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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 43  |  Issue : 3  |  Page : 138-144

‘Gatekeeper’ mutation in patients with chronic myeloid leukemia resistant to imatinib therapy: effect on survival


Department of Haematology, Medical Research Institute, Alexandria University, Alexandria, Egypt

Date of Submission20-Apr-2018
Date of Acceptance27-Jun-2018
Date of Web Publication3-Dec-2018

Correspondence Address:
Mohamed A.M El-Menoufy
Department of Hematology, Medical Research Institute, Alexandria 21561
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejh.ejh_18_18

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  Abstract 


Background T315I is the most difficult type of point mutation that appears during treatment of chronic myeloid leukemia (CML). It represents kind of a ‘gatekeeper’ that controls access of small molecule inhibitors and confers resistance to the most known tyrosine kinase inhibitors.
Aim The aim of the present study was to assess the characteristics of Egyptian patients with CML harboring T315I mutation and to evaluate its effect on the patients’ survival.
Patients and methods A total of 45 patients with CML in chronic phase resistant to imatinib mesylate (IM) treatment were enrolled in this study. Allele-specific oligonucleotide-PCR was used to detect T315I BCR-ABL gene mutation in all patients at the time of IM resistance.
Results T315I mutation was present in 11 (24.4%) patients. The level of resistance was heterogeneous. Responses were observed in two resistant T315+ patients with IM dose escalation and three patients who were shifted to second-generation tyrosine kinase inhibitor. There was no significant difference in patient characteristics and overall survival between T315I+ and T315I resistant patients. Overall survival is significantly associated with the duration of response and the phase of the disease at the time of resistance.
Conclusion Evaluation of T315I mutation is recommended in all patients with CML, even in the early phase of the disease, which may be subsequently associated with resistance or progression of their disease in the future and requires the need for an alternative therapeutic option(s).

Keywords: chronic myeloid leukemia, gatekeeper mutation, imatinib resistance, T315I


How to cite this article:
El-Menoufy MA, El Naggar AA, Ziada LE. ‘Gatekeeper’ mutation in patients with chronic myeloid leukemia resistant to imatinib therapy: effect on survival. Egypt J Haematol 2018;43:138-44

How to cite this URL:
El-Menoufy MA, El Naggar AA, Ziada LE. ‘Gatekeeper’ mutation in patients with chronic myeloid leukemia resistant to imatinib therapy: effect on survival. Egypt J Haematol [serial online] 2018 [cited 2018 Dec 16];43:138-44. Available from: http://www.ehj.eg.net/text.asp?2018/43/3/138/246777




  Introduction Top


Typically, chronic myeloid leukemia (CML) has three phases: an early chronic phase (CP), in which the disease is usually diagnosed, followed by a transient accelerated phase (AP), which eventually progresses to a fatal blast phase (BP) if left untreated [1].

Imatinib mesylate (IM) represents the gold standard for front-line therapy of this disease. It is a tyrosine kinase inhibitor (TKI) that targets ATP binding site of the BCR-ABL protein, resulting in selective inhibition of the growth of the BCR-ABL+ hematopoietic cells and their apoptosis [2]. However, the acquisition of point mutation within the ABL kinase domain that interferes with IM binding represents the most important mechanism responsible for IM resistance and relapse [3].

T315I is the most difficult type of point mutation as it represents kind of a ‘gatekeeper‘ that controls access of small molecule inhibitors and confers resistance to the most known ATP-competitive BCR-ABL inhibitors; it also confers additional features to all the leukemogenic potential of BCR-ABL. Hence, T315I is of particular concern in clinical setting [4].

Concerning patients harboring this mutation, different studies reported controversial clinical effects. Some studies suggested that the presence of T315I mutation is associated with poor survival [5],[6], whereas other authors denied any significant difference in survival between resistant patients harboring T315I mutation and those without or carrying other type(s) of mutation [7].

The aim of the present study was to assess the characteristics of Egyptian patients with CML harboring T315I mutation, and to evaluate its effect on the patients’ survival.


