or hypersplenism or thrombocytopenia, and should be favored over splenic irradiation. CONCLUSIONS The prognosis for patients with CML has signiﬁcantly improved over the last 20 years. Whereas the median survival rates were 4 –5 years in the era of hydroxyurea, the introduction of IFN-␣, both alone and in combination with Ara-C, has nearly doubled these numbers. However, the development of imatinib has represented one of the biggest leaps forward in the treatment of CML. As a small molecule targeting a protein speciﬁc for the leukemic cells, it helped to irreversibly shift the focus to an understanding of the molecular processes that underlie the malignant phenotype as a basis for successful therapy. In addition to the impressive clinical results achieved with imatinib itself, the possibility of being able to interfere with speciﬁc signaling pathways of tumor cells has spurred a ﬂurry of activity in the development of other targeted therapies such as FTIs, SRC inhibitors, inhibitors of PI-3-kinase, and proteasome inhibitors. Therefore, a true paradigm shift has occurred in changing our therapeutic thinking and approach, not only in CML, but in other malignancies as well. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. REFERENCES 1. 2. 3. 4. 5. Fialkow PJ, Jacobson RJ, Papayannopoulou T. Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage. Am J Med. 1977;63:125–130. Bedi A, Zehnbauer B, Barber JP, Sharkis S, Jones RJ. Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia. Blood. 1984;83:2038 –2044. McGahon A, Bissonnette R, Sohmitt M, Cotter K, Green D, Cotter T. BCR-ABL maintains resistance of chronic myelogenous leukemia cells to apoptotic cell death. Blood. 1994; 83:1179 –1187. Harrison-Findik D, Susa M, Varticovski L. Association of phosphatidylinositol 3-kinase with SHC in chronic myelogenous leukemia cells. Oncogene. 1995;10:1385–1391. Horita M, Andreu EJ, Benito A, et al. Blockade of the BcrAbl kinase activity induces apoptosis of chronic myeloge- 19. 20. 21. 22. 451 nous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of BclxL. J Exp Med. 2000;191:977–984. Skorski T, Kanakaraj P, Nieborowska-Skorska M, et al. Phosphatidylinositol-3 kinase activity is regulated by BCR/ ABL and is required for the growth of Philadelphia chromosome-positive cells. Blood. 1995;86:726 –736. Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science. 1960;132:1497. Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identiﬁed by quinacrine ﬂuorescence and Giemsa staining [letter]. Nature. 1973; 243:290 –293. Faderl S, Talpaz M, Estrov Z, O’Brien S, Kurzrock R, Kantarjian HM. The biology of chronic myeloid leukemia. N Engl J Med. 1999;341:164 –172. Deininger M, Goldman JM, Melo J. The molecular biology of chronic myeloid leukemia. Blood. 2000;96:3343–3356. Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/ abl gene of the Philadelphia chromosome. Science. 1990; 247:824 – 830. Kelliher MA, McLaughlin J, Witte ON, Rosenberg N. Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL. Proc Natl Acad Sci USA. 1990;87:6649 – 6653. Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J. Acute leukaemia in bcr/abl transgenic mice. Nature. 1990;344:251–253. Deininger MW, Bose S, Gora-Tybor J, et al. Selective induction of leukemia-associated fusion genes by high-dose ionizing radiation. Cancer Res. 1998;58:421– 425. Biernaux C, Loos M, Sels A, Huez G, Stryckmans P. Detection of major bcr-abl gene expression at a very low level in blood cells of some healthy individuals. Blood. 1995;86: 3118 –3122. Bose S, Deininger M, Gora-Tybor J, Goldman JM, Melo J. The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: biologic signiﬁcance and implications for the assessment of minimal residual disease. Blood. 1998;92:3362–3367. Kantarjian HM, Deisseroth A, Kurzrock R, Estrov Z, Talpaz M. Chronic myelogenous leukemia: a concise update. Blood. 1993;82:691–703. Kantarjian HM, O’Brien S, Anderlini P, Talpaz M. Treatment of chronic myelogenous leukemia: current status and investigational options. Blood. 1996;87:3069 –3081. Kantarjian HM, Giles FJ, O’Brien SM, Talpaz M. Clinical course and therapy of chronic myelogenous leukemia with interferon-alpha and chemotherapy. Hematol Oncol Clin North Am. 1998;12:31– 80. Brincker H. Population-based age- and sex-speciﬁc incidence rates in the 4 main types of leukaemia. Scand J Haematol. 