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Chronic Myelogenous LeukemiaPublished on Diagnostic Imaging (http://www.diagnosticimaging.com)

Chronic Myelogenous LeukemiaApril 01, 2005By Jorge E. Cortes, MD [1], Moshe Talpaz, MD [2], and Hagop M. Kantarjian, MD [3]

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder resulting from theneoplastic transformation of the primitive hemopoietic stem cell [1-4]. The disease is monoclonal inorigin, affecting myeloid, monocytic, erythroid, megakaryocytic, B-cell, and, sometimes, T-celllineages [4,5].

IntroductionEpidemiologyEtiologyClinical CharacteristicsLaboratory FeaturesStaging of CMLCytogenetic and Molecular ChangesTherapyMinimal Residual DiseasePatients in the Accelerated or Blastic PhasePh-Negative CMLReferences

Introduction

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder resulting from theneoplastic transformation of the primitive hemopoietic stem cell [1-4]. The disease is monoclonal inorigin, affecting myeloid, monocytic, erythroid, megakaryocytic, B-cell, and, sometimes, T-celllineages [4,5]. Bone marrow stromal cells are not involved [6]. CML has a very significant historicalrelevance, because it was the first disease in which a specific chromosomal abnormality was linkedto its pathogenesis, implicating activation of a specific oncogene in the chromosomal rearrangement[7-10]. At the therapeutic level, it is also historically important, because it is one of the firstneoplastic diseases for which the use of a biologic agent (ie, interferon) could suppress theneoplastic clone [11] and prolong survival [12]. Some of the most impressive results with bonemarrow transplantation (BMT) also come from studies of patients with CML [13].

Epidemiology

CML accounts for 7% to 15% of all leukemias in adults, with approximately 1 to 1.5 cases per100,000 population [14-16]. There is a male predominance, with a male to female ratio of 1.42.2 to1 [15-17]. The incidence of CML has remained steady for the last 50 years [16]. The median age atpresentation is 50 to 60 years [15,17], but the disease can be seen in all age groups. In earlierreports, 54% to 63% of patients were 60 years old and older [15,18], but the incidence hasdecreased in more recent reports to as low as 12% [3]. This may be a consequence of earlierdetection in recent years or the exclusion of patients having CML-like pictures (ie, othermyeloproliferative disorders, Philadelphia [Ph] chromosome-negative CML, chronic myelomonocyticleukemia), who are usually significantly older.

Etiology

The etiology of CML is not clear. There is little evidence for genetic factors linked to CML. Offspring ofparents with CML do not have a higher incidence of CML than does the general population[19]. There is also no correlation in monozygotic twins, suggesting that CML is an acquired disorder[19]. However, there may be some correlation with human leukocyte antigens (HLAs) CW3 and CW4[20].Survivors of the atomic disasters at Nagasaki and Hiroshima had a significantly higher incidence of

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http://www.diagnosticimaging.com/authors/jorge-e-cortes-mdhttp://www.diagnosticimaging.com/authors/moshe-talpaz-mdhttp://www.diagnosticimaging.com/authors/hagop-m-kantarjian-md/node/164991#Introduction/node/164991#Epidemiology/node/164991#Etiology/node/164991#Clinical Characteristics/node/164991#Laboratory Features/node/164991#Staging of CML/node/164991#Cytogenetic and Molecular Changes/node/164991#Therapy/node/164991#Minimal Residual Disease/node/164991#Patients in the Accelerated or Blastic Phase/node/164991#Ph-Negative CML/node/164991#References


CML [21]. Therapeutic radiation has also been associated with increased risk of CML [22]. This wasthe case in patients with ankylosing spondylitis treated with spinal irradiation [23] and in womenwith uterine cervical cancer given radiation therapy [24]. Chemicals have not been associated withincreased risk for CML.

Clinical Characteristics

The disease usually has a biphasic, and sometimes triphasic, course. The initial phase is the chronicphase, which is frequently asymptomatic. The incidence of asymptomatic cases has increased overthe last decade from 15% to about 40% of all cases [3] as a result of more widespread use of routineblood testing. Patients with symptoms usually have a gradual onset of fatigue, anorexia, weight loss,increased sweating, left upper quadrant discomfort, and early satiety as a result of splenicenlargement [25]. Rare patients with very high counts of white blood cells (WBCs) may havemanifestations of hyperviscosity, including priapism, tinnitus, stupor, visual changes from retinalhemorrhages, and even cerebrovascular accidents [26]. There are a few case reports of CMLpresenting as diabetes insipidus [27]. On physical exam, splenomegaly was documented inapproximately 70% of the patients in older series, but its incidence has decreased to 30% in morerecent series. Sometimes the spleen may be massive. The liver is also enlarged in 10% to 40% ofcases.The accelerated phase is an ill-defined transitional phase [28] that is frequently asymptomatic. Thediagnosis is made from changes in peripheral blood or bone marrow. Some patients may have fever,night sweats, and progressive enlargement of the spleen. At least 20% of patients enter a blasticphase without evidence of having had accelerated phase [3].Patients in the blastic phase are more likely to have symptoms, including weight loss, fever, nightsweats, and bone pains [17]. Symptoms of anemia, infectious complications, and bleeding arecommonly seen. Subcutaneous nodules or hemorrhagic tender skin lesions and lymphadenopathyare more common in this phase, and signs of central nervous system (CNS) leukemia can also beseen [17]. In the blastic phase, tissue infiltration can occur, most frequently to the lymph nodes,skin, subcutaneous tissues, and bone.

