Monitoring molecular response in chronic myeloid leukemia

Monitoring Molecular Response in ChronicMyeloid LeukemiaJorge Cortes, MD; Alfonso Quintas-Cardama, MD; and Hagop M. Kantarjian, MD

Before the advent of tyrosine kinase inhibitor (TKI) therapy, the evaluation of hematologic and cytogenetic responses

was sufficient to gauge treatment efficacy in patients with chronic myeloid leukemia. However, with more potent TKI

therapies, the majority of patients achieve complete cytogenetic response. Furthermore, deeper molecular responses

are now commonly achieved, necessitating a reliance on molecular monitoring to assess residual leukemic disease.

The prognostic significance between molecular responses and duration of complete cytogenetic response, progres-

sion-free survival, and event-free survival is described herein. A discussion of the concept of complete molecular

response is also provided, and the potential for imatinib treatment discontinuation is evaluated. The implications of

rising BCR-ABL1 transcript levels and caveats of molecular monitoring are also described. Cancer 2011;117:1113–22.

VC 2010 American Cancer Society.

KEYWORDS: chronic myeloid leukemia, tyrosine kinase inhibitor, BCR-ABL, imatinib, molecular response.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disease resulting in expansion of hematopoietic cellscarrying the oncogenic BCR-ABL1 fusion, which encodes the constitutively active BCR-ABL1 protein tyrosine kinase.1

This fusion, known as the Philadelphia (Ph1) chromosome, is the result of a reciprocal translocation between the longarms of chromosomes 9 and 22, t(9;22)(q34;q11) and can be detected by cytogenetic analysis.2 The resulting BCR-ABL1tyrosine kinase is upstream of numerous signaling pathways and necessary for initiation of leukemogenesis.2-4 Imatinib(Gleevec/Glivec; formerly STI571, Novartis Pharmaceuticals, East Hanover, NJ), nilotinib (Tasigna; Novartis Pharma-ceuticals Corporation), and dasatinib (Sprycel; Bristol-Myers Squibb, Princeton, NJ) are BCR-ABL1 tyrosine kinaseinhibitors (TKIs) designed to inhibit BCR-ABL1 activity and have dramatically improved outcomes for patients withCML.5-7 A recent 8-year follow-up of patients with newly diagnosed CML in chronic phase (CML in chronic phase)treated with imatinib in the phase 3 IRIS (International Randomized Study of Interferon and STI571) trial reported acumulative rate of complete cytogenetic response of 83% and an estimated overall survival (OS) of 93% when only CML-related deaths were considered.8 This review describes the approaches to measuring responses in light of the success ofTKI therapy in the treatment of CML and the prognostic significance of those responses.

Definitions and Approaches to Measuring Response in CML

The goals of CML treatment are the return of blood counts to normal values, reduction and elimination of the Ph1chromosome, and reduction and elimination of BCR-ABL1 gene expression. Progress toward these goals can bedetermined by the measurement of hematologic, cytogenetic, and molecular responses, respectively. Before the advent ofTKI therapy, the evaluation of hematologic and cytogenetic responses was sufficient to gauge treatment efficacy. However,with more potent TKI therapies, deeper responses are now commonly achieved, necessitating more sensitive methods ofdisease detection.

Hematologic responses

A complete hematologic response (CHR) is achieved when laboratory values return to normal levels, with a whiteblood cell count<10,000/mm3, a platelet count<450,000/mm3, the presence of<5%myelocytes plus metamyelocytes,the presence of <5% basophils, the absence of blasts and promyelocytes in peripheral blood, and the absence of

DOI: 10.1002/cncr.25527, Received: March 10, 2010; Revised: May 19, 2010; Accepted: June 2, 2010, Published online October 19, 2010 in Wiley Online Library

(wileyonlinelibrary.com)

Corresponding author: Jorge Cortes, MD, Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Fourth

Floor/Room 3000, Box 0428, Houston, TX 77030; Fax: (713) 794-4297; [email protected]

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

Cancer March 15, 2011 1113

Review Article

extramedullary involvement.5,9 European LeukemiaNetrecommendations state that achievement of CHR within3 months from the start of therapy is an optimalresponse.10 Nearly all patients with CML in chronic phaseachieve a CHR with TKI therapy.