1982;29:241–249. Surveillance, Epidemiology, and End Results (SEER) Program. Program public use CD-ROM (1973-1994), Bethesda, MD: National Cancer Institute, DCPC, Surveillance Program, Cancer Statistics Branch, released October 1997, based on the August 1996 submission. 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. 452 CANCER August 1, 2003 / Volume 98 / Number 3 23. Kantarjian HM, Smith TL, O’Brien S, Beran M, Pierce S, Talpaz M. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. The Leukemia Service. Ann Intern Med. 1995;122:254 – 261. Kurzrock R, Gutterman JU, Talpaz M. The molecular genetics of Philadelphia chromosome-positive leukemias. N Engl J Med. 1988;319:990 –998. Bartram CR, de Klein A, Hagemeijer A, et al. Translocation of a c-abl oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. Nature. 1983;306:277–280. Groffen J, Stephenson JR, Heisterkamp N, de Klein A, Bartram CR, Grosveld G. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell. 1984;36:93–99. Lugo TG, Pendergast AM, Muller AJ, Witte ON. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science. 1990;247:1079 –1082. Kantarjian H, Shtalrid M, Kurzrock R, et al. Signiﬁcance and correlations of molecular analysis results in patients with Philadephia chromosome-negative chronic myelogenous leukemia and chronic myelomonocytis leukemia. Am J Med. 1988;85:639 – 644. Kurzrock R, Bueso-Ramos C, Kantarjian H, et al. BCR rearrangement-negative chronic myelogenous leukemia revisited. J Clin Oncol. 2001;19:2915–2926. Cortes J, Talpaz M, O’Brien S, Rios MB, Stass S, Kantarjian H. Philadelphia chromosome negative chronic myelogenous leukemia with rearrangement of the breakpoint cluster region: long-term follow-up results. Cancer. 1995;75: 464 – 470. Kantarjian H, Keating MJ, Walters RS, McCredie KB, Body GP, Freireich EJ. Clinical and prognostic features of Philadelphia chromosome-negative chronic myelogenous leukemia. Cancer. 1986;58:2023–2030. Kurzrock R, Kantarjian H, Shtalrid M, Gutterman JU, Talpaz M. Philadelphia chromosome-negative chronic myelogenous leukemia without breakpoint cluster region rearrangement: a chronic myeloid leukemia with a distinct clinical course. Blood. 1990;75:445– 452. Zion M, Ben-Yehuda D, Avraham A, et al. Progressive de novo DNA methylation at the bcr-abl locus in the course of chronic myelogenous leukemia. Proc Natl Acad Sci USA. 1994;91:10722–10726. Melo JV. The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype. Blood. 1996;88: 2375–2384. Ravandi F, Cortes J, Albitar M, et al. Chronic myelogenous leukaemia with p185(BCR/ABL) expression: characteristics and clinical signiﬁcance. Br J Haematol. 1999;107:581–586. Lichty BD, Keating A, Callum J, et al. Expression of p210 and p190 BCR-ABL due to alternative splicing in chronic myelogenous leukemia. Br J Haematol. 1998;103:711–715. Van Rhee F, Hochhaus A, Lin F, Melo JV, Goldman JM, Cross NC. P190 BCR-ABL mRNA is expressed at low levels in p210-positive chronic myeloid and acute lymphoblastic leukemias. Blood. 1996;87:5213–5217. Verstovsek S, Lin H, Kantarjian H, et al. Neutrophilicchronic myeloid leukemia: low levels of p230 BCR/ABL mRNA and undetectable BCR/ABL protein may predict an indolent course. Cancer. 2002;94:2416 –2425. Skorski T, Bellacosa A, Nieberowska-Skorska M, et al. Transformation of hematopoietic cells by BCR/ABL re- 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. quires activation of a PI-3k/Akt-dependent pathway. EMBO J. 1997;16:6151– 6161. Hallek M, Donauser Riedl S, Herbst R, et al. Interaction of the receptor tyrosine kinase p145c-kit with the p210bcr/abl kinase in myeloid cells. Br J Haematol. 1996;94:5–16. Wilson Rawls J, Xie S, Liu J, et al. P210 Bcr-Abl interacts with the interleukin 3 receptor beta(c) subunit and constitutively induces its tyrosine phosphorylation. Cancer Res. 1996;56:3426 –3430. Senechal K, Halpern J, Sawyers CL. The CRKL adaptor protein transforms ﬁbroblasts and functions in transformation by the BCR-ABL oncogene. J Biol Chem. 1996;271: 23255–23261. Heaney C, Kolibaba K, Bhat A, et al. Direct binding of CRKL to BCR-ABL is not required for BCR-ABL transformation. Blood. 1997;89:297–306. Skorski T, Wlodarski P, Daheron L, et al. BCR/ABL-mediated leukemogenesis requires the activity of the small GTPbinding protein Rac. Proc Natl Acad Sci USA. 1998; 95:11858 –11862. Cotez D, Reuther GW, Pendergast AM. The BCR-ABL tyrosine kinase activates mitotic signaling pathways and stimulates G1-to-S phase transition in hematopoietic cells. Oncogene. 