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Keywords:

  • BCR/ABL;
  • deletion of derivative chromosome 9;
  • chronic myeloid leukemia;
  • imatinib mesylate

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND.

Although deletion of the derivative chromosome 9 (der 9; del-der 9) carries a poor prognosis in patients with chronic myeloid leukemia (CML) who are treated with hydroxyurea or interferon, its significance in patients on imatinib mesylate (IM) therapy is debated.

METHODS.

In the current study, the authors used a locus-specific indicator breakpoint cluster region/receptor tyrosine kinase (BCR/ABL) probe to evaluate the significance of del-der 9 in 163 patients with CML who had fluorescence in situ hybridization (FISH) results available. Serial changes in BCR/ABL fusion transcript levels also were monitored by using messenger RNA (mRNA) quantitative polymerase chain reaction (PCR).

RESULTS.

Of 163 patients, 22 (13.5%) had del-der 9 before commencing IM therapy. No differences were noted in the time to hematologic response (P = .598), major cytogenetic response (CyR) (P = .281), complete CyR (P = .883), major molecular response (MoR) (P = .125), or complete MoR (P = .834). In addition, the times to loss of response (LOR) (P = .974), treatment failure (P = .455; including primary hematologic or cytogenetic resistance and LOR), transformation-free survival (P = .276), and dose escalation of IM (P = .816) did not differ significantly between patients with and without del-der 9. The results of serial BCR/ABL mRNA quantitative PCR revealed similar patterns of BCR/ABL fusion gene reduction between the 2 groups.

CONCLUSIONS.

The presence of del-der 9 in patients with CML did not influence 1) the response to IM therapy in terms of hematologic response, CyR, or MoR; 2) LOR; 3) treatment failure; 4) progression to accelerated phase/blast crisis; or 5) time to dose escalation of IM. Therefore, the authors concluded that the detection of del-der 9 does not have an impact on the current management of patients with CML who are receiving IM therapy. Cancer 2008. © 2008 American Cancer Society.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of the Philadelphia chromosome (Ph-positive) and is formed by a reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34;q11.2).1 This translocation generates 2 novel fusion genes: the breakpoint cluster region/receptor tyrosine kinase gene BCR/ABL on the derivative chromosome 22q, known as the Ph-positive chromosome, and a reciprocal ABL/BCR fusion gene on the derivative chromosome 9q (der 9). Fluorescence in situ hybridization (FISH) can detect the presence of deletions adjacent to the translocation breakpoint on der 9 in approximately 10% to 15% of patients with CML. Large deletions in der 9, the reciprocal counterpart of the Ph-positive chromosome, have been identified in 10% to 15% of patients with CML.2–7 The deletions span up to several megabases and have variable translocation breakpoints.2, 3, 8

Imatinib mesylate (IM) (Gleevec; Norvatis, Basel, Switzerland) is a small-molecule inhibitor with selective activity against ABL tyrosine kinases.9, 10 High response rates and durable remissions have been reported in the majority of patients with CML who receive IM.7, 11 However, some patients fail to attain durable clinical responses to IM, and some patients develop IM resistance. In light of these observations, several studies have tried to identify the predictors of response to IM therapy.12, 13 Because the prognosis for patients with CML who have deletion of der 9 (del-der 9) is inferior to that for patients without the deletion on hydroxyurea or interferon-α treatment,3, 4 it also is believed that the deletion status of der 9 is a marker of poor response to IM therapy. However, its prognostic implications in IM-treated patients remains a subject of debate largely because of conflicting results from studies.14 For example, 1 study reported that IM therapy could improve but could not fully reverse the poor prognosis of CML patients with del-der 9,6 whereas another study suggested that IM therapy may completely negate the poor prognostic significance of del-der 9.7