Laboratory Features

Peripheral Blood The most common feature of CML is an elevated WBC count, usually above 25,000/L, andfrequently above 100,000/L [29]. Some patients have wide cyclic variations in their WBC count,with peak counts every few days or separated by up to 70 days [30]. The WBC differential usuallyshows granulocytes in all stages of maturation, from blasts to mature granulocytes that lookmorphologically normal. The number of basophils is usually increased from that normally expected,but only 10% to 15% of patients have 7% or more basophils in peripheral blood; a very highproportion (ie, 20% or more) of basophils in the peripheral blood usually signals acceleration of CML[28]. The number of eosinophils is also frequently higher than normal, but to a smaller degree. Theabsolute lymphocyte count is usually elevated, mostly representing an expansion of Tlymphocytes[31]. The platelet count is elevated in 30% to 50% of patients and is higher than 1,000,000/L in afew patients. Thrombocytopenia can also be seen and usually signals acceleration of the disease[28]. Most patients have mild anemia at diagnosis, but untreated patients may be severely anemic.The neutrophil function is usually normal or only mildly impaired [32]. Patients in the chronic phasedo not have an increased risk for infections. However, the activity of their natural killer cells isimpaired because of the defective maturation of these cells [33]. Platelet function is frequentlyabnormal as measured in the laboratory and most frequently shows a decreased secondaryaggregation with epinephrine, but this usually does not have clinical significance.Bone MarrowThe bone marrow is hypercellular, with cellularity of 75% to 90% and very little fat. The myeloid toerythroid ratio is 10:1 to 30:1 rather than the normal 2:1 to 5:1 [34]. The myelocyte is thepredominant cell in the bone marrow during the chronic phase, with promyelocytes and blastsaccounting for less than 10% of all cells. Megakaryocytes are increased early in the disease and mayshow dysplastic features. Cells mimicking Gaucher cells can be seen in 10% of cases, as canseablue histiocytes [35]. Fibrosis may be evident at diagnosis and increases with diseaseprogression [36]. Surprisingly, reticulin fibrosis grades 3 to 4 are seen in up to 30% to 40% of casesand has been associated with a worse prognosis [36].Other Laboratory Findings

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The activity of leukocyte alkaline phosphatase is reduced in nearly all patients at diagnosis [37]. Thesignificance of this finding is unclear, but, interestingly, the activity can be restored after transfusingleukocytes from patients with CML to neutropenic patients, which suggests extrinsic regulation [38].Granulocyte colony-stimulating factor can induce synthesis of leukocyte alkaline phosphatase in vitro[39]. The activity of leukocyte alkaline phosphatase also increases with infections, stress, and uponachievement of remission or progression to the blastic phase.Serum levels of vitamin B12 and transcobalamin are increased, sometimes up to 10 times the normallevels. Although this is, in part, due to the high WBC count, these levels may remain high even afterhematologic remission. Serum levels of uric acid and lactic dehydrogenase are also frequentlyelevated.CML PhasesAs mentioned, CML has a bi- or triphasic course. There is an initial chronic phase that eventuallyleads to a blastic phase, sometimes preceded by an intermediate or accelerated phase. The chronicphase, if untreated, has a median duration of 3.5 to 5 years before evolving to the more aggressivephases. The diagnosis is based on the characteristics mentioned above.The blastic phase resembles an acute leukemia. Its diagnosis requires the presence of at least 30%of blasts in the bone marrow or peripheral blood [40]. In some patients, the blastic phase ischaracterized by extramedullary deposits of leukemia called myeloblastomas [41]. These usuallyappear in the CNS, lymph nodes, or bones and occasionally occur in the absence of blood or bonemarrow evidence of blastic transformation. Most of these cases, however, will have hematologicmanifestations within a few months [42]. Patients in the blastic phase usually die within 3 to 6months. Approximately 50% of patients have a myeloid blastic phase, 25% lymphoid, and 25%undifferentiated [43]. Although median survival is slightly better for patients with a lymphoid blasticphase than for those who have myeloid or undifferentiated cases (9 vs 3 months), the outcome isstill very poor [43].Seventy-five to 80% of patients go through an accelerated phase before entering the blastic phase[3]. The definition for the accelerated phase is not uniform [28]. Specific criteria associated with asurvival shorter than 18 months by multivariate analysis have been proposed, including thepresence of 15% or more blasts in peripheral blood, 30% or more blasts and promyelocytes in theblood, 20% or more basophils in the blood, or a platelet count less than 100,000/L (Table 1) [28].Cytogenetic clonal evolution has been considered a criterion for acceleration. Recent analysissuggests that its prognostic effect depends on the specific abnormality, its predominance in marrowmetaphases, and the time of appearance [44]. Patients with chromosome 17 abnormalities, 25% ormore abnormal metaphases, clonal evolution longer than 25 months after diagnosis, and no priortherapy with alpha interferon (IFN-alfa) have the worst outcome. The median survival for patientswith none of these features is 51 months compared with 24, 14, and 7 months when 1, 2, or 3 or 4features, respectively, are present [42].