1997;15:2333–2342. Pendergast AM, Quilliam LA, Cripe LD, et al. BCR-ABLinduced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Cell. 1993; 75:175–185. Cahill MA, Janknecht R, Nordheim A. Signaling pathways: jack of all cascades. Curr Biol. 1996;6:16 –19. Marais R, Light Y, Paterson HF, et al. Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation. EMBO J. 1995;14:3136 –3145. Mitelman F. The cytogenetic scenario of chronic myeloid leukemia. Leuk Lymphoma. 1993;1:11–15. Stuppia L, Calabrese G, Peila R, et al. p53 loss and point mutations are associated with suppression of apoptosis and progression of CML into myeloid blastic crisis. Cancer Genet Cytogenet. 1997;98:28 –35. Serra A, Guerrasio A, Gaidano G. Molecular defects associated with the acute phase CML. Leuk Lymphoma. 1993;1: 25–28. Savage DG, Szydlo RM, Goldman JM. Clinical features at diagnosis in 430 patients with chronic myeloid leukaemia seen at a referral centre over a 16-year period. Br J Haematol. 1997;96:111–116. Kantarjian HM, Dixon D, Keating MJ, et al. Characteristics of accelerated disease in chronic myelogenous leukemia. Cancer. 1988:61;1441–1446. Savage DG, Szydlo RM, Chase A, Apperley JF, Goldman JM. Bone marrow transplantation for chronic myeloid leukaemia: the effects of differing criteria for deﬁning chronic phase on probabilities of survival and relapse. Br J Haematol. 1997;99:30 –35. Kantarjian HM, Keating MJ, Talpaz M, et al. Chronic myelogenous leukemia in blast crisis. Analysis of 242 patients. Am J Med. 1987;83:445– 454. Kantarjian HM, Talpaz M, Kontoyiannis D, et al. Treatment of chronic myelogenous leukemia in accelerated and blastic phases with daunorubicin, high-dose cytarabine, and granulocyte- macrophage colony-stimulating factor. J Clin Oncol. 1992;10:398 – 405. Chronic Myelogenous Leukemia/Garcia-Manero et al. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. Rosenthal S, Canellos GP, Whang-Peng J, Gralnick HR. Blast crisis of chronic granulocytic leukemia. Morphologic variants and therapeutic implications. Am J Med. 1977;63: 542–547. Cervantes F, Rozman M, Rosell J, Urbano-Ispizua A, Montserrat E, Rozman C. A study of prognostic factors in blast crisis of Philadelphia chromosome-positive chronic myelogenous leukaemia. Br J Haematol. 1990;76:27–32. Allen SL, Coleman M. Terminal-phase chronic myelogenous leukemia: approaches to treatment. Cancer Invest. 1985:3;491–503. Grifﬁn JD, Todd RF, Ritz J, et al. Differentiation patterns in the blastic phase of chronic myeloid leukemia. Blood. 1983; 61:85–91. Derderian PM, Kantarjian HM, Talpaz M., et al. Chronic myelogenous leukemia in the lymphoid blastic phase: characteristics, treatment response, and prognosis. Am J Med. 1993;94:69 –74. Cervantes F, Villamor N, Esteve J, et al. ‘Lymphoid’ blast crisis of chronic myeloid leukaemia is associated with distinct clinicohaematological features. Br J Haematol. 1998; 100:123–128. Terjanian T, Kantarjian H, Keating M, Talpaz M, McCredie K, Freireich EJ. Clinical and prognostic features of patients with Philadelphia chromosome-positive chronic myelogenous leukemia and extramedullary disease. Cancer. 1987; 59:297–300. Dekmezian R, Kantarjian HM, Keating MJ, Talpaz M, McCredie KB, Freireich EJ. The relevance of reticulin stain measured ﬁbrosis at diagnosis in chronic myelogenous leukemia. Cancer. 1987;59:1739 –1743. Majlis A, Smith TL, Talpaz M, O’Brien S, Rios MB, Kantarjian HM. Signiﬁcance of cytogenetic clonal evolution in chronic myelogenous leukemia. J Clin Oncol. 1996;14:196 – 203. Kantarjian HM, Smith TL, McCredie KB, et al. Chronic myelogenous leukemia: a multivariate analysis of the associations of patient characteristics and therapy with survival. Blood. 1985;66:1326 –1335. Kantarjian HM, Keating MJ, Smith TL, Talpaz M, McCredie KB. Proposal for a simple synthesis prognostic staging system in chronic myelogenous leukemia. Am J Med. 1990;88: 1– 8. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood. 1984;63:789 –799. Hasford J, Pﬁrrmann M, Hehlmann R, et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. J Natl Cancer Inst. 1998;90:850 – 858. Sokal J, Gomez G, Baccarani M, et al. Prognostic signiﬁcance of additional cytogenetic abnormalities at diagnosis of Philadelphia chromosome-positive chronic granulocytic leukemia. Blood. 1988;72:294 –298. Mahon FX, Delbrel X, Cony-Makhoul P, et al. Follow-up of complete cytogenetic remission in patients with chronic myeloid leukemia after cessation of interferon-␣. J Clin Oncol. 2002;20:214 –220. Bonifazi F, de Vivo A, Rosti G, et al. Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders. Blood. 