Although the cumulative incidences of major and complete cytogenetic responses (MCyR and CCyR, respectively) at 12 months were 85% and 69%, respectively, as reported in the International Randomized Study of Interferon-α Plus Cytarabine Versus STI571 (IM) (the IRIS trial),11, 15 a substantial number of patients with CML experienced loss of response (LOR) to IM or required dose escalation to overcome suboptimal responses or LOR. This suggests that, to determine the prognostic markers that predict long-term and durable responses to IM, it will be necessary to use analyses that include not just short-term endpoints (ie, cytogenetic or molecular response) but also long-term endpoints (such as LOR or dose escalation). Accordingly, the objective of the current study was to evaluate the impact of der 9 deletion status on the treatment outcomes of CML patients IM-treated CML patients using multiple parameters to measure the short- and long-term therapeutic effects of IM, including hematologic, cytogenetic, and molecular responses (HR, CyR, and MoR, respectively); LOR and treatment failure rates; and serial BCR/ABL messenger RNA (mRNA) quantitative polymerase chain reaction (PCR) monitoring.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Group

One hundred sixty-three patients with Ph-positive CML who received IM at the Princess Margaret Hospital (Toronto, Ontario, Canada) between August 2000 and December 2006 were enrolled retrospectively in this study. Only those patients who had informative cytogenetic or FISH studies in their medical records before commencing IM therapy were included. The current study was approved by the Research Ethics Board of the University Health Network. Patient characteristics are summarized in Table 1. The definitions of chronic phase (CP), accelerated phase (AP), and blast crisis (BC) are the same as those used in previously published studies.15, 16

Table 1. Demographic and Disease Characteristics of Patients According to the Presence of Deletion of Derivative Chromosome 9
CharacteristicDel-der 9No DeletionP
  • Del-der 9 indicates deletion of derivative chromosome 9; SE, standard error; CML, chronic myeloid leukemia; IM, imatinib mesylate; WBC, white blood cell.

  • *

    Late/early indicates <6 months/≥6 months.

  • The following additional cytogenetic abnormalities other than t(9;22) were detected in the group with del-der 9: inv(9q) (n=1); −X (n=1); and t(1;22), der(1), del(9), der(22), and lesion of der 9 (n=1); and the following cytogenetic abnormalities were observed in the group without del-der 9: double Philadelphia-positive chromosome (n=4); −Y (n=4); t(7;8) (n=2); t(7;8), +8, and +der(22) (n=1); t(9;22;17) (n=1); t(9;22;22) (n=1); der (17), t(17;20), and der (20)(p13) (n=1); t(12;16) (n=1); t(2;9;22) (n=1); t(3;19) (n=1); t(4;6), 47-52, +X, +6, +8, +18, +19, +der(22) (n=1); and inv(11) (n=1) in the group without del-der 9.

Total no. of patients (%)22 (13.5)141 (86.5) 
Median age [range], y47.5 [25-75]56 [21-82].4
No. of women/men (%)9/13 (41/59)59/82 (42/58).9
Disease characteristics at the time of administration of IM   
 Median interval between diagnosis of CML and IM [range], mo2.5 [1-80.5]6.5 [1-231].07
 Mean±SE hemoglobin, g/L122.7 ± 5.6119.2 ± 1.9.5
 Mean±SE WBC count, ×109/L65.3 ± 12.782 ± 9.8.3
 Mean±SE Platelet count, ×109/L691 ± 130400 ± 29.1
 Mean±SE Peripheral blasts, ×109/L2.4 ± 1.18.2 ± 2.4.3
Stage: No. of patients (%)   
 Chronic phase18 (82)123 (87).6
 Early/late*13/5 (59/23)58/65 (41/46) 
 Accelerated phase4 (18)16 (11) 
 Blast crisis0 (0)2 (2) 
Presence of additional cytogenetic abnormalities3 (14)19 (14)1.0
Previous treatment for CML: No of patients (%)   
Interferon-α/cytarabine6/0 (29/0)71/15 (51/11).06/.2
Allogeneic transplantation/busulfan1/1 (5/5)7/13 (5/9)1.0/.7