Table 1. Clinical Characteristics ofPatients With Different Phases of Chronic Myelogenous Leukemia Percentage of patients with characteristics

Chronic phase Accelerated phaseBlast phase

CharacteristicsBefore 1982 (N=336) Since 1983 (N=494)PBefore 1983 (N=51)Since 1983 (N=139)PBefore 1983 (N=48)Since 1983

(N=61)P

Age > 60 yr 18 12 .031611NS1321NS

Asymptomatic 15 37< .01 420.02 824NS

Hepatomegaly 46 18< .015119< .016022.01

Splenomegaly 76 54< .018470NS9156.01

Hemoglobin < 12 g/dL 58 48 .015055NS7950.05

WBC count >100,000/L

69 56< .016764.844546NS

Platelet count >700,000/L

28 19< .012014NS 817NS

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Peripheral blasts 65 56.034841NS8350.03

Peripheral basophils >7%

17 14NS1727NS1413NS

Marrow blasts > 5% 16 9< .013534NS9591NS

Marrow basophils >3%

40 35NS5752NS3319NS

NS = not significantWBC = white blood cell

Staging of CML

Several clinical characteristics have been identified to have prognostic significance in CML. Theseinclude age, spleen size, liver size, platelet count, WBC count, percentages of blasts and basophils inblood or bone marrow, number of nucleated red blood cells, and cytogenetic clonal evolution. Thesefactors have been incorporated in staging systems [45-48]. A synthesis staging system hasincorporated factors from all these systems and resulted in a simple model for staging that canidentify four CML stages with different outcomes (Table 2) [49]. The stage at diagnosis has beenidentified as one of the most important predictors of survival after treatment with interferon- (IFN-)alfa therapy [50,51] but is somehow less predictive for patients treated with chemotherapy alone[52]. The response to therapy with IFN-alfa is a significant prognostic factor for long-term survivaland will be discussed later in this review.

Table 2. Synthesis Staging System forChronic Myelogenous Leukemia Criteria Stage Definition Criteria Stage Definition

For chronic phase

Age > 60 years 1 0 or 1 characteristics

Spleen > 10 cm 2 2 characteristics below costal margin

Blasts > 3% in blood 3 > 3 characteristics or > 5% in marrow

For acceleratedphase

4 > 1 characteristic (regardless ofcharacteristics for chronic phase)

Cytogenetic clonalevolution

Blasts > 15% in blood

Blasts +promyelocytes > 30%in blood

Basophils > 20% inblood

Platelets < 100,000/L

Other factors have been suggested to be predictive of response to therapy and survival. The site ofthe breakpoint in the bcr gene has been thought to have prognostic significance [53,54], but largestudies show a lack of correlation with response to therapy or survival [55].

Cytogenetic and Molecular Changes

Ninety to 95% of all patients with CML have the Ph chromosome [56]. Initially identified as a short

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chromosome 22, it actually represents a balanced translocation between the long arms ofchromosomes 9 and 22, t(9;22)(q34;q11) [56]. The c-abl proto-oncogene located on chromosome9q34 is homologous to the transforming element of the Abelson murine leukemia virus, v-abl. Itcodes for a nonreceptor proteintyrosine kinase expressed in most mammalian cells, but its normalfunction is unknown. In the Ph chromosome, the breakpoint occurs within the first intron of c-abl,therefore translocating exons 2 through 11 to chromosome 22 [56]. In chromosome 22, thebreakpoint occurs within the bcr gene, a large 70-kb gene with 20 exons. The breakpoint usuallyinvolves a 5.8-kb area known as the breakpoint cluster region, either between exons b3 and b4 or b2and b3 [56]. Therefore, two different fusion genes can be formed, both of them joining exon 2 of ablwith either exon 2 of bcr (b2a2) or exon 3 of bcr (b3a2). This hybrid gene is then transcribed into an8.5-kb mRNA, in contrast to the normal c-abl, which is 6 to 7 kb [57].Upon translation, a new protein is synthesized that has a molecular mass of 210 kDa (p210bcr/abl);the normal c-abl is 145 kDa. The normal tyrosine kinase activity of c-abl is dysregulated as aconsequence of its binding to bcr, with markedly increased autophosphorylating activity [58]. Thebinding to bcr also activates an actin-binding function associated with c-abl [59]. The expression ofp210bcr/abl is sufficient to induce leukemic transformation of transfected cells [60] and can induceleukemia in transgenic mice [61]. Although the mechanism by which this new protein can inducetransformation is not well known, recent data have clarified this issue to some extent. The first exonof bcr is essential for the transforming ability of bcr/abl and binds to an ABL SH2 domain in aphosphotyrosine-independent manner [62]. Disruption of this binding eliminates the transformingactivity of bcr/abl. Upon autophosphorylation, several tyrosine residues are phosphorylated. Themost critical one seems to be Y177, which then links p210bcr/abl to a 26-kDa protein with SH2 andSH3 domains called GRB-2 [63]. This protein links tyrosine kinases to ras signaling [64]. Rasactivation is in fact required for transformation by several tyrosine kinases [65], and suggests that italso plays a major role in bcr/abl directed transformation. The actin-binding function of abl seems tobe important for the transforming ability [66]. Other proteins may also be bound and phosphorylatedby bcr/abl. One such protein is CRKL, which is the most abundant phosphorylated protein in someCML cell lines [67], but its specific role in leukemic transformation is not yet clear. It is likely,however, that more than one pathway is involved in leukemic transformation after bcr/ablautophosphorylation. When the bcr/abl SH2 domain (ie, the major tyrosine autophosphorilation siteof the kinase domain) is mutated, transforming activity is lost, but it can be restored by theoverexpression of c-myc [68]. It is not known whether signals generated through GRB-2 feed intoboth pathways (ie, ras and myc) or whether other pathways are involved. It has also been suggestedthat the activation of the tyrosine kinase activity may suppress apoptosis in hemopoietic cells [69].The reciprocal fusion gene (ie, abl/bcr) is transcribed in approximately two thirds of patients withCML, but the significance of this event is not clear [70].As mentioned earlier, additional chromosomal abnormalities are a marker of acceleration of thedisease. The most common events are the appearance of an additional Ph chromosome, trisomy 8,and isochromosome 17q. The molecular events of acceleration, however, are not well defined [71].Mutations of p53 have been found frequently by some investigators [72], but others found mutationsa less common event, whereas deletions and rearrangements may occur during the blastic phase[73]. Overall, loss of function of p53 is probably associated with disease progression inapproximately 25% of CML patients [74].Besides the intrinsic abnormalities of CML cells determined by the bcr/abl and associatedintracellular signal elements, external regulatory factors are also affected in CML. Cells from CMLpatients have a defect in cellular adhesion to stromal cells that affects the regulation of myeloid cellgrowth [75]. CML progenitor cells are deficient in the expression of the cytoadhesion moleculelymphocyte function antigen-3 [76]. This deficiency is corrected by exposure to IFN-alfa [76]. IFN-alfacan also increase adhesion to stroma by a mechanism that can be blocked by antibodies tointegrins a4, a5, and b1 [77]. This is not related to a deficient expression of the integrins but to afunctional defect of these molecules [77]. More evidence for the dysregulation of CML cells byexternal influences was provided by studies on interleukin-1. Levels of interleukin-1-b have beenreported to be elevated in patients with CML, and inhibitors of interleukin-1 can suppress CMLclonogenic growth [78]. Elevated levels of interleukin-1 have been correlated with an adverseprognosis [79].