2001;98:3074 –3081. Giles FJ, Kantarjian H, O’Brien S, et al. Results of therapy with interferon alpha and cyclic combination chemotherapy in patients with Philadelphia chromosome positive 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 453 chronic myelogenous leukemia in early chronic phase. Leuk Lymphoma. 2001;41:309 –319. Kantarjian H, O’Brien S, Cortes J. Complete cytogenetic and molecular responses to interferon-alfa-based therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis. Cancer. 2003;97:1033–1041. Cortes J, Tapaz M, Giles F, et al. Prognostic signiﬁcance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy. Blood. 2003;101:3794 –3800. O’Dwyer M, Mauro M, Kurilik G, et al. The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. Blood. 2002;100:1628 –1633. Cortes J, Talpaz M, O’Brien, et al. Suppression of cytogenetic clonal evolution with interferon alfa therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. J Clin Oncol. 1998;16:3279 –3285. Przepiorka D, Thomas ED. Prognostic signiﬁcance of cytogenetic abnormalities in patients with chronic myelogenous leukemia. Bone Marrow Transplant. 1988;3:113–119. Huntly B, Reid A, Bench A, et al. Deletions of the derivative chromosome 9 occur at the time of the Philadelphia translocation and provide a powerful and independent prognostic indicator in chronic myeloid leukemia. Blood. 2001;98: 1732–1738. Ben-Yehuda D, Krichevsky S, Rachmilewitz E, et al. Molecular follow-up of disease progression and interferon therapy in chronic myelocytic leukemia. Blood. 1997;90:4918 – 4923. Issa JP, Kantarjian H, Mohan A, et al. Methylation of the ABL1 promoter in chronic myelogenous leukemia: lack of prognostic signiﬁcance. Blood. 1999;93:2075–2080. Boultwood J, Peniket A, Watkins F, et al. Telomere length shortening in chronic myelogeous leukemia is associated with reduced time to accelerated phase. Blood. 2000;96: 358 –361. Schmidt M, Hochhaus A, Konig-Mereditz SA, et al. Expression of interferon regulatory factor 4 in chronic myeloid leukemia: correlation with response to interferon alpha therapy. J Clin Oncol. 2000;18:3331–3338. Fischer T, Aman J, van der Kuip H, et al. Induction of interferon regulatory factors 2⬘-5⬘ oligoadenylate synthetase, P68 kinase and RNase L in chronic myelogenous leukaemia cells and its relationship to clinical responsiveness. Br J Haematol. 1996;92:595– 603. Dewald GW, Wyatt WA, Juneau AL, et al. Highly sensitive ﬂuorescence in situ hybridization method to detect double BCR/ABL fusion and monitor response to therapy in chronic myeloid leukemia. Blood. 1998;91:3357–3365. Seong DC, Kantarjian HM, Ro JY, et al. Hypermetaphase ﬂuorescence in situ hybridization for quantitative monitoring of Philadelphia chromosome-positive cells in patients with chronic myelogenous leukemia during treatment. Blood. 1995;86:2343–2349. Cuneo A, Bigoni R, Emmanuel B, et al. Fluorescence in situ hybridization for the detection and monitoring of the Phpositive clone in chronic myelogenous leukemia: comparison with metaphase banding analysis. Leukemia. 1998;12: 1718 –1723. Grand FH, Chase A, Iqbal S, et al. A two-color BCR-ABL probe that greatly reduces the false positive and false negative rates for ﬂuorescence in situ hybridization in chronic myeloid leukemia. Genes Chromosomes Cancer. 1998;23: 109 –115. 454 CANCER August 1, 2003 / Volume 98 / Number 3 89. Muhlmann J, Thaler J, Hilbe W, et al. Fluorescence in situ hybridization (FISH) on peripheral blood smears for monitoring Philadelphia chromosome-positive chronic myeloid leukemia (CML) during interferon treatment: a new strategy for remission assessment. Genes Chromosomes Cancer. 1998;21:90 –100. Cross NC, Melo JV, Feng L, Goldman JM. An optimized multiplex polymerase chain reaction (PCR) for detection of BCR-ABL fusion mRNAs in haematological disorders. Leukemia. 1994;8:186 –189. Lee M, Khouri I, Champlin R, et al. Detection of minimal residual disease by polymerase chain reaction of bcr/abl transcripts in chronic myelogenous leukaemia following allogeneic bone marrow transplantation. Br J Haematol. 1992;82:708 –714. Faderl S, Talpaz M, Kantarjian HM, Estrov Z. Should polymerase chain reaction analysis to detect minimal residual disease in patients with chronic myelogenous leukemia be used in clinical decision making? Blood. 