  Patients and methods Top


The study included 45 patients with CML resistant to imatinib therapy. The patients were selected from the Department of Hematology, Medical Research Institute and Alexandria University Hospitals from November 2013 till February 2018. The patients were selected in CP and were treated by the standard dose of imatinib (400 mg/day). There were 20 males and 25 females, and their mean age was 45.9 years (range, 22–65 years). The study was conducted in accordance with the local ethical committee, and informed consent was obtained from all patients included in the study.

IM resistance was defined according to the European LeukemiaNet guidelines [8]. Failure of achievement of either complete hematologic response (CHR) at 3 months, complete cytogenetic response (CCyR) at 12 months, and major molecular response (MMR) at 18 months of IM initiation, or loss of previously achieved response.

Among the studied patients, three patients had failure to achieve CHR at 3 months and 16 patients had failure to achieve CCyR at 12 months and/or MMR at 18 months (primary resistance); three patients had loss of CHR and CCyR and 10 patients had loss of CCyR and MMR; and 13 patients had progression to advanced stages (AP/BP) (secondary resistance).

According to the presence or absence of T315I mutation expression, the patients in our study were categorized in two groups:
  1. Group I: patients who were harboring the mutation (T315I+).
  2. Group II: patients who were not harboring T315I mutation (T315I) but they might harbor other BCR-ABL mutation(s).


Statistical analysis

The χ2 test was used to determine the significance between variables. P value less than 0.05 was considered statistically significant. Kaplan–Meier survival curves [9] were used to assess survival of patients with and without mutations. Log rank test was used to compare between groups. Duration of response )DR) was calculated from start of treatment until the first reported treatment failure. Overall survival (OS) was calculated from the time of IM failure until death or last follow-up. All analyses were performed using the statistical package for the social sciences (version 24.0; SPSS IBM Corporation, New York, New York, USA).

Methods

Allele-specific oligonucleotide-PCR [10] was used to detect T315I BCR-ABL gene mutation in all patients with CML at the time of IM resistance. Total RNA was extracted from whole blood using ABIOpure total RNA extraction kit (Alliance Bio, Bothell, Washington, USA). Complementary DNA (cDNA) was synthesized by SuperScript III cDNA synthesis kit (Invitrogen, California, USA) following the manufacturer’s instructions. Sequence of forward and reverse primers for wild-type ABL, T315I mutant type, and internal control (β-actin) used for allele-specific oligonucleotide-PCR was adapted from a previous report. Sequences were specifically amplified in a PCR reaction. The amplified products were detected and assessed by electrophoresis on 2% agarose gel.

Fluorescence in-situ hybridization performed on bone marrow samples was used for cytogenetic analysis and Philadelphia chromosome detection [11].

Real-time quantitative PCR was used for quantitation of BCR-ABL mRNA transcripts using bone marrow or peripheral blood samples [12].


  Results Top


Eleven (24.4%) patients were expressing T315I gene mutation (T315I+) and 34 (75.6%) patients did not (T315I).

Demographic data of patients with chronic myeloid leukemia

The demographic characteristics of patients with CML at the time of IM failure are summarized in [Table 1]. There was no statistical significant difference between both groups of patients with CML regarding their clinical characteristics.
Table 1 The demographic characteristics of patients with chronic myeloid leukemia at the time of imatinib mesylate failure

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Response milestone achieved for patients with chronic myeloid leukemia before treatment failure

Before treatment failure, nine (81.8%) patients with T315I mutation achieved CHR and six (54.5%) patients achieved CCyR and MMR. For T315I patients, 30 (88.2%) patients achieved CHR, 26 (76.5%) patients achieved CCyR, and 25 (73.5%) patients achieved MMR. There was no significant relationship between the mutation status (presence or absence of T315I) and CCyR to treatment (P=0.163).

Types of imatinib resistance in the studied patients with chronic myeloid leukemia

Seven (63.6%) patients of group I showed primary resistance to IM, whereas only four (36.4%) showed secondary resistance, and paradoxically in group II patients, 64.7% (22 patients) showed secondary resistance and 35.3% (12 patients) showed primary resistance, with no significant statistical difference between both groups regarding type of imatinib resistance (P=0.098).