One hundred forty-seven patients were started on IM at a dose of 400 mg per day, and 16 patients were started at doses of 600 mg per day (n = 14 patients) or 800 mg per day (n = 2 patients). All patients in CP started at a dose of 400 mg per day (n = 141 patients); whereas patients in AP or BC started at doses of 400 mg per day (n = 6 patients), 600 mg per day (n = 14 patients), or 800 mg per day (n = 2 patients). Treatment interruptions, dose adjustments, and dose escalations were applied as described previously.11, 15, 17

Evaluation During IM Therapy

Before commencing IM therapy, in addition to routine history taking and physical examination, all patients had a complete blood cell (CBC) count, including white blood cell (WBC) differential and standard biochemistry. Baseline tests also included bone marrow evaluation for morphology, conventional cytogenetic analysis, BCR/ABL mRNA PCR, and FISH for t(9;22). Cytogenetic analysis was performed by using the G-banding technique. Patients were monitored regularly on an outpatient basis: Biweekly physical examinations, blood counts, and biochemistry tests were obtained during the first month of IM therapy, then monthly until a CyR was achieved, and every 3 months thereafter. Until a CCyR was confirmed, bone marrow evaluations and FISH studies were performed every 3 months. The quantification of peripheral blood BCR/ABL fusion gene transcripts was performed every 3 months regardless of whether patients had a CyR using quantitative BCR/ABL mRNA PCR. Annual bone marrow evaluation with conventional cytogenetic analysis was performed to detect cases of clonal evolution.

Definition of Response Criteria and Endpoints

The response criteria and clinical endpoints are summarized in Table 2. Response criteria were the same as those defined in previous studies of IM.11, 15–17 Briefly, an HR was defined as a normalized peripheral blood cell counts (WBC <1 × 109/L and platelet count <450 × 109/L) without evidence of peripheral blasts, promyelocytes, or myelocytes and without evidence of extramedullary disease, including the disappearance of palpable splenomegaly that lasted for at least 4 weeks. CyRs were categorized as complete (CCyR) (0% Ph-positive cells in bone marrow determined by conventional cytogenetics or FISH), partial (1%-34% Ph-positive cells in bone marrow), or minor (35%-90% Ph-positive cells in bone marrow). An MCyR was defined as the sum of CCyRs and partial CyRs (0%-35% Ph-positive cells in bone marrow). A major MoR (MMoR) was defined as a log reduction ≥3 of BCR/ABL fusion gene transcripts by quantitative PCR compared with the baseline value, and a complete MoR (CMoR) was defined as the disappearance of detectable BCR/ABL fusion gene transcripts, equivalent to a 5-log reduction.

Table 2. Statistical Endpoints of the Current Study
  1. HR indicates hematologic response; CBC, complete blood cell counts; WBC, white blood cells; CP, chronic phase; PB, peripheral blood; BM, bone marrow; CyR, cytogenetic response; CCyR, complete cytogenetic response; Ph+, Philadelphia chromosome positive; MCyR, major cytogenetic response; MoR, molecular response; BCR/ABL, breakpoint cluster region/receptor tyrosine kinase fusion transcript; mRNA, messenger RNA; PCR, polymerase chain reaction; IM, imatinib mesylate; AP, accelerated phase; BC, blast crisis; CML, chronic myeloid leukemia.

HR
 Complete HR: Normal full CBC and WBC differentials, no evidence of extramedullary disease
 HR without recovery of normal hematopoiesis
 Return to CP: <0% Blasts in PB and BM
CyR
 CCyR: 0% Ph+ cells
 MCyR: 0-35% Ph+ cells
MoR
 Major MoR: >3 Log reduction of BCR/ABL mRNA
 Complete MoR: Negative BCR/ABL mRNA PCR
Primary hematologic resistance
 Failure to achieve any HR until 3 mo of IM therapy
Primary cytogenetic resistance
 Failure to achieve major CyR (0-35% of Ph+ cells) after 6 mo of therapy
 Failure to achieve complete CyR (0% of Ph+ cells) after 12 mo of therapy
Loss of response
 Transformation from CP to AP or BC
 Cytogenetic evolution in Ph+ cells
 Loss of CCyR/MCyR
 Confirmed increase of ≥0.5 log for patients in CCyR or better
 Detection of ABL tyrosine kinase domain mutation
Treatment failure
 Primary hematologic or cytogenetic resistance
 Loss of response
Transformation-free survival
 Progression to AP or BC from first or second CP of CML
 Death from any cause
Dose escalation to achieve further response to IM
 Dose escalation to 600 mg from 400 mg/d of IM
 Dose escalation to 800 mg from 600 mg or 400 mg/d of IM