1999;93:2755–2759. Hochhaus A, Reiter A, Saussele S, et al. Molecular heterogeneity in complete cytogenetic responders after interferon-alpha therapy for chronic myelogenous leukemia: low levels of minimal residual disease are associated with continuing remission. German CML Study Group and the UK MRC CML Study Group. Blood. 2000;95:62– 66. Malinge MC, Mahon FX, Delfau MH, et al. Quantitative determination of the hybrid Bcr-Abl RNA in patients with chronic myelogenous leukaemia under interferon therapy. Br J Haematol. 1992;82:701–707. Hochhaus A, Lin F, Reiter A., et al. Quantiﬁcation of residual disease in chronic myelogenous leukemia patients on interferon-alpha therapy by competitive polymerase chain reaction. Blood. 1996:87:1549 –1555. Guo JQ, Wang JY, Arlinghaus RB. Detection of BCR-ABL proteins in blood cells of benign phase chronic myelogenous leukemia patients. Cancer Res. 1991;51:3048 –3051. Hochhaus A, Reiter A, Skladny H, Reichert A, Saussele S, Hehlmann R. Molecular monitoring of residual disease in chronic myelogenous leukemia patients after therapy. recent results. Cancer Res. 1998:144:36 – 45. Radich JP, Gehly G, Gooley T, et al. Polymerase chain reaction detection of the BCR-ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: results and implications in 346 patients. Blood. 1995;85:2632–2638. Kantarjian H, Talpaz M, Cortes J, et al. Quantitative polymerase chain reaction monitoring of BCR-ABL during therapy with imatinib mesylate (STI571; Gleevec) in chronic phase chronic myelogenous leukemia. Clin Cancer Res. 2003;9:160 –166. Lee W-I, Kantarjian H, Glassman A, Talpaz M, Lee M-S. Quantitative measurement of BCR/abl transcripts using real-time polymerase chain reaction. Ann Oncol. 2002;13: 781–788. Merx K, Muller MC, Krell S, et al. Early reduction of BCRABL mRNA transcript levels predicts cytogenetic response in chronic phase CML patients treated with imatinib after failure of interferon-␣. Leukemia. 2002;16:1579 –1583. Wu CJ, Neubert D, Chillemi A, et al. Quantitative monitoring of BCR/ABL transcript during STI-571 therapy. Leuk Lymphoma. 2002;43:2281–2289. Anderson MK, Pedersen-Bjergaard J, Kjeldsen L, Dufva IH, Brondum-Nielsen K. Clonal Ph-negative hematopoiesis in 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. CML after therapy with imatinib mesylate is frequently characterized by trisomy 8. Leukemia. 2002;16:1390 –1393. Medina J, Kantarjian H, Talpaz M, et al. Chromosomal abnormalities in Philadelphia chromosome (Ph) negative metaphases appearing during treatment with imatinib mesylate in patients (pts) with Ph positive chronic myeloid leukemia (CML) in chronic Phase (CP). Blood. 2002:100: 368a. Fayad L, Kantarjian H, O’Brien S, et al. Emergency of new clonal abnormalities following interferon-alpha induced complete cytogenetic response in patients with chronic myeloid leukemia: report of three cases. Leukemia. 1997;1: 767–771. Kantarjian HM, Giles FJ, O’Brien S, Giralt S, Talpaz M. Therapeutic choices in younger patients with chronic myelogenous leukemia. Cancer. 2000;89:1647–1658. Lee SJ, Anasetti C, Horowitz MM, Antin JH. Initial therapy for chronic myelogenous leukemia: playing the odds. J Clin Oncol. 1998;16:2897–2903. Goldman JM, Druker BJ. Chronic myeloid leukemia: current treatment options. Blood. 2001;98:2039 –2042. Galton D. Myleran in chronic myeloid leukemia. Lancet. 1953;1:208 –213. Clift RA, Buckner CD, Thomas ED, et al. Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide. Blood. 1994;84:2036 – 2043. Hehlmann R, Heimpel H, Hasford J, et al. Randomized comparison of busulfan and hydroxyurea in chronic myelogenous leukemia: prolongation of survival by hydroxyurea. The German CML Study Group. Blood. 1993;82:398 – 407. Goldman JM, Szydlo R, Horowitz MM, et al. Choice of pretransplant treatment and timing of transplants for chronic myelogenous leukemia in chronic phase. Blood. 1993;82:2235–2238. Kennedy BJ. Hydroxyurea therapy in chronic myelogenous leukemia. Cancer. 1972;29:1052–1056. Horowitz MM, Rowlings PA, Passweg JR. Allogeneic bone marrow transplantation for CML: a report from the International Bone Marrow Registry. Bone Marrow Transplant. 1996;17:S5–S6. Gratwohl A, Hermans J, Niederwieser D, et al. Bone marrow transplantation for chronic myeloid leukemia: longterm results. Chronic Leukemia Working Party of the European Group for Bone Marrow Transplantation. Bone Marrow Transplant. 1993;12:509 –516. Clift RA, Storb R. Marrow transplantation for CML: the Seattle experience. Bone Marrow Transplant. 