Therapy

Conventional Therapy and Other Chemotherapy

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For a long time, therapy for CML has consisted mostly of busulfan (Myleran) or hydroxyurea(Hydrea). Busulfan allows long periods of hematologic control and is not expensive, making itattractive for use when socioeconomic issues are important or in patients for whom follow-up iserratic. Busulfan therapy is associated with lung, marrow, and heart fibrosis and can causeAddison-like disease; in 10% of patients, prolonged myelosuppression may be observed. The dose ofbusulfan is usually 0.1 mg/kg/d until the WBC counts decrease by 50%, and then the dose is reducedby 50%. Therapy is discontinued when the WBC count drops below 20,000/L and is restarted whenit increases above 50,000/L.Hydroxyurea has a lower toxicity profile but shorter control of hematologic manifestations, requiringmore frequent follow-up [80]. It is usually given at a dose of 40 mg/kg/d and is reduced by 50% whenthe WBC count drops below 20,000/L. The dose is then adjusted individually to keep the WBC countat 5 to 10,000/L. One study used higher doses of hydroxyurea (2 g/m/d) until the absoluteneutrophil count reached


Complete 72 (26)

Partial 32 (12)

Minor 55 (20)CML = chronic myelogenous leukemiaIFN-alfa = alpha interferon

a M.D. Anderson experience with 274 patients

b All with complete hematologic response

Cytogenetic responses are considered complete if Ph-positive cells constitute 0% of all cells, partial ifthey represent between 1% and 34% of all cells, and minor if they represent 35% to 90% of all cells.Complete and partial cytogenetic responses constitute major cytogenetic responses [91]. Otherstudies have used different criteria, making comparisons of results among studies difficult. Standardresponse criteria, as proposed in Table 4, will help such comparative studies in the future, becauseCHR and cytogenetic responses have prognostic relevance. The median time to achieve ahematologic remission is 6 to 8 months [51,91]. For cytogenetic responses, the median time is 22 to24 months for a complete response, 12 to 18 months for a partial response, and 8 to 14 months for aminor response [3,51,91]. Responses may be faster with recombinant than with natural IFN-alfa [91].The cytogenetic responses achieved with IFN-alfa are durable in > 50% of patients achieving them,or in about 25% to 30% of all patients in the early chronic phase [3]. The durability is greater inpatients who achieve complete or partial responses than in those with lesser degrees of majorcytogenetic responses. Several other groups have confirmed these observations, but the results vary[51,92-96]. In analyzing these results, several factors must be considered, including the dose, thepatients selected for treatment trials and their phase of disease, the type of therapy given, and thetoxic effects patients experience.

Table 4. Criteria for Response to IFN-alfa in CML Response Category Criteria

Hematologic remission Complete Normalization of WBC counts to< 9,000/L with normal differential

Partial Decrease in WBC to < 50% of pretreatmentlevel and to < 20,000/L, orNormalization of WBC with persistentsplenomegaly or immature peripheral cells