Cytogenetic responses

Cytogenetic analysis remains the gold standard forresponse to treatment monitoring in CML.10 Conven-tional cytogenetics requires a bone marrow sample andevaluation of >20 metaphases for the Ph1þ chromo-some. Categories of cytogenetic response include minimalcytogenetic response, with 36% to 95% Ph1þ meta-phases; partial cytogenetic response, with 1% to 35%Ph1þ metaphases; major cytogenetic response, with 0%to 35% Ph1þ metaphases; and complete cytogeneticresponse, with 0% Ph1þ metaphases. Although cytoge-netic studies are associated with a wide confidence intervalbecause of the limited number of metaphases evaluated,the association between cytogenetic response and positiveoutcomes has been well established.11,12

Fluorescent in situ hybridization (FISH) is an alter-native method for assessing cytogenetic response in whichapproximately 200 interphase cells are analyzed from aperipheral blood sample. Although newer FISH techni-ques use 3 to 4 probes (double-fusion FISH) and reducethe number of false-positive results (sensitivity is 1%-5%), achievement of complete cytogenetic responsecannot always be confirmed by FISH; hence, cliniciansshould be cautious in declaring treatment failure based onlow-level FISH positivity.

Molecular responses

The majority (83%) of patients with CML treatedwith TKI therapy achieve a complete cytogenetic response(elimination of the Ph1 chromosome in bone marrowmetaphases), and therefore more sensitive measurementsare necessary to detect minimal residual disease.13 Molec-ular monitoring accomplishes this by detecting the pres-ence of BCR-ABL1 mRNA using real-time quantitativepolymerase chain reaction (QPCR). Molecular monitor-ing is capable of detecting low levels of disease and is >3logs more sensitive than conventional cytogenetics.14 Inaddition, the analysis can be performed on peripheralblood samples, making it more convenient than bonemarrow sampling.15 Molecular responses are quantifiedby measuring the reduction in BCR-ABL1 transcriptsrelative to a standardized baseline.9 The InternationalStandardization process has led to the development of a

conversion factor that enables individual laboratories toexpress BCR-ABL1 transcript levels on an agreed-uponinternational scale, thus allowing comparison of molecu-lar response between laboratories.16,17 In the IRIS trial,patients in the imatinib group who had a reduction in thelevel of BCR-ABL1 transcripts of >3 logs compared withthe standardized baseline had a negligible risk of diseaseprogression over the subsequent 12 months.18 As a result,a major molecular response was defined as a 3-log reduc-tion or a BCR-ABL1 (international scale) ¼ 0.1%.18 Agood correlation exists between bone marrow cytogeneticsand transcript levels in peripheral blood, with a BCR-ABL1 (international scale) �10% equivalent to a majorcytogenetic response and a BCR-ABL1 (internationalscale) �1% equivalent to a complete cytogeneticresponse. However, unlike cytogenetics, molecular analy-sis does not provide information about bone marrowmor-phology or additional chromosomal abnormalities.19

Prognostic Significance ofMolecular Responses

There is much evidence that the degree of cytogeneticresponse at certain time points is well correlated withprognosis. Patients who achieve a complete cytogeneticresponse have been shown to have low rates of progressionto accelerated phase/blast crisis (AP/BC) and excellentrates of OS.10,20 The degree of molecular response at cer-tain time points has also been associated with reduced riskof cytogenetic relapse, improved duration of completecytogenetic response, progression-free survival (PFS), andevent-free-survival (EFS).

Major molecular response is associated withduration of complete cytogenetic response

Several studies have demonstrated that achievementof a major molecular response is associated with improveddurations of complete cytogenetic response comparedwith patients who did not achieve the same depth ofmolecular response (Table 1). For example, in a study of29 patients with complete cytogenetic response followedfor a median of 13 months, none of the 16 patients withBCR-ABL1 (international scale) �0.1% lost completecytogenetic response, whereas 6 (46%) of 13 patients withBCR-ABL1 (international scale) �0.1% lost a completecytogenetic response (P ¼ .004).21 In another report on280 patients with CML in chronic phase who achieved acomplete cytogenetic response on imatinib treatment,only 9 (5%) of 166 evaluable patients who also achieved amajor molecular response lost complete cytogenetic