1996;17:S1–S3. van Rhee F, Szydlo RM, Hermans J, et al. Long-term results after allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic phase: a report from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 1997;20:553–560. Goldman JM, Gale RP, Horowitz MM, et al. Bone marrow transplantation for chronic myelogenous leukemia in chronic phase. Increased risk for relapse associated with T-cell depletion. Ann Intern Med. 1988;108:806 – 814. Gratwohl A, Hermans J, Goldman JM, et al. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet. 1998;352:1087–1092. Chronic Myelogenous Leukemia/Garcia-Manero et al. 120. McGlave P, Bartsch G, Anasetti C, et al. Unrelated donor marrow transplantation therapy for chronic myelogenous leukemia: initial experience of the National Marrow Donor Program. Blood. 1993;81:543–550. 121. Beatty PG, Anasetti C, Hansen JA, et al. Marrow transplantation from unrelated donors for treatment of hematologic malignancies: effect of mismatching for one HLA locus. Blood. 1993;81:249 –253. 122. Hansen JA, Gooley TA, Martin PJ, et al. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med. 1998;338:962–968. 123. Clift RA, Appelbaum FR, Thomas ED. Treatment of chronic myeloid leukemia by marrow transplantation. Blood. 1993; 82:1954 –1956. 124. Giralt S, Szydlo R, Goldman JM, et al. Effect of short-term interferon therapy on the outcome of subsequent HLAidentical sibling bone marrow transplantation for chronic myelogenous leukemia: an analysis from the International Bone Marrow Transplant Registry. Blood. 2000;95:410 – 415. 125. Lee SJ, Klein J, Anasetti C, et al. The effect of pretransplant interferon therapy on the outcome of unrelated donor hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia in ﬁrst chronic phase. Blood. 2001;98:3205–3211. 126. Hehlmann R, Hochhaus A, Kolb H-J, et al. Interferon-␣ before allogeneic bone marrow transplantation in chronic myelogenous leukemia does not affect outcome adversely, provided it is discontinued at least 90 days before the procedure. Blood. 1999;94:3668 –3677. 127. Weisdorf DJ, Anasetti C, Antin J, et al. Allogeneic bone marrow transplantation for chronic myelogenous leukemia: comparative analysis of unrelated versus matched sibling donor transplantation. Blood. 2002;99:1971–1977. 128. Or R, Shapira M, Resnick I, et al. Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in ﬁrst chronic phase. Blood. 2003;101: 441– 445. 129. Arcese W, Goldman JM, D’Arcangelo E. Outcome for patients who relapse after allogeneic bone marrow transplantation for chronic myeloid leukemia. Chronic Leukemia Working Party. European Bone Marrow Transplantation Group. Blood. 1993:82:3211–3219. 130. Kolb HJ, Schattenberg A, Goldman JM, et al. Graft-versusleukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood. 1995;86:2041–2050. 131. Higano CS, Chielens D, Raskind W, et al. Use of alpha-2ainterferon to treat cytogenetic relapse of chronic myeloid leukemia after marrow transplantation. Blood. 1997;90:2549 – 2554. 132. Steegmann JL, Casado LF, Tomas JF, et al. Interferon alpha for chronic myeloid leukemia relapsing after allogeneic bone marrow transplantation. Bone Marrow Transplant. 1999;23:483– 488. 133. Collins RH Jr., Shpilberg O, Drobyski WR, et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol. 1997;15:433– 444. 134. Mrsic M, Horowitz MM, Atkinson K, et al. Second HLAidentical sibling transplants for leukemia recurrence. Bone Marrow Transplant. 1992;9:269 –275. 135. Kantarjian H, O’Brien S, Cortes J, et al. Imatinib mesylate 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 455 therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood. 2002;100: 1590 –1595. Talpaz M, Kantarjian H, Kurzrock R, Trujillo JM, Gutterman JU. Interferon-alpha produces sustained cytogenetic responses in chronic myelogenous leukemia. Philadelphia chromosome-positive patients. Ann Intern Med. 1991;114: 532–538. Allan NC, Richards SM, Shepherd PC. UK Medical Research Council randomised, multicentre trial of interferon- alpha n1 for chronic myeloid leukaemia: improved survival irrespective of cytogenetic response. The UK Medical Research Council’s Working Parties for Therapeutic Trials in Adult Leukaemia. Lancet. 1995;345:1392–1397. Monitoring treatment and survival in chronic myeloid leukemia. Italian Cooperative Study Group on Chronic Myeloid Leukemia and Italian Group for Bone Marrow Transplantation. J Clin Oncol. 1999;17:1858 –1868. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Long-term follow-up of the Italian trial of interferon-alpha versus conventional chemotherapy in chronic myeloid leukemia. Blood. 