Cytogenetic response Completea No evidence of Ph-positive cells

Partiala 5% to 34% of metaphases Ph-positive

Minor 35% to 95% of metaphases Ph-positive

None Persistence of Ph chromosome in all analyzablecells

CML = chronic myelogenous leukemiaIFN-alfa = alpha interferonPh = Philadelphia chromosomeWBC = white blood cell

a Major cytogenetic response includes complete and partial cytogentic response

Dose: There is a dose-response effect with IFN-alfa in CML. The dose used in most studies thatdocumented significant response is 5,000,000 U/m/d [51]. With lower doses the results are inferior[3]. In one study, patients were randomized to receive 2,000,000/U/m three times a week or5,000,000/U/m three times a week [97]. The CHR rate was lower with the lower dose (24% vs 47%; P = .06). Patients who did not respond to the lower dose still achieved a CHR with the higher dose.The same group observed a CHR rate of 87% when they used a daily schedule [97]. One recentreport suggests that low doses are as effective as high doses [93]. These results may be influencedby patient selection and should be considered cautiously. At this point, the recommended dose istherefore 5,000,000 U/m/d or the maximally tolerated individual dose, not to exceed 5,000,000

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U/m/d.Patient Selection: Several patient characteristics are associated with failure to achieve a majorcytogenetic response and with worse survival after treatment with IFN-alfa. These include poorperformance status, the presence of symptoms at diagnosis, splenomegaly, anemia, leukocytosis, ahigh percentage of blasts in the peripheral blood, peripheral nucleated red blood cells, and marrowbasophilia [50]. The stage of disease, whether staged with Sokal's model [47] or the synthesisstaging system [49], is strongly predictive of response and survival [50]. Patients at low risk have aCHR rate of 80% to 90%, with 40% having major cytogenetic responses compared with 50% to 60%and 20% to 30%, respectively, for patients at intermediate risk and 20% to 60% and 5% to 10%,respectively, for patients at high risk [3] (Table 5). Age is a significant survival factor, with patients60 years old and older having a worse prognosis [47,49]. However, a recent report from M.D.Anderson Cancer Center suggests that patients in this age group may have responses to IFN-alfasimilar to those in younger patients, albeit with more toxic effects [98].

Table 5. Response to Alpha Interferon (IFN-alfa) Therapy With Different Dose Schedules

Study IFN-alfadose CHR(%)

MDACC 5,000,000U/mDaily27480583826

Schofieldet al

2,000,000U/mDaily27703322 7

Alimenaet al

5,000,000U/m2,000,000U/m

TIWTIW30306324NSNSNSNSNSNS

Freund etal

5,000,000 UTIW1033 0 0 0

Anger etal

3,000,000 UTIW 92220 0 0

CHR = complete hematologic responseMDACC = M.D. Anderson Cancer CenterNS = not statedTIW = three times a week

CML Phase: The phase of the disease at the time of treatment is a major determinant of response.Patients in the chronic phase have the best response to IFN-alfa [3]. Among those in the chronicphase, patients treated within 1 year from diagnosis (ie, early chronic phase) have a CHR rate of60% to 80%, and 20% to 30% of them have major cytogenetic responses compared with a CHR rateof 50% to 60% in fewer than 10% of patients treated more than 1 year from diagnosis. Patients inthe accelerated or blastic phase have CHR rates of less than 40% and only occasionally have acytogenetic response (Table 7) [3].

Table 7. Response to Alpha Interferon byChronic Myelogenous Leukemia Phase Cytogenetic

response (%)

Phase CHR (%) Any Major

Early chronic 6080 4050 2030

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Late chronic 5060 1020 < 10

Accelerated 3040 < 10 0

Blastic 2030 < 10 0

CHR = completehematologicremission

Several groups have documented a survival advantage for patients treated with IFN-alfa comparedwith conventional chemotherapy [50,51,94-96]. Time to progression to blastic phase was alsoprolonged. In all three randomized studies [51,94,96], IFN-alfa produced higher rates of major andcomplete cytogenetic remission compared with conventional chemotherapy, but one of these studiesshowed no survival advantage over that achieved with hydroxyurea [96]. The recent update from theItalian Cooperative Study Group on CML [51], which compared treatment with IFNa vs conventionalchemotherapy, documented a longer median survival for patients treated with IFN-alfa (median 72+vs 52 months; P = .002). The 6-year survival rate was 50% vs 29% for patients treated with IFN-alfaand chemotherapy, respectively (P = .002). The time to the acceleration or blastic phase was alsosignificantly prolonged for the IFN-alfa group (72+ vs 45 months; P < .001) [51]. Similar results werereported by Allan et al [94]. A recent study by Hehlmann et al [96] randomized patients to receiveIFN-alfa or conventional chemotherapy. Patients treated with IFN-alfa had a median survival of 5.5years (5-year survival rate of 59%) compared with 3.8 years (32%) for those treated with busulfan(P = .008) and 4.7 years (44%) for those treated with hydroxyurea (not statistically significant).Several points may explain the findings: (1) some patients entered on the IFN-alfa arm may not havebeen in the chronic phase (blasts up to 35%, platelets less than 100,000/L) (2) the actualdoseschedule of IFN-alfa delivered was 2,000,000 U/m/d after the initial 4 weeks and (3) thecomplete and major cytogenetic response rates were low (7% and 10%, respectively). The latter twoobservations are important because some studies show superior survival only with achievement of amajor cytogenetic response, which is enhanced by higher dose schedules of IFN-alfa.Achievement of a cytogenetic response is associated with a survival advantage in several studies.However, two studies failed to document such a correlation [92,96]. These studies had a low rate ofmajor cytogenetic responses, possibly because of the patients selected or because the actual dosesof IFN-alfa administered were lower [92,96]. Two other studies show that patients who achieve acytogenetic response have a survival advantage, whereas those who fail to achieve such a responsehave a survival similar to that of patients treated with conventional chemotherapy [50,51]. In a trialfrom the Medical Research Council, even though patients who did not respond to IFN-alfa had ashorter survival than did responders, they still showed a survival advantage over those treated withchemotherapy [94]. Multivariate analysis has not been completed in this study [94].Combination Therapy Using IFN: IFN-alfa-based combinations have attempted to improve on theresults of single agent trials. Initial studies with IFN-gamma documented a CHR rate of 23%, andsome patients who were refractory to one type of IFN-(alfa or gamma) responded to the other [99].These results prompted the use of a combination of IFN-alfa and IFN-gamma [100,101]. Thecombination is well tolerated, but the results are not better than those achieved with IFN-alfa alone[100,101].Cytarabine has selective in vitro activity against CML, and preliminary studies reported cytogeneticresponses in patients treated with it alone [83]. The combination of cytarabine and IFN-alfa inpatients in late chronic phase achieved a CHR rate of 55% and a cytogenetic response rate of 15%,which compares favorably with the 28% (P < .01) and 5% (not significant), respectively, achievedwith IFN-alfa alone. Survival rates were also better with the combination. For patients in theaccelerated phase, no improvement in the response rate was observed [102]. Among patients in theearly chronic phase, Arthur and Ma reported a CHR rate of 93%, a cytogenetic response rate of 67%,and a complete cytogenetic response rate of 30% [103]. Guilhot et al randomized patients to receiveIFN-alfa alone or with low-dose cytarbine and reported a trend for a higher complete cytogeneticresponse rate in patients treated with the combination schedule (23% vs 14%; P < .24) [104].Other combinations are less effective. The use of busulfan with IFN-alfa can be complicated byprolonged myelosuppression. Hydroxyurea can be given safely with IFN-alfa and is popular in clinicalpractice because CHR is achieved faster; however, the cytogenetic response rates are similar. Withthe results reported by Hehlmann et al [96], this combination may be investigated further in future