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1114 Cancer March 15, 2011

response, compared with 25 (37%) of 68 patients whodid not achieve a major molecular response over a medianfollow-up period of 31 months.22 Likewise, in 97 patientswith CML serially treated with imatinib 400 mg/d, thosewith a major molecular response at 12 months were lesslikely to lose complete cytogenetic response than patientswho did not achieve major molecular response by thattime point (Fig. 1).23 Marin et al have reported similarfindings in a study of 224 patients in which the probabil-ity of losing complete cytogenetic response by 60 monthswas 2.6% versus 23.6% for patients who achieved a majormolecular response by 12 months compared with patientswho did not achieve a major molecular response, respec-tively.24 At 18 months, the probability of losing completecytogenetic response was 0% versus 24.6% for patientswith major molecular response and without majormolecular response, respectively. In addition, Press et aldescribed 90 patients with complete cytogenetic responsefollowed for a median of 49 months in which only 15%(12 of 79 patients) with BCR-ABL1 (international scale)�0.1% lost complete cytogenetic response comparedwith 57% (8 of 14 patients) with BCR-ABL1 (inter-national scale)>0.1%.25

Impact of molecular responseson PFS, EFS, and OS

The impact of molecular response rates on PFS andEFS has also been evaluated. Among patients with com-plete cytogenetic response at 12 months in the IRIS trial,there was a statistically significant difference in PFS ratesbetween patients with and without major molecularresponse at 12 months (100% vs 95%, P¼ .007).18 How-ever, in a more recent update of the molecular data fromthe IRIS trial, with longer follow-up, there was no differ-ence between achievement of a major molecular response

by 12 months compared with lesser rates of molecularresponse (BCR-ABL1 [international scale] >0.1%-1%)in EFS rates at 7 years (92% vs 91%, P¼ .25).26 A differ-ence in rates of EFS was observed, however, when molecu-lar responses at the 18-month landmark were considered(95% vs 86%, P ¼ .01). There was little difference in 7-year rates of progression to advanced phase diseasebetween patients with a major molecular response andthose with BCR-ABL1 (international scale)>0.1% to 1%at the 18-month landmark (99% vs 96%, P ¼ .054).There was no difference in OS between these 2 groups.Importantly, with 8 years of follow-up on the IRIS trial,

Table 1. Duration of Complete Cytogenetic Response by Achievement of MajorMolecular Response

Study No. % Losing CCyR Length ofFollow-up(mo)Pts With MMR

at 12 MonthsPts Without MMRat 12 Months

Paschka 200321 29 0% 46% Median 13

Cortes 200522 280 5% 37% Median 31

Iacobucci 200623 97 8% (est) 30% (est) 36

Marin 200824 224 2.6% 23.9% 60

0%a 24.6%a 60

Press 200725 90 16% 57% Median 49

CCyR indicates complete cytogenetic response; Pts, patients; MMR, major molecular response; est, estimated.a Patients with and without MMR at 18 months.

Figure 1. Landmark analysis of duration of complete cyto-genetic response (CCyR) by molecular response at 12 monthsis shown. Reproduced and adapted with permission fromthe American Association for Cancer Research: Iacobucci I,Saglio G, Rosti G, et al. Achieving a major molecular responseat the time of a complete cytogenetic response (CCgR) pre-dicts a better duration of CCgR in imatinib-treated chronicmyeloid leukemia patients. Clin Cancer Res. 2006;12:3037-3042.

Monitoring Molecular Response in CML/Cortes et al


none of the patients who achieved complete cytogeneticresponse and major molecular response at 12 months onimatinib progressed to AP or BC.8 The degree of molecu-lar response was also found to correlate with the risk ofprogression in a single-institution study of 85 patientstreated with imatinib (400 mg/d in chronic phase patients[n ¼ 72] and 600 mg/d in AP patients [n ¼ 13]).27

Results demonstrated that compared with patients with a�3-log reduction in BCR-ABL1 levels, patients with �2-to <3-log reductions in BCR-ABL1 transcript levels wereat a higher risk for progression (hazard ratio, 3.8; 95%confidence interval [CI], 0.92-16; P ¼ .049), as werepatients with a <2-log reduction (hazard ratio, 10; 95%CI, 3.8-28; P< .001) (Fig. 2).