1998;92:1541–1548. Silver RT, Woolf SH, Hehlmann, R, et al. An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: developed for the American Society of Hematology. Blood. 1999;94:1517– 1536. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med. 1994;330:820 – 825. Interferon alfa versus chemotherapy for chronic myeloid leukemia: a meta-analysis of seven randomized trials: Chronic Myeloid Leukemia Trialists’ Collaborative Group. J Natl Cancer Inst. 1997;89:1616 –1620. Hehlmann R, Heimpel H, Hossfeld DK, et al. Randomized study of the combination of hydroxyurea and interferon alpha versus hydroxyurea monotherapy during the chronic phase of chronic myelogenous leukemia (CML Study II). The German CML Study Group. Bone Marrow Transplant. 1996;17(Suppl 3):S21–S24. Kantarjian H, Keating M, Estey E, et al. Treatment of advanced stages of Philadelphia chromosome-positive chronic myelogenous leukemia with interferon-alpha and low-dose cytarabine. J Clin Oncol. 1992;10:772–778. Kantarjian HM, O’Brien S, Smith TL, et al. Treatment of Philadelphia chromosome-positive early chronic phase chronic myelogenous leukemia with daily doses of interferon alpha and low-dose cytarabine. J Clin Oncol. 1999; 17:284 –292. Arthur CK, Ma DD. Combined interferon alfa-2a and cytosine arabinoside as ﬁrst-line treatment for chronic myeloid leukemia. Acta Haematol. 1993;89:15–21. Kantarjian H, O’Brien S, Smith TL, et al. Treatment of Philadelphia chromosome-positive early chronic myelogenous leukemia with daily doses of interferon alpha and low dose cytosine arabinoside. J Clin Oncol. 1998;17:284 –296. Guilhot F, Chastang C, Michallet M, et al. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group. N Engl J Med. 1997;337:223–229. 456 CANCER August 1, 2003 / Volume 98 / Number 3 149. Baccarani M, Rosti G, de Vivo A, et al. A randomized study of interferon-alpha versus interferon-alpha and low- dose arabinosyl cytosine in chronic myeloid leukemia. Blood. 2002;99:1527–1535. 150. Druker BJ, Lydon NB. Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest. 2000;105:3–7. 151. Druker BJ. Imatinib alone and in combination for chronic myeloid leukemia. Semin Hematol. 2003;40:50 –58. 152. 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. 153. 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. 154. Deininger MW, Goldman JM, Lydon N, Melo JV. The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood. 1997;90:3691–3698. 155. 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. 156. Druker BJ, Sawyers CL, Kantarjian, H. 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. 157. 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. 158. 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. 159. Kantarjian H, Cortes J, O’Brien S, et al. Imatinib mesylate for Philadelphia chromosome-positive chronic-phase myeloid leukemia after failure of interferon-␣: follow-up results. Clin Cancer Res. 2002;8:2177–2187. 160. Kantarjian H, O’Brien S, Cortes J, et al. Treatment of Philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Can Res. 2002;8:2167–2176. 161. 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. 162. Kantarjian HM, Cortes JE, O’Brien S, et al. Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses. Blood. 2003;101:97–100. 163. O’Brien SG, Guilhot F, Larson RA, et al., for the IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994 –1004. 164. Kantarjian H, Sawyers C, Hochhaus A, et al. Imatinib (Gleevec™) results in sustained hematologic and cytogenetic responses among chronic-phase chronic myeloid leukemia (CML) failing interferon-alpha (IFN) – up to 31month follow-up of 454 patients on phase II study. Blood. 2002;100:94a. 165. Talpaz M, Silver R, Druker B, et al. Imatinib (STI571, Gleevec) achieves prolonged survival in patients with accelerated phase Ph⫹ chronic myeloid leukemia (CML-AP): up to 36 months follow-up of a phase II study. Blood. 2002;100:163a. 166. Cortes J, Talpaz M, O’Brien S, et al. High rates of major cytogenetic response in patients with newly diagnosed chronic myeloid leukemia (CML) in early chronic phase treated with imatinib at 400 mg or 800 mg daily. Blood. 2002;100:95a. 167. Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L. Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. Lancet Oncol. 2003;4:75– 85. 168. Talpaz M, O’Brien S, Rose E, et al. Phase 1 study of polyethylene glycol formulation of interferon alpha-2B (Schering 54031) in Philadelphia chromosome-positive chronic myelogenous leukemia. Blood. 