Sokal risk score

Patient categories according to Sokal risk score are shown in [Table 1], where most patients of group I (72.7%) and group II (64.7%) had high-risk Sokal score, with no statistical significant difference between both groups (P=0.855).

Duration of response, phase of the disease, and mutation status

The median DR)from start of treatment until treatment failure) in T315I+ and T315I patients was 30 months (8–62 months) and 35.5 months (5–80 months), respectively, with no significant relationship found between the mutation status and duration of treatment response (P=0.278).

Our study also demonstrated no significant relationship between the mutation status and the phase of the disease at IM failure (P=0.163).

Overall survival and mutation status

After a median follow-up period of 31 months from IM failure, the mean OS from the time of IM failure of all the studied patients with CML with IM resistance was 45 months. The mean OS of T315I+ and T315I patients was 37.5 and 47.5 months, respectively, with no significant difference in survival between the two groups of patients (P=0.268) ([Figure 1]a).
Figure 1 (a) Overall survival of resistant patients since IM failure according to the mutation status. (b) Overall survival of resistant patients since IM failure according to the duration of response to imatinib. (c) Overall survival of resistant patients since IM failure according to the phase of the disease at imatinib failure. IM, imatinib mesylate.

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Overall survival and duration of response

The estimated mean OS for patients with response duration more than or equal to 1 year(s) was 68.5 months and less than 1 year was 25.4 months, with 95% confidence interval of 62.4–74.5 and 16.9–33.9 months, respectively, with highly significant difference (P<0.001). Short DR is associated with poor survival ([Figure 1]b).

Overall survival and phase of the disease

The estimate mean OS from IM failure of patients in chronic and advanced phases was 73.7 and 23.5 months, with 95% confidence interval of 68.6–78.8 and 16.6–30.4 months, respectively, with highly significant difference (P<0.001). Advanced disease phase (AP and BP) is significantly associated with poor survival ([Figure 1]c).


  Discussion Top


The T315I mutation frequency in this cohort was 24.4% which is relatively higher than that reported by others [13],[14],[15],[16] ranging between 2 and 20% of patients with IM-resistant CML. This difference in frequency may be attributed to the different sensitivity of the technique, the phase of the disease at which the mutation was detected, and eventually the differences in the genetic make-up of the patient population [17].

In the present study, there was no statistically significant difference between group I and group II regarding the clinical presentation of the disease. However, several pretreatment clinical characteristics have been found to have prognostic significance in CML. Sokal score was developed in the pre-imatinib era, and it has some value in predicting response to IM [18]. In the present study, high-risk constituted ∼73% of patients harboring T315I mutation, and this finding was consistent with that observed by Nicolini et al. [19]. Similarly, ∼65% of T315I patients (group II) had high-risk Sokal score, with no significant difference between both the groups. The occurrence of IM resistance in group II patients would rise the possibility of the development of other mutation(s) as suggested by previous authors [20],[21], who concluded that CML-CP patients with high SOKAL score showed significantly higher incidence of mutation.

The onset of T315I mutation in chronic myeloid leukemia

In the present study, most of the T315I+ patients (63.6%) did not respond to IM from the start of treatment (primary resistance) whereas only 35.3% of the T315I patients showed primary resistance to IM treatment. This may support the suggestions of some authors [22],[23] that T315I mutation may be present at diagnosis before starting treatment. However, others [24] postulated no chance of mutation development in early disease stage and most will develop during treatment. Thus, the onset of T315I mutation in CML remains challenging.

Disease phase at the time of imatinib mesylate failure and mutation status

Six (54.5%) patients with detectable mutation were in CP, suggesting that the existence of T315I mutation is not restricted to patients in advanced phase (AP or BP). However, the frequency of advanced phase was higher in patients expressing T315I mutation (45.5%) compared with that in patients not harboring the mutation (23.5%), suggesting a more relation between disease progression and the development of this mutation. However, this relationship did not reach the level of significance. Our small sample size of group I patients who carry T315I mutation (11 patients) might be an obstacle to prove or disprove the relation between the occurrence of mutation and advanced stage of the disease. However, previous authors [25],[26] postulated frequent occurrence of clonal evolution and genomic alterations at the time of CML progression into advanced phases regardless of the presence or absence of T315I mutation.