The time to treatment failure was defined as the interval between the initiation of IM therapy and the occurrence of events indicating that patients had failed IM, including primary hematologic resistance, cytogenetic resistance, or LOR. The time to LOR was defined as the interval between the date of any confirmed response and the date at which the criteria for response no longer were met. The time to transformation-free survival was defined as the interval between the initiation of IM therapy and confirmation of progression to AP or BC or death from any cause, whereas overall survival (OS) was calculated from the initiation of IM therapy until the date of death from any cause or the date of last follow-up. The time to dose escalation of IM was defined as the interval between the initiation of IM therapy and the date that the dose of IM was increased to 600 mg per day or 800 mg per day to achieve a primary response or to overcome LOR to a lower dose of IM.

Fluorescence in Situ Hybridization and BCR/ABL Quantitative PCR

Bone marrow cells were analyzed for the presence of del-der 9 by using the Vysis Dual Color Dual Fusion Probe (D-FISH; Vysis, Ill) according to the manufacturer's instructions. By using this technique, colabeling of the ABL and BCR probes in Ph-positive cells produces a yellow signal, which indicates the fusion of the orange probe (ABL gene) and the green probe (BCR gene). Two orange signals correspond to the presence of nontranslocated ABL gene, and 1 green signal corresponds to the presence of the nontranslocated BCR gene. Ph-positive cells with del-der 9 produce 1 orange signal and 1 green signal in addition to the yellow fusion signal.

In the current study, peripheral blood samples (5mL) were analyzed by using quantitative PCR to determine the levels of BCR/ABL fusion gene transcripts according to the manufacturer's instructions (ABI 9700 Thermal Cycler; Applied Biosystems, Foster City, Calif). The glyceraldehyde-3-phosphate dehydrogenase gene GAPDH was used as a reference gene, and BCR/ABL values were expressed as a logarithmic reduction from the baseline BCR/ABL transcript levels before the commencement of IM. Nested PCR techniques were used to confirm the results in selected samples that had unquantifiable BCR/ABL transcript levels. All blood samples were collected after informed consent had been obtained from patients in accordance with the Declaration of Helsinki.

Statistical Analyses

The medical records of all patients were reviewed until the end of July 2008. The demographic and disease characteristics were compared according to der 9 deletion status by using chi-square, Fisher exact, or Mann-Whitney U tests. The treatment outcomes, such as HR, MCyR, CCyR, MoR, LOR, treatment failure, progression to AP/BC, death, and IM dose escalation, also were compared according to der 9 deletion status by using chi-square tests. The probability of each outcome was estimated by using the Kaplan-Meier method, and differences according to der 9 deletion status were compared between outcomes by using the log-rank test.

The MCyR, CCyR, MMoR, and CMoR rates were compared and plotted according to the deletion status of der 9 at time points 1 year, 1.5 years, 2 years, 3 years, 4 years, and 5 years after the initiation of IM therapy. The quantity of BCR/ABL fusion gene transcripts was measured every 3 months by using peripheral blood samples and a quantitative PCR technique. The results were compared by using a generalized estimating equations test and were plotted as mean values in a log-reduction format.