Other studies, however, have shown that rates of OSand PFS appear independent of molecular response. In ananalysis conducted at The University of Texas M. D.Anderson Cancer Center, 276 patients were analyzed, andresponses were coded according to best response andresponse at specific treatment intervals.13 Achievement ofmolecular response (major molecular response and<major molecular response) was not associated withimproved OS in patients who achieved a complete cyto-genetic response (Fig. 3). Although there was a trend sug-gesting that higher rates of PFS correlated with bettermolecular responses, the difference was not clinically rele-vant (Fig. 3). In a similar single-institution analysis, inves-tigators at the Hammersmith Hospital found nosignificant difference in PFS or OS rates in patientsachieving complete cytogenetic response at 12 months

(n¼ 121) or at 18 months (n¼ 106) by whether they hadalso achieved a major molecular response at those timepoints (n ¼ 30 at 12 months; n ¼ 38 at 18 months).24,28

At 12 months, OS and PFS were 96% and 94% versus93% and 85% for patients with major molecular responseand without major molecular response, respectively (P ¼.8, P ¼ .3).24 At 18 months, OS and PFS were 96% and95% versus 95% and 88% for patients with major molec-ular response and without major molecular response,respectively (P ¼ 1, P ¼ .4).24 One possible explanationfor the lack of association between molecular responseand long-term outcomes in these studies is that loss ofcomplete cytogenetic response may (and should) trigger achange in therapy. This early intervention can successfullyprevent progression to AP/BC in most patients, thusmasking the adverse consequences of lack of a majormolecular response. In fact, the European LeukemiaNetrecommendations suggest that loss of complete cyto-genetic response is a criterion for imatinib failure andsupport change of therapy in this situation.10

Influence of time to molecular response

The correlation between outcomes and the time toachieve molecular response has been investigated. Thesestudies suggest that the degree of molecular response atearly time points predicts later achievement of major mo-lecular response and improved rates of PFS and EFS. Forexample, in an analysis of 55 patients treated with imati-nib 400 mg/d who had peripheral blood collected at >1time points, patients with a >2-log reduction in BCR-ABL1 transcripts at 3 months had significantly better ratesof major molecular response at 24 months compared withpatients who had a �2-log reduction in BCR-ABL1 tran-scripts at 3 months (100% vs 54%, P < .001) (Fig. 4).29

Muller et al have also observed that patients with BCR-ABL1 (international scale) >10% at the 6-month land-mark had a statistically significantly higher probability ofprogression and events by 72 months.30 The 5-year PFSrate was 93% versus 72% (P ¼ .0023), and the 5-yearEFS rate was 88% versus 77% (P¼ .012) in patients withBCR-ABL1 (international scale) <10% and �10%,respectively (Fig. 5). Early molecular responses at 1 and 3months have also been associated with higher rates ofPFS.31 A decrease in BCR-ABL1/ABL1 ratio of 50% at4 weeks or 10% at 3 months of therapy was associatedwith a higher probability of PFS (Fig. 6). An alternativeanalysis by M. D. Anderson Cancer Center investigatorsfocused on the long-term outcomes of patients not achiev-ing complete cytogenetic response or major molecular

Figure 2. Duration of complete cytogenetic response (CCyR)by molecular response at time of achieving CCyR is shown.Reproduced and adapted with permission from the AmericanSociety of Hematology: Press RD, Love Z, Tronnes AA, et al.BCR-ABL mRNA levels at and after the time of a completecytogenetic response (CCR) predict the duration of CCR inimatinib mesylate-treated patients with CML. Blood. 2006;107:4250-4256.

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response at specific time points, in an attempt to test theimportance of the timing of cytogenetic and molecularresponses during imatinib therapy.32 For patients not incomplete cytogenetic response, the probability of achiev-ing a complete cytogenetic response or major molecularresponse with continued imatinib therapy markedlydiminished, and the risk of progression increased at 3, 6,and 12 months during the first year of imatinib therapy.Patients exhibiting BCR-ABL1/ABL1 ratios >1% to10% after 3 months of treatment had a 92% probabilityof eventually attaining complete cytogenetic response,which is similar to a 98% probability for patients withBCR-ABL1/ABL1 �1%. However, risk of developing anevent on therapy was 3-fold higher than that of patientswith BCR-ABL1/ABL1 �1%, which was quite similar tothat of patients with transcript levels>10%. These results

underscore the importance of attaining complete cyto-genetic response and possibly major molecular response atearly time points during imatinib therapy (Table 2).