On the contrary, the occurrence of IM resistance and disease progression in T315I group of patients may imply the presence of other BCR-ABL mutations (not investigated) and/or other unknown BCR-ABL independent mechanisms of IM resistance/progression [27],[28],[29].

Response to alternative treatment options after imatinib mesylate failure

After IM failure, dose escalation of IM (600–800 mg/day) was attempted in 11 patients. Three of T315I patients showed good response, and two patients showed no improvement. For T315I+ patients, two patients in CP showed good response and four patients showed no improvement. Thus, unlike previous studies [30],[31], and in concordance with that of Ernst et al. [32], our study showed a good response, although not sustained, to IM dose increase in patients carrying T315I mutation. An explanation of this finding is that dose escalation might overcome the resistance owing to the increased activity of ABL tyrosine kinase induced by T315I mutation [33]. This finding also supports the observation of Nicolini et al. [34] that the levels of IM resistance are heterogeneous, regardless of the presence or absence of T315I mutation, ranging from a mild decreased sensitivity to IM therapy (overcome by IM dose escalation) to absolute insensitivity to IM (requiring other treatment option).

Among T315I+ patients, six patients were shifted to second-generation TKI (Dasatinib) after failure of IM therapy. Responses were observed in three patients (sustained CHR; sustained CHR and CCyR; and sustained PHR associated with transient minor cytogenetic response). Unlike previous studies, [18],[35] which showed that resistant CML patients bearing T315I mutation do not respond to second-generation TKI, our finding in this respect run in parallel with that of Jabbour et al. [7] who first reported sustained responses of T315I+ CML patients to second-generation TKI, indicating that not all cases with this mutation are always resistant to second-generation TKI.

The presence of controversy in responses to IM dose escalation and second-generation TKI in some of our T315I+ IM-resistant patients versus most of the previous studies might be related to the heterogeneity of the mutation pattern and to the ethnical and geographical differences of the studied population. This suggestion was supported by the finding of Ng et al. [36] who identified a novel mechanism of primary resistance to TKIs among East Asian population not present in other ethnic groups.

Effect of the mutational status, disease phase, and response duration on overall survival

Although an in-vitro study [37] showed that T315I mutation provides the BCR-ABL mutated clone with a more proliferative capacity and favors disease progression potency, our study demonstrated no difference in survival between patients with and without T315I mutation. This is in concordance with the previous studies of Jabbour et al. [7],[14] who found that neither the presence of mutation(s) nor the type of mutation was significantly associated with survival of patients resistant to IM.

On the contrary, other studies [18],[34],[38] demonstrated a reduced OS and significant poor prognosis associated with the presence of T315I mutation. Yet, it remains unobvious whether T315I mutation is actually responsible for disease progression through its interaction with other factors of disease progression such as additional cytogenetic mutations (clonal evolution) in addition to interference of IM binding or it is simply co-existing in a clone of cells that are resistant to IM for other unknown causes. Therefore, cytogenetic abnormalities (other than Philadelphia chromosome), and additional mutation analysis should be evaluated at the time of T315I identification to know if there are other mechanisms of resistance. Furthermore, the level of T315I mutation itself which initiates IM resistance varies greatly from one patient to another patient [39],[40] and this may explain why some patients developed IM resistance with detectable levels of T315I, whereas others do not [24]. However, the effect of T315I mutation on patient survival appears to depend on multiple factors [14] that deserve more profound study.

Our results showed no significant relationship between T315I mutation and patients’ clinical signs, blood parameters, DR to treatment, and cytogenetic response to treatment. The OS of patients resistant to IM was mostly dependent on DR to IM treatment and the disease phase at the time of IM resistance, regardless of the T315I mutation expression. However, the role of T315I mutation in inducing resistance to IM remains clear.

Therefore, it had been concluded that once T315I mutation was detected in BCR-ABL+ resistant patients, patient survival will depend on other multiplefactors. However, evaluation of this mutation is recommended in all patients with CML, even in early CP with optimal response to therapy, which may be subsequently associated with resistance or progression of their disease in the future and requires the need for more and early therapeutic options.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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