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trials. Intensive chemotherapy can produce complete and major cytogenetic responses in 30% to50% of patients who have chronic-phase CML [105], but these responses are transient and last onlyfor 3 to 9 months. The use of IFN-alfa as a maintenance drug following the induction of intensivechemotherapy does not improve the survival rate or the durability of cytogenetic responses overthose achieved with IFN-alfa alone [106].Toxicity of IFN: Most patients treated with IFN-alfa experience a transient flu-like syndrome withfever, chills, malaise, fatigue, and anorexia. These are transient, not dose-limiting, and manageablesymptomatically. Simple measures such as starting with 25% to 50% of the dose of IFN-alfa for thefirst week, giving it at night, reducing the initial WBC count to between 10,000 and 20,000/L withother chemotherapy before the start of IFN-alfa, and premedicating with acetaminophen can helpcontrol these symptoms [3].With long-term administration of IFN-alfa, late side effects occur that may be dose-limiting in 10% to25% of patients [3]. The most common are chronic fatigue (61% of patients) and weight loss (50%).Less frequent (ie, less than 20%) side effects include diarrhea, alopecia, stomatitis, andneurotoxicity, usually in the form of recent memory loss or depression [91]. Patients 60 years oldand older experience more side effects with IFN-alfa, particularly neurotoxicity [98,107]. Fewer than2% of patients develop bone marrow aplasia, particularly when they had received prior busulfantherapy [108]. Autoimmune phenomena occur in fewer than 5% of patients and include hemolyticanemia, thrombocytopenia, hypothyroidism, Raynaud's phenomenon, arthritis, lupus erythematosus,and cardiac problems such as arrhythmias and congestive heart failure [109]. Interestingly, 91% ofpatients with hypothyroidism and 75% of those with diseases involving connective tissue had somedegree of cytogenetic response [109].When side effects develop, dose reduction may be indicated as follows: (1) for grade-3 or -4 toxicity,hold therapy until recovery and restart at 50% of the dose; (2) for persistent grade-2 toxicity, reducethe dose by 25%; and (3) for WBC counts lower than 2,000/L or platelet counts less than 60,000/L,reduce the dose by 25%.Allogeneic BMTAnother treatment used in patients with CML is allogeneic BMT, which is curative. Results are moreencouraging for patients in chronic than accelerated or blastic phase. Several studies have reportedlong-term survival rates of 50% to 80% and disease-free survival rates of 30% to 70% in patientswith chronic-phase CML [110-117]. The results, however, are not uniform in all studies and aredependent on the patient's age at the time of BMT, the stage of disease, regimens used to preparepatients for BMT, and manipulation of bone marrow to enhance the chances of a good response.Age at Time of Transplant: Younger patients have a better outcome with allogeneic BMT, but the agecutoff is controversial. Patients younger than 20 years have the best outcome, with long-termdisease-free survival of 60% to 70% in most studies and a very low incidence of transplant-relatedmortality (approximately 10%) and leukemia relapse (20%) [110,115]. With increased age, the rateof complications increases, but the relapse rate remains similar. Data from the International BoneMarrow Transplant Registry suggest that after age 20, there is a significant drop in the disease-freesurvival rate [110,115]. Data from a Seattle study show that selected patients age 50 to 60 yearsmay have 4-year disease-free survival rates of greater than 80% [13]. Most studies, however, show adecline in long-term survival after age 20 to 30 years [114,117]. Until the results from Seattle can bereproduced more widely, patients older than 20 to 30 years, depending on the experience at eachinstitution, should be considered to have a higher risk of transplant-related complications.Stage of Disease: The results with allogeneic BMT are also better for patients in the chronic phasethan for those in the accelerated or blastic phase. Long-term survival rates are 50% to 60%, 15% to40%, and less than 15% for those three groups, respectively [110,115]. Among patients in thechronic phase, early transplantation is important in achieving good results. Some groups advocatethat transplantation within 1 year from diagnosis produces better results than later transplant[111,116]. This may be influenced by prior therapy: patients previously treated with busulfan doworse because of higher transplant-related morbidity; when these patients are excluded, thedifference is less significant [111]. Prior treatment with IFN-alfa, however, does not adversely affectoverall survival, disease-free survival, time to neutrophil or platelet recovery, incidence ofgraft-vs-host disease (GVHD), or the 100-day BMT-related mortality [114]. Data from theInternational Bone Marrow Transplant Registry show only a significant trend for better outcome forpatients who undergo BMT within 1 year from diagnosis compared with those who have BMTs 1 to 3years or more than 3 years after diagnosis [114], but this has not been confirmed in the EuropeanBone Marrow Transplant Registry [110]. Recent data from Seattle suggest that patients who undergoBMT 1 to 2 years after diagnosis have a similar outcome to those who have BMT within the first year