Significance of rising BCR-ABL1 transcript levels

Despite the importance of molecular monitoring inpredicting long-term outcomes and evaluating treatmentsuccess, minor fluctuations in patients’ BCR-ABL1 tran-script levels should not be overinterpreted. For example,an evaluation of 116 patients who achieved durable com-plete cytogenetic response (>18 months) with increases inBCR-ABL1 transcript levels verified by 2 consecutivemeasurements has been conducted.33 Progression wasobserved in 11 (9.5%) of 116 patients (Table 3). Ten ofthese were among 44 patients who lost or never achieved amajor molecular response and experienced a >1-log

Figure 3. Overall survival and progression-free survival by molecular response at specific time points are shown. PCR indicatespolymerase chain reaction. Reproduced with permission: Kantarjian H, O’Brien S, Shan J, et al. Cytogenetic and molecularresponses and outcome in chronic myelogenous leukemia: need for new response definitions? Cancer. 2008;112:837-845.



increase in BCR-ABL1 transcript levels. The majority ofpatients who had achieved complete cytogenetic responseretained the same degree of response despite increasingtranscript levels. Therefore, minor fluctuations in BCR-ABL1 should not necessarily provoke a treatment change.However, patients who lose major molecular response ornever achieved major molecular response and have a sig-nificant increase in transcripts should be closely moni-tored. The magnitude of the increase that should beconsidered significant varies in different reports, from 2-fold to 1-log. Some of this difference depends on the vari-

ability of the test at the local laboratory, but for most labo-ratories an increase of 5-fold or greater should triggerclose monitoring and perhaps additional assessments (eg,cytogenetic analysis, mutation analysis).

Complete molecular responses

Elimination of the leukemic clone is the ultimategoal of therapy and the only potential for a CML cure.With TKI therapy, many patients are able to achieve acomplete molecular response, defined as undetectableBCR-ABL1 mRNA transcripts by real-time QPCR and/or nested PCR in 2 consecutive high-quality samples (sen-sitivity >104).10 The potential use of second-generation

Figure 5. Progression-free survival (PFS) and event-free sur-vival (EFS) rates at 5 years by molecular response at 6months are shown. IS indicates international scale. Repro-duced with permission from the American Society of Hema-tology. Muller MC, Hanfstein B, Erben P, et al. Molecularresponse to first line imatinib therapy is predictive for longterm event free survival in patients with chronic phasechronic myelogenous leukemia: an interim analysis of therandomized German CML study IV [abstract]. Blood.2008;112:129. Abstract 333.

Figure 4. Achievement of major molecular response (MMR)by 24 months based on molecular responses at 3 and 6months is shown. Reproduced with permission from Macmil-lan Publishers Ltd: Branford S, Rudzki Z, Harper A, et al. Ima-tinib produces significantly superior molecular responsescompared to interferon alfa plus cytarabine in patients withnewly diagnosed chronic myeloid leukemia in chronic phase.Leukemia. 2003;17:2401-2409.

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TKIs nilotinib and dasatinib in the frontline setting couldincrease the number of patients achieving this level ofresponse even more.34-36 However, without eliminationof the leukemic stem cell population, a cure is not feasible,and currently there is little evidence that achievement of a

complete molecular response correlates with improvedlong-term EFS, PFS, or OS.

Several studies have examined the potential of discon-tinuing imatinib therapy in patients with a completemolecular response.37-40 The STIM (Stop Imatinib) studyevaluated the impact of imatinib discontinuation inpatients with sustained complete molecular response for atleast 2 years.40 After 12 months of follow-up, molecularrelapse (loss of complete molecular response) occurred in40 (58%) of 69 patients. The relapse rate was slightly loweramong patients previously treated with interferon com-pared with those who were not (53% vs 66%, P was notsignificant) and was more common among women thanmen (70% vs 42% relapse rate, P¼ .02). Relapse rates cor-related with Sokal risk score: low, 45%; intermediate, 64%;high, 86%; and unknown, 78%. All patients reachievedcomplete molecular response after reinitiation of imatinibtherapy. As a result of the high relapse rate, discontinuationof TKI therapy in responding patients is not currently rec-ommended outside a clinical study setting.