2001;98:1708 –1713. 169. Lipton JH, Khoroshko ND, Golenkow AK, et al. A randomized multicenter comparative study of peginterferon alfa-2a (40KD) vs interferon-alfa-2a in patients with treatment-naı̈ve chronic-phase chronic myelogenous leukemia. Blood. 2002;100:782a. 170. Garcia-Manero G, Talpaz M, Giles F, et al. Treatment of Philadelphia chromosome positive chronic myelogenous leukemia with weekly polyethylene glycol formulation of interferon ␣-2b (Schering 54031) and low-dose cytarabine. Cancer. 2003;97:3010 –3016. 171. Kuhr T, Eisterer W, Apfelbeck U, et al. Treatment of patients with advanced chronic myelogenous leukemia with interferon-alpha-2b and continuous oral cytarabine ocfosfate (YNK01): a pilot study. Leuk Res. 2000;24:583– 587. 172. Mollee P, Taylor K. Arthur C, et al. A phase II study of interferon alpha (IFN) and intermittent oral cytarabine (YNK01) in the treatment of newly diagnosed chronic myeloid leukemia (CML). Blood. 1998;91:1810 –1819. 173. O’Brien S, Kantarjian H, Keating M, et al. Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase. Blood. 1995; 86:3322–3326. 174. Kantarjian HM, Talpaz M, Smith TL, et al. Homoharringtonine and low-dose cytarabine in the management of late chronic-phase chronic myelogenous leukemia. J Clin Oncol. 2000;18:3513–3521. 175. O’Brien S, Kantarjian H, Koller C, et al. Sequential homoharringtonine and interferon-alpha in the treatment of early chronic phase chronic myelogenous leukemia. Blood. 1999;93:4149 – 4153. 176. O’Brien S, Talpaz M, Cortes J, et al. Simultaneous homoharringtonine and interferon-alpha in the treatment of patients with chronic-phase chronic myelogenous leukemia. Cancer. 2002;94:2024 –2032. 177. Kantarjian H, Talpaz M, Santini V, Murgo A, Cheson B, O’Brien SM. Homoharringtonine – history, current research, and future directions. Cancer. 2001;92:1591–1605. 178. Kantarjian HM, O’Brien SM, Keating M, et al. Results of decitabine therapy in the accelerated and blastic phases of chronic myelogenous leukemia. Leukemia. 1997;11:1617– 1620. 179. Santini V, Kantarjian HM, Issa JP. Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications. Ann Intern Med. 2001;134:573–586. Chronic Myelogenous Leukemia/Garcia-Manero et al. 180. Sacchi S, Kantarjian HM, O’Brien S, et al. Chronic myelogenous leukemia in nonlymphoid blastic phase: analysis of the results of ﬁrst salvage therapy with three different treatment approaches for 162 patients. Cancer. 1999;86:2632– 2641. 181. Peters DG, Hoover RR, Gerlach MJ, et al. Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia. Blood. 2001; 97:1404 –1412. 182. Karp JE, Lancet JE, Kaufmann SH, et al. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood. 2001;97: 3361–3369. 183. Cortes J, Albitar M, Thomas D, et al. Efﬁcacy of the farnesyl transferase inhibitor, Zarnestra™ (R115777), in chronic myeloid leukemia and other hematologic malignancies. Blood. 2003;101:1692–1697. 184. Falkenburg JH, Wafelman AR, Joosten P, et al. Complete remission of accelerated phase chronic myeloid leukemia by treatment with leukemia-reactive cytotoxic T lymphocytes. Blood. 1999;94:1201–1208. 185. Pinilla-Ibarz J, Cathcart K, Korontsvit T, et al. Vaccination of patients with chronic myelogenous leukemia with bcr- 186. 187. 188. 189. 190. 191. 457 abl oncogene breakpoint fusion peptides generates speciﬁc immune responses. Blood. 2000;95:1781–1787. Molldrem JJ, Kant S, Jiang W, Lu S. The basis of T-cellmediated immunity to chronic myelogenous leukemia. Oncogene 2002;21:8668 – 8673. Cortes J, Kantarjian H, O’Brien S, et al. GM-CSF can improve the cytogenetic response obtained with interferonalpha therapy in patients with chronic myelogenous leukemia. Leukemia. 1998;12:860 – 864. Smith D, Matusi W, Miller C, et al. GM-CSF and interferon (INF) rapidly induce cytogenetic remissions in chronic myeloid leukemia (CML). Blood. 2000;96:544a. Cortes JE, Talpaz M, Giles FJ, et al. High-dose imatinib mesylate (STI571, Gleevec) in patients with chronic myeloid leukemia (CML) resistant or intolerant to interferonalpha (IFN). Proc Am Soc Clin Oncol. 2002;21:262a. Kantarjian HM, Talpaz M, O’Brien S, et al. Dose escalation of imatinib mesylate can overcome resistance to standarddose therapy in patients with chronic myelogenous leukemia. Blood. 2003;101:473– 475. Donato NJ, Wu JY, Talpaz M, et al. Novel tyrosine kinase inhibitors suppress BCR-ABL signaling and induce apoptosis in STI-571 sensitive and resistant CML cells. Blood. 2002;100:370a.
© Copyright 2019