Univariate analyses were performed to detect associations between the deletion status of der 9 and disease phase (CP vs AP or BC), the presence of additional cytogenetic abnormalities, age (>50 years or <50 years), the presence of peripheral blasts, and CBC parameters, such as hemoglobin (≥120 g/L or <120 g/L), WBC counts (≥30 × 109/L or <30 × 109/L), platelet counts (≥300 × 109/L or <300 × 109/L), and peripheral basophil counts (≥1 × 109/L or <1 × 109/L). Multivariate analysis was performed using der 9 deletion status and the variables that were identified as statistically significant in the univariate analyses (P<.1), including disease phase, the presence of peripheral blasts, and additional cytogenetic abnormalities. Cox proportional-hazards models were used to identify factors that had a strong association with the probabilities of attaining an MCyR, a CCyR, and an MMoR; LOR; the probabilities of treatment failure and progression to AP or BC; OS; and the probability of IM dose escalation by using backward, stepwise modeling and a P value >.05 for the likelihood ratio test. The hazard ratios and 95% confidence intervals also were estimated. A cutoff P value of .05 was adopted for all statistical analyses unless stated otherwise. The statistical data were obtained by using the SPSS software package (version 13.0; SPSS Inc., Chicago, Ill or SAS (version 9.0; SAS Institute, Cary NC).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Demographic and Disease Characteristics Before IM Therapy According to the Deletion Status of Der 9

Of 163 patients, 22 (13.5%; 95% CI, 8.2%-18.8%) demonstrated the presence of del-der 9. Eighteen patients (81.8%) were in CP, and 4 patients (18.2%) were in AP before the commencement of IM therapy.

The demographic and disease characteristics of patients with and without del-der 9 before the commencement of IM therapy are summarized in Table 1. No significant differences were observed between the 2 groups in terms of CBC parameters, disease stage, or additional cytogenetic abnormalities. However, among patients without del-der 9, a trend toward longer disease duration before the initiation of IM (P = .07) and a higher frequency of antecedent interferon-α therapy (P = .06) were noted.

Initial Response to IM Therapy According to the Deletion Status of Der 9

The response to IM therapy is summarized in Table 3 and Figure 1A. Among this cohort of patients, the incidence of HR was 96% ± 2% at 3 months. The incidence of MCyR was 56% ± 4% at 6 months and 76% ± 4% at 1 year after the initiation of IM therapy. The incidence of CCyR was 57% ± 4% at 1 year and 72% ± 4% at 2 years. The incidence of MMoR was 29% ± 4% at 1 year, 45% ± 4% at 2 years, and 57% ± 5% at 3 years, and the incidence of CMoR was 23% ± 4% at 2 years and 25% ± 4% at 3 years.

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Figure 1. Treatment outcomes of patients with chronic myeloid leukemia who received treatment with imatinib mesylate (n = 165). (A) The incidences of major or complete cytogenetic or molecular responses. (B) The probability of freedom from loss of response or treatment failure. (C) The probability of overall survival or transformation-free survival. (D,E) No differences were observed in the complete cytogenetic response (D) or the loss of response (E) according to the deletion status of derivative chromosome 9 (del-der 9).

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Table 3. Treatment Outcomes of Patients According to the Presence of Deletion of Derivative Chromosome 9
VariableNo. of Patients (%)P
Del-der 9 (n=22; %)No Deletion
  • Del-der 9 indicates deletion of derivative chromosome 9; IM, imatinib mesylate; BCR/ABL, breakpoint cluster region/receptor tyrosine kinase fusion transcript; CCyR, complete cytogenetic response; AP, accelerated phase; BC, blast crisis; CML, chronic myeloid leukemia.

  • *

    The following BCR/ABL tyrosine kinase mutations were detected: E459K (n=1) in the group with del-der 9; T315I (n=4), E355G (n=2), M244V (n=2), M351T (n=2), G250E (n=2), D275G (n=1), F311L (n=1), L387M (n=1), W405stop (n=1), E255V with F317L (n=1), and an undetermined tyrosine kinase mutation (n=1) in the group without del-der 9.

