Cytogenetic Response in Chronic Myeloid Leukaemia Patients Treated with Imatinib Mesylate Homolog-Drugs : 6 Year ’ s Transitional Study

Background: Treatment for Chronic Myeloid Leukaemia (CML) is mainly imatinib mesylate (IM) from original-brand, Glivec® or generic-type homologs, Imatib®. Materials and Methods: A collection of 149 CML patients was treated over a period of 6 years at Hiwa hospital. These patients were clustered into three groups: Group A was treated with Imatib for more than one year. All survivors of group A patients were switched to Glivec, classified as group B. Group C received only Glivec after June 2011. Imatib and Glivec are administered at doses 400-, 600and 800-mg according to the CML stage. Results: Among group A patients, 68 (60%) were in complete haematological response (CHR), 32 (28.3%) developed acceleration and 13 (11.5%) patients were deceased. After switching to Glivec (group B), 69 (69%) patients remained in CHR, 10 (10%) patients were deceased and 21 (21%) patients remained in acceleration. Of the 36 patients in group C, 33 (91.7%) were in CHR, 1 (2.8%) were in acceleration and 2 (5.5%) deceased. Those patients with CHR were tested randomly for BCR/ABL by FISH, and only 1/25 (4%) patients were found with complete cytogenetic response (CCyR) in group A, while 31/42 (73.8%) and 13/17 (76.5%) have CCyR in Corresponding author.


Introduction
Chronic myelogenous leukaemia (CML) is a clonal myeloproliferative disorder, characterized by presence of Philadelphia (Ph) chromosome [1]- [5], which is a reciprocal translocation t (9q34; 22q11) that creates an aberrant mRNA product, leading to production of a fusion protein p210 BCR-ABL that has a constitutive tyrosine kinase (TK) activity of ABL [6]- [8].In the past, CML had been treated with busulfan and hydroxyurea but with high rates of progression from chronic to accelerated phase and median survival of 39 to 47 months [9].Then after, interferon alpha provided a further improvement in treatment with a complete haematological response (CHR) in 73% of patients and cytogenetic remission (CyR) in 50%, with a significant survival advantage over busulfan [10]- [13].
Tyrosine kinase inhibitors, imatinib and/or imatinib derivatives provide specific-targeted therapy to the BCR-ABL fusion product and it is the first-line clinical treatment for CML patients [9] [14].The Novartis drug imatinib mesylate, commercially recognized as Glivec ® /Gleevec ® , was approved by federal drug administration (FDA) in 2001 for the treatment of CML.The high frequencies of complete hematological response (CHR), cytogenetic response (CyR), and molecular remission (MR) were evident [15].A seven-year follow-up of CML patients in the International Randomized Study of Interferon (IRIS) and ST1571 trial with imatinib mesylate have showed 81% event free survival, 86% overall survival and low rates of transformation (7%) [16].
In 2006, a generic imatinib mesylate, known as Imatib ® , appeared in the market produced by Cipla (India) and was supposed to be as efficient as Gilvec ® .Generic IM appeared in many developing countries, bypassing international pharmaceutical patent regulations.In Iraq, this drug has been provided for public-health sector for a period of time.However, the Iraqi health sector in 2011 displaced Imatib ® to Glivec ® .This transference provided an ideal opportunity to evaluate the clinical efficacy of generic and patented forms of imatinibmesylate as a retrospective transition study on patients treated at our site as a single-governmental institution, over a period of 6 years.
Although we have not found any reported data in Iraq, two cases were published in Egypt, describing therapy by shifting from Glivec to Imatib.Clearly, the data indicated a worsening of CML progression status [17].In this work, the generic IM has been proven to decline the response after the successful Glivec ® therapy [17].In other reports, the difference in clinical efficacy has been shown between the authorized form of IM (Glivec ® ) and the generic IM (Imatib) [18] [19].The exact cause for the clinical efficacy difference is not known, but it is likely to be related to structural polymorphic forms of the drug [18].