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of diagnosis [11]. Even when the difference is found to be significantly in favor of transplantationduring the first year, the disease-free survival rate improves by less than 10% [118] and may be lesswith time [119]. Interestingly, this difference is not due to more resistant disease, but to a higherBMT-related mortality.Preparative Regimens: The initial studies of allogeneic BMT in patients with CML used conditioningregimens containing cyclophosphamide and total body irradiation [115,116]. An escalation in thedose of total body irradiation resulted in a decrease in the relapse rate but increased the risk ofdeath due to causes other than relapse [112]. Substituting busulfan for total body irradiationresulted in an outcome comparable with that of patients whose regimens included total bodyirradiation [111]. In a randomized trial comparing the two alternatives, the busulfan-containingregimen resulted in a nonsignificant trend to better overall and disease-free survivals [113]. The useof total body irradiation was associated with significantly more patients with GVHD, fever, andprolonged hospitalization [113]. A recent report suggests that patients with advanced diseasetreated with busulfan may have more early toxic effects and increased transplant-related mortality[120]. Other preparative regimens produce similar results [121].Bone Marrow Manipulation: Several groups have used T-cell depletion in an effort to decrease theincidence of GVHD in patients undergoing allogeneic BMT [122,123]. Although this approach can infact reduce the incidence of GVHD, it also leads to an increased risk of relapse and graft failure[117,122,123]. More selective depletion of specific subtypes of T-cells may preserve the cellsresponsible for the graft-vs-leukemia effect [124]. Selective T-cell purging is an encouraginginvestigational trend.Several approaches have become available for patients whose disease relapses after allogeneic BMT.A second transplant has been used with some success, particularly among patients who received asecond BMT 1 year after the first [125]. Recent investigations have focused on immune-mediatedmechanisms to control relapse. For instance, the infusion of leukocytes from the original bonemarrow donor after disease relapses in patients with CML [126-130] has resulted in thedisappearance of the malignant clone [126-129] even when assessed with the polymerase chainreaction (PCR) [126]. Another approach is to give IFN-alfa therapy to patients whose disease recursafter BMT [130,132]. In two studies using this alternative, 6 of 18 patients who had a hematologicrelapse and 8 of 11 who had a cytogeneticonly relapse [132] responded to IFN. A recent studycombined IFN-alfa and donor leukocyte infusions to treat eight patients with chronic-phase CML thatrecurs after BMT [133]. PCR showed no evidence of cells bearing the Ph chromosome in six of thesepatients [133].Because only a small fraction of patients have donors for an allogeneic BMT, interest has focused onBMT using matched unrelated donors [134,135]. The 2-year disease-free survival rate is 37% to 45%[134,135], with better results among patients who receive transplants when the disease is in theearly chronic phase (45% vs 36%) [134]. The best results are obtained in children [135]. Acute GVHDgrades II to IV was seen in 77% to 82% [134,135], and extensive chronic GVHD was seen in morethan 50%. One disadvantage to this approach is the long time to identify a donor; in one study, themedian time from the start of the search to the BMT was 8.4 months [135]. Thus, although apromising alternative for patients without family donors, allogeneic BMT with matched unrelateddonors is still a high-risk procedure with significant mortality and morbidity that is related to GVHD,which is most prevalent in patients 30 years or older and those with a mismatch of one or moreantigens.Autologous BMTSome patients with CML have early progenitors (ie, CD34+, DR- cells) that do not express the bcr/ablgene and are thus probably unaffected by CML [136]. The early progenitors allow normalhematopoiesis to exist in these patients' bone marrows, even though the marrow is dominated bythe malignant CML clone. The normal early progenitors can be collected by leukapheresis duringearly recovery following intensive chemotherapy [137,138].Cells collected in this way are more frequently Phnegative than cells harvested from the bonemarrow [138]. This has led to investigations on autologous BMT as a therapeutic alternative in theseCML patients. Although 40% to 70% of these patients can achieve some degree of suppression ofPh-positive cells upon engraftment after the transplant, this is usually a short-lived phenomenon,and disease in most patients eventually recurs [137,139-142]. The use of stem cells may enablefaster engraftment but does not prolong survival [142].Interestingly, some patients previously refractory to IFN-alfa may regain sensitivity after autologousBMT [139]. Patients who receive a BMT with unpurged bone marrow show no survival advantageover those who receive conventional chemotherapy only [143]. Studies using retrovirus-marked