Total22 (13.5)141 (86.5) 
IM therapy   
 Initial dose, mg/d   
 40022 (100)125 (89).1
 6000 (0)14 (10) 
 8000 (0)2 (1) 
 Median duration of IM administration [range], mo22.5 [1.5-60]42.5 [1-79.5].06
Discontinuation of IM therapy4 (18)34 (24).8
 Cause of IM discontinuation   
 Intolerance0 (0)3 (2)1.0
 Resistance4 (18)31 (22).6
Escalation of IM dose6/22 (27)58/141 (41).2
 Escalation to 600 mg/d6/22 (27)53/125 (42).2
 Escalation to 800 mg/d3/22 (14)31/141 (22).6
Response to IM therapy   
 Hematologic response   
  Complete22 (100)138 (98)1.0
  Cytogenetic response   
  Major15 (68)116 (82).1
  Complete15 (68)105 (75).6
 Molecular response   
  Major14 (64)80 (57).6
  Complete4 (18)32 (23).8
Primary resistance   
 Hematologic0 (0)3 (2)1.0
 Cytogenetic5 (23)32 (23)1.0
Treatment failure6 (27)60 (43).3
Loss of response6/20 (30)43/117 (37).6
 Increasing BCR/ABL transcript427 
 Loss of CCyR06 
 No achievement of CCyR26 
 Progression to AP/BC04 
Progression to AP/BC0 (0)10 (7).4
Development of tyrosine kinase mutations*1 (5)18 (13).5
Second-line treatment for CML   
 Allogeneic transplantation3 (14)12 (9).4
 Dasatinib0 (0)16 (11).1
 Nilotinib1 (5)6 (4)1.0

The median duration of IM administration was 40 months for all patients, 22.5 months in the group with del-der 9, and 42.5 months in the group without del-der 9. No differences were noted in the incidences of HR (P = .598), MCyR (P = .281), CCyR (P = .883), MMoR (P = .125), and CMoR (P = .834) between groups. Figure 2 shows that the response rates at 1 year, 1.5 years, 2 years, 3 years, 4 years, and 5 years were quite similar between the 2 groups in terms of MCyR, CCyR, MMoR, and CMoR.

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Figure 2. No differences were observed in response rates according to the deletion status of derivative chromosome 9 (del-der 9) in patients with chronic myeloid leukemia. No differences in serial response rates were noted between the 2 groups in terms of major cytogenetic responses (A), complete cytogenetic responses (B), major molecular responses (C), and complete molecular responses (D).

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Failure on IM Therapy According to the Deletion Status of Der 9

With a median follow-up of 48 months, 66 patients (40.5%) were documented with IM treatment failure. The reasons for declaring treatment failure are summarized in Table 3. The probability of freedom from LOR was 71% ± 4% at 2 years, 60% ± 5% at 3 years, and 53% ± 5% at 4 years after any response to IM therapy had been attained (Fig. 1B). The probability of freedom from treatment failure was 69% ± 4% at 2 years, 58% ± 4% at 3 years, and 49% ± 5% at 4 years after the initiation of IM therapy (Fig. 1B). The probability of transformation-free survival was 92% ± 2% at 3 years, and the 3-year OS rate was 94% ± 2% (Fig. 1C). Again, no differences were noted between the 2 groups with and without del-der 9 with respect to the probabilities of LOR (P = .974), treatment failure (P = .455), transformation-free survival (P = .276), or OS (P = .779)

IM Dose Escalation or Discontinuation According to the Deletion Status of Der 9

Of 163 patients, 38 discontinued IM because of intolerance (n = 3 patients) or treatment failure (n = 35 patients). The incidence of IM discontinuation was 7% ± 2% at 1 year and 13% ± 3% at 2 years. The reasons for discontinuation are summarized in Table 3. The most common reason was IM resistance. Again, no differences were observed between the 2 groups.

Sixty-four patients (40%) required escalated doses of IM because of treatment failure, including LOR. Fifty-nine patients (36%) were escalated to 600 mg per day from 400 mg per day, and 34 patients (21%) received an escalated dose of 800 mg per day from 600 mg per day. The requirement for dose escalation was not significantly different between the 2 groups (P = .816).