Conclusions

Treatment advances for patients with CML have resultedin excellent long-term outcomes. TKI therapy with imati-nib, nilotinib, or dasatinib results in high response rates,many of which can only be measured at a molecular level.As a result, there is an increasing reliance on molecularmonitoring as a more sensitive measure to assess treatmentefficacy and monitor response. Although it has been estab-lished that patients who achieve a complete cytogeneticresponse also have excellent outcomes, data indicate thatachieving high levels of molecular response illustratestreatment efficacy and should be a goal of therapy. Theprognostic significance of molecular responses at earlytime points also provides valuable information and sug-gests more careful monitoring of patients with suboptimalmolecular responses. In patients with major molecular

Figure 6. Rates of progression-free survival by molecularresponses at 1 and 3 months are shown. Reproduced withpermission from Wiley-Blackwell, Inc.: Wang L, Pearson K,Ferguson JE, Clark RE. The early molecular response to imati-nib predicts cytogenetic and clinical outcome in chronic mye-loid leukaemia. Br J Haematol. 2003;120:990-999.

Table 2. Risk of Event Versus Probability of Achieving a Complete Cytogenetic Response According to Molecular Response atSpecific Time Points32

BCR-ABL1/ABL1Transcript Ratio

Percentage Probability of Outcome According to Transcript Ratio at SpecifiedTime Points (Median mo to Outcome)

MMR (BCR-ABL1/ABL1 <0.05%) Event

3 Months 6 Months 12 Months 3 Months 6 Months 12 Months

�0.1% 100 (3) 96 (6) 97 (12) 4 (13) 1 (38) 3 (40)

>0.1% to 1% 84 (6) 69 (12) 61 (18) 3 (46) 7 (30) 2 (48)

>1% to 10% 53 (17) 44 (18) 20 (33) 11 (21) 9 (34) 8 (47)

>10% 33 (15) 15 (18) 7 (46) 13 (47) 23 (14) 50 (19)

MMR indicates major molecular response.



response (BCR-ABL1 [international scale] �0.1%),molecular monitoring in peripheral blood may be used inplace of cytogenetic analysis to monitor response, thus for-going the need for bone marrow sampling. However, it mustbe emphasized that molecular monitoring does not provideinformation concerning bone marrow morphology or thepresence of additional chromosomal abnormalities in Ph1þmetaphases. Therefore, occasional cytogenetic analysis is stillrecommended. One must also keep in mind that low assaysensitivity and sample quality could result in false-negativeresults, and that variations in results of up to 0.5 log canoccur because of differences in assay technique and samplequality. Because of these caveats, changes in treatment shouldnot be based on a single molecular assessment. Instead, fluc-tuations in transcripts should be monitored and confirmedwith follow-up testing and, if necessary, cytogenetic or muta-tion analysis should be used in conjunction with molecularmonitoring when transcript levels rise significantly (�5-fold)or if the patient is in danger of losing a major molecularresponse. Various studies also suggest that although deepmo-lecular response should be a goal for all patients and is an in-dication of treatment success, patients who achieve acomplete cytogenetic response have been shown to havealmost as good long-term outcomes as patients with a majormolecular response, thus making complete cytogeneticresponse a valid surrogate of long-term survival and themini-mal goal to be achieved during TKI therapy.

CONFLICT OF INTEREST DISCLOSURESFinancial support for editorial assistance was provided by NovartisPharmaceuticals. We thank Daniel Hutta, PhD (Articulate Science)for medical editorial assistance. J.C. received research grant funding

from Wyeth, Bristol-Myers Squibb, and Novartis PharmaceuticalsCorporation. H.M.K. received research grant funding from Bristol-Myers Squibb, Novartis Pharmaceuticals Corporation, and Gen-zyme. A.Q.-C. has no relevant financial disclosures.

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QPCR LogIncrease

Number ofPatients

Imatinib DoseEscalation

CMLProgression

Follow-up FromQPCR Increase

(mo)

Median Range

Persistent MMRAny 28 0 0 36 3-62

Loss of MMR>0.5 to 1 12 0 0 34 14-59

>1 to 2 25 0 2 31 6-52

>2 11 4 4 45 20-57

Not in MMR<1 32 3 1 35 10-70

>1 8 1 4 25 12-56

QPCR indicates quantitative polymerase chain reaction; CML, chronic myeloid leukemia; MMR, major molecular

response.

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Review Article


Monitoring molecular response in chronic myeloid leukemia

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