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autologous bone marrow have shown that the disease recurs at least in part from infused leukemiccells [144]. This suggests the need for better bone marrow purging. Several approaches have beenused for this purpose [145], including the use of a long-term bone marrow culture that can selectPh-negative cells [146], although usually significant numbers of Ph-positive cells are still detectable[147]. In vitro purging with mafosfamide [148,149], interferon-g [150], antisenseoligodeoxynucleotides to c-myb [151] or bcr/abl [152-154], and other immunologic approaches [155]are also used, as is in vivo purging using intensive chemotherapy and early stem-cell collection. Theideal purging technique is not yet known, and active research in this area is currently beingconducted. The use of IFN-alfa for maintenance therapy after autologous BMT has not resulted insustained remissions.

Minimal Residual Disease

With the availability of more sensitive techniques, detection of minimal residual disease in CML,which has the advantage of having a specific marker (ie, Ph chromosome), has become possible[120]. However, the information regarding methods to detect minimal residual disease and itssignificance may be confusing, and the clinician has to be careful with interpretation of the results.After treatment with IFN-alfa, the bcr/abl gene can be detected in nearly all patients with the PCR[156,157], even although a few patients do become negative for this gene [158]. However, mostpatients will remain in complete remission even if bcr/abl is still present [157]. This may beexplained by the extreme sensitivity of this technique, which may detect bcr/abl-positive cells thatare either not clonogenic or not myeloid (eg, T-cells) long-lived cells. Some investigators haveadvocated the use of a semiquantitative PCR procedure that would identify an increase in theexpression of bcr/abl, which may predict relapse [159,160]. The use of fluorescent in situhybridization may reveal the Ph chromosome in proliferating cells, which may be more useful forpredicting relapse [161,162], but this hypothesis needs further testing. Hypermetaphase fluorescentin situ hybridization is a technique that allows the analysis of 500 or more metaphases and thusoffers an intermediate level of sensitivity between cytogenetics and the PCR. Interestingly, patientstreated with IFN-alfa may continue to show bcr/abl-positive cells on PCR tests for some time [158]after they achieve a cytogenetic response [158]. Some patients have turned negative as late as 5years after the initial response, but even after becoming negative on PCR tests, residual disease maybe detected in some patients by clonogenic assay [158], which suggests a state of tumor dormancy.Unlike the situation with IFN-alfa, the PCR test has been more predictive of long-term outcome whenused on samples from patients who have had a BMT, particularly when done 1 year after the BMT.Ph-positive cells may be detected soon after BMT, but they frequently disappear [163]. Persistent orincreasing proportions of Ph-positive cells, however, may herald a relapse [163]. Single positiveresults on PCR within the first 6 months after BMT do not predict relapse [164-166], but positive PCRsamples after 6 months may be predictive [167]. When serial studies are performed, persistentpositivity on PCR tests will be followed by a relapse in 75% of patients, whereas disease in only 20%with both positive and negative results and in none with all negative results will recur [168]. Patientswho receive unmanipulated BMT may still eventually become bcr/abl negative despite positiveresults on PCR tests after 1 year from the transplant [169,170].

Patients in the Accelerated or Blastic Phase

Patients in the accelerated or blastic phase of CML respond poorly to therapy. Regimens includinghigh-dose cytarabine and daunorubicin induce remissions in only 25% to 35% of patients, with amedian survival of 8 to 18 months for those in the accelerated phase and 3 months for those in theblastic phase [171]. Regimens that do not contain cytarabine produce similarly poor results in thesepatients [172]. Results with allogeneic BMT are also worse than for patients in the chronic phase. The4-year survival rate is 20% to 40% [111,173]. Some studies report more optimistic results [174], butpatient selection may be different. Patients who are in the accelerated phase only on the basis ofclonal evolution and who undergo BMT less than 1 year after diagnosis of CML have a 4-yearprobability of survival of 74% [173]. As mentioned earlier, this is a group with a good outcome [44].Autologous BMT has been used with the intention of reinstituting a second chronic phase [175].Although most patients achieve this status, their disease eventually recurs after a mediandisease-free survival of 8 months [175].

Ph-Negative CML

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In 5% to 10% of patients with otherwise typical clinical features of CML, the Ph chromosome is notfound in cytogenetic studies [176-179]. One third of these patients have evidence of the bcr/abltranslocation when analyzed at the molecular level [177]. These patients have similar clinicalfeatures, response to IFN therapy, and long-term prognosis similar to those of patients withPh-positive disease [178]. Patients without molecular evidence of the translocation are older, have ahigher incidence of thrombocytopenia, lower WBC counts, and fewer basophils than Ph-positive orPh-negative, bcr-positive patients. Their median survival is significantly shorter than that of patientswith Ph-positive or Ph-negative, bcr-positive CML (25 months vs 73 and 68 months, respectively)[178]. However, disease in these patients does not evolve to a blastic phase as it does in Ph-positiveor Ph-negative, bcr-positive patients. Instead, their natural history is characterized by increasingleukemia burden, with progressive leukocytosis, organomegaly, extramedullary infiltrates, and bonemarrow failure without a significant increase in blasts [179]. References:

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