Serial Monitoring of BCR/ABL mRNA Quantitative PCR According to the Deletion Status of Der 9

We also compared the changes over time in BCR/ABL mRNA transcript levels by using quantitative PCR. The 2 groups had similar patterns of BCR/ABL mRNA change (P = .9) (Fig. 3).

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Figure 3. Serial monitoring of breakpoint cluster region/receptor tyrosine kinase (BCR/ABL) messenger RNA (mRNA) quantitative polymerase chain reaction (PCR) according to the deletion status of derivative chromosome 9 (Del-der 9). Serial monitoring of BCR/ABL mRNA quantitative PCR revealed similar patterns of BCR/ABL mRNA reduction between the 2 groups.

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Multivariate Analysis

To verify our results in univariate analyses, we performed multivariate analyses with respect to MCyR, CCyR, MMoR, CMoR, LOR, treatment failure, transformation-free survival, OS, and the need for IM dose escalation by using a Cox proportional-hazards model. The presence of del-der 9 before the commencement of IM therapy did not have an adverse impact on the therapeutic efficacy of IM (Table 4).

Table 4. Multivariate Analyses of Multiple Parameters, Including Response to and Treatment Failure on Imatinib Mesylate Therapy and the Escalation of Imatinib Mesylate Dose
ParameterPresence of Del-der 9Advanced Stage [AP/BC]Presence of Peripheral BlastsAdditional Cytogenetic Abnormalities
PHR (95% CI)PHR (95% CI)PHR (95% CI)PHR (95% CI)
  1. Del-der 9 indicates deletion of derivative chromosome 9; AP, accelerated phase; BC, blast crisis; HR, hazard ratio; CI, confidence interval; IM, imatinib mesylate.

Response to IM therapy        
 Major cytogenetic response.3.030.42 (0.19-0.92).030.59 (0.36-0.96).1
 Complete cytogenetic response.7.030.58 (0.35-0.96).040.37 (0.15-0.92).3
 Major molecular response.1.040.28 (0.08-0.93).020.48 (0.27-0.86).4
Treatment failure        
 Loss of response.6.042.96 (1.03-8.58).0083.92 (1.44-10.70).0034.95 (1.69-14.44)
 Treatment failure.6.022.94 (1.15-7.52).012.97 (1.28-6.91.052.69 (1.00-7.13)
 Progression to AP/BC1.01.01.0.00425.49 (2.8-228.2)
Survival or dose escalation        
 Overall survival.9.00511.46 (2.08-63.04).4.5
 Dose escalation.7.2.052.37 (1.01-5.54).8

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The presence of del-der 9 has been associated with inferior outcomes in patients with CML who are treated with hydroxyurea and interferon-α, but its impact in IM-treated patients remains uncertain. A preliminary report by Huntly et al suggested that standard-dose IM therapy could improve (but not fully reverse) the poor prognosis of patients with del-der 9.6 However, results from another study indicated that IM therapy, in fact, could overcome the poor prognosis associated with del-der 9 in patients with CML.7 In the latter study by Quintas-Cardama et al,7 in contrast to the study by Huntly et al,6 a significant proportion of the study population (36%) was treated with high-dose IM therapy (ie, 800 mg per day).7 Accordingly, the authors suggested that high-dose IM therapy may have an important neutralizing effect on the poor prognosis of patients with CML who have del-der 9. Recently, a large, multicenter study from the Italian Group for Adult Hematologic Diseases reported the outcomes of >400 patients with CP CML who were treated with IM and concluded that del-der 9 did not adversely affect their response to IM.18 In the current study, using standard-dose IM therapy (90% patients overall and 100% of patients in CP received 400 mg per day), the deletion status of der 9 did not influence the overall response to IM therapy, the occurrence of treatment failure (including primary resistance and LOR), or transformation-free survival or OS.

