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. 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