The different outcomes with standard-dose IM therapy between the current study and previous results reported by Huntly et al6 can be explained by differences in the patient population. The study by Huntly et al included approximately 30% of patients in advanced phases (AP and BC); whereas, in our study, we included only 13% of patients in advanced phases. In addition, in our study, approximately 50% of patients in CP were in an early stage (<6 months after diagnosis), which meant that approximately 50% of CP patients were naive to previous treatment, such as interferon or transplantation. In contrast, in the report by Huntly et al,6 80% of patients in CP previously had received other kinds of treatment before IM therapy.

In the current study, 22 of 163 patients (13.5%) were determined to have del-der 9 before they commenced IM therapy. The frequency of del-der 9 was not different from that reported in other studies.2–7 The demographic and disease characteristics did not differ between patients with and without del-der 9, indicating that no baseline clinical factors are predictive of deletion status and that any potential negative effects of del-der 9 on outcome in this study were unlikely to be because of an imbalance in patient or disease characteristics within the groups.

Several theories have been put forward to explain the association between del-der 9 and poor prognosis in patients with CML, including the loss of ABL/BCR gene expression, different expression levels of BCR/ABL transcripts, and loss of tumor suppressor genes.5 In addition, there is evidence that the presence of del-der 9 is a consequence of pre-existing genetic instability within the CML cells5 and that it may predispose them to progression from CP to an advanced phase, thus affecting patient prognosis.

It has been demonstrated that the BCR/ABL fusion tyrosine kinase can inhibit p53 accumulation in response to DNA damage,19 induce resistance to apoptosis in CML cells,20–23 and induce oxidative stress24 or DNA damage.25 Accordingly, BCR/ABL fusion tyrosine kinase, a genetic key engine of CML, could induce genetic instability of CML cells,26, 27 predisposing them to further cytogenetic abnormalities, including del-der 9. This means that the del-der 9 reflects a degree of genetic instability that has been accumulated in CML cells through action of the BCR/ABL fusion tyrosine kinase. In contrast to other therapies, such as hydroxyurea or interferon-α (which could not overcome the poor prognostic features of CML with del-der 9), IM directly targets ABL kinase activity and presumably abrogates its negative effects on cellular stability. Therefore, it is plausible that IM may overcome the genetic instability derived from the BCR/ABL fusion tyrosine kinase by blocking a key genetic engine of CML.

One strength of our analysis is the finding that multiple endpoints were evaluated to detect the potential adverse effects of del-der 9 on the outcome of IM-treated patients, including short-term endpoints (HR, MCyR, CCyR, MMoR, and CMoR) and long-term endpoints (treatment failure, LOR, progression to AP/BC, survival, and dose escalation). The latter endpoints are particularly important to the clinical management of patients with CML, who now can expect excellent long-term survival on IM. Although data show that the cumulative incidence of MCyR and CCyR at 12 months is as high as 85% and 69%, respectively,11, 15 a substantial number of patients with CML experience late events, such as LOR, or require escalated doses of IM to overcome suboptimal responses. Accordingly, it is necessary to evaluate the impact of a potential prognostic marker like del-der 9 on both early endpoints (CyR or MoR) and late endpoints (such as LOR or dose escalation). The current study provides such information about the prognostic implications of the deletion status of der 9 in patients with CML.

Another strength of the current study is that we were able to measure MoRs to IM and serial changes in the levels of BCR/ABL fusion gene transcripts after the initiation of IM therapy during a median of 48 months of follow-up. We were able to compare changes in transcript levels between patients with and without del-der 9. No differences in the occurrences of MMoR or CMoR were noted between the 2 groups. In addition, the clearance kinetics of the BCR/ABL fusion gene transcripts from peripheral blood were quite similar between the 2 groups. These findings suggest that the presence of del-der 9 has no adverse effects on the MoR to IM.

In conclusion, the presence of del-der 9 in patients with CML before the initiation of IM therapy does not affect 1) the probabilities of attaining HR, CyR, and MoR; 2) LOR; 3) treatment failure; 4) the rate of progression to AP/BC; or 5) the need for IM dose escalation. Therefore, we conclude that the detection of del-der 9 should not have an impact on the current management of patients with CML who are receiving IM therapy.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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