Patients
A total of 149 cases of CML were diagnosed in Hiwa hospital from January 2005 through December 2012.For all cases, the complete blood count and bone marrow examination was done and FISH analysis for diagnosis of CML-fusion gene was performed on peripheral blood samples and/or bone marrow samples.In addition, the status of CML patients was defined depending on complete blood picture and ultrasound of spleen, into chronic-, accelerated-and blastic-phases according to international definitions as described in references [8] [20]- [22].We categorize all these patients (149 individuals) into three groups: group A consisted of 113 patients who treated with Imatib for one year or more prior to June 2011.From June 2011, survivors of group A patients (100 patients) were switched to Glivec and grouped as group B. Group C (36 patients), who were diagnosed with CML after June 2011 and they were received only Glivec.

Criteria for CML Treatment Response
For all three group patients, who had CHR and are on IM medication for one year or more, FISH analysis were done to assess the cytogenetic response and the response criteria were summarized in Table 1 and Table 2 [11] [22]- [25].Written informed consent was obtained from all patients in accordance with the amended Declaration of Helsinki 2008.

Statistical Analysis
For the statistical purpose the data accumulated and analyzed using Average, Ratio, Range, Chi-square method and P-value.

Discussion
Tyrosine kinase inhibitor is a principal care to cure CML patients in Iraq.However, still the expense of therapy is an issue when we decide to choose the type of drug non-generic, generic or copy.Whatever the type of the drug applied in the treatment of CML, the best efficacy and response rate is the goal of physicians and health centers.Our data showed, a significant difference in hematological response between group A (60%) and C (91.7%) (Table 3).Also a significant difference in CyR rate between patients who initiated Imatib (group A) 1 (4%) and Glivec in (group C) (76.5%) with significant P-value of < 0.001.We observed significant raise in response rate for CML patients, who were initiated Glivec, while the cytogenetic response for patients who started with imatib increased from 1% to 73.8% when they were shifted to Glivec.This is a clear improvement in the management response (Figure 2).Indeed, a lower rate of progression and mortality showed in group C patients who started Glivec 1 (2.8%) and 2 (5.5%) respectively, while in group A the progression and mortality rates were much more (28.3%)and (11.5%) respectively (Table 3).Consequently, this is mostly due to lower rate of complete cytogenetic response for patients started with imatib among group A and B with significant P-value <0.001.The exact reasons for this difference in clinical efficacy are unknown, but may be related to the use of an alternative polymorphic form of the drug.Every effort should be made to maintain patients in remission on specific medication, and careful follow-up is needed if patients who have achieved remissions are shifted to generic/copy drug.This management will ensure that the response is not compromised.Without supportive clinical evidence of efficacy and safety of this (or any other) copy product caution should be used in substitution of imatinib for CML patients in general.

Conclusion
Our study suggests a clear difference in clinical efficacy between the branded form of IM (Glivec) and generic form (Imatib).This is supported by the significant differences in cytogenetic responses among different groups with the significant higher response rate between Glivec groups.Pharmaceutical and biologic equivalence needed to be evaluated before a generic/copy product can be administered without proper clinical trial procedure to insure patient safety and determine the clinical efficacy.

Figure 1 .
Figure 1.The age and gender distribution of all 149 CML patients.The overall male to female ratio is calculated to be 1.1.The 44-years age is the mean of the ages 10 -85.These patients were registered between 2005 until 2012.

Figure 2 .
Figure 2. Cytogenetic remission in CML patient groups treated with Imatib and Glivec at 12 months of treatment.High percentage of CCyR found among group C patients who were randomly tested for detection of the BCR-ABL fusion by FISH technique.

Table 1 .
Criteria for the assessment of patients' status based on FISH for BCR-ABL gene analysis.
The cytogenetic response according to percentage of Ph + chromosome to complete, partial, minor, and failure in CML patients tested by FISH.

Table 2 .
Response criteria for chronic myelogenous leukemia treatment.
−The criteria are measured according to the definitions of the European Leukemia Net (ELN) and National Comprehensive Cancer Network (NCCN).The guidelines were followed with positive chronic-phase that includes the presence of Philadelphia (Ph) chromosome.PCyR, partial cytogenetic response; MMR, major molecular response; CCA, clonal chromosomal abnormalities.( * ) ELN criteria refer to previously untreated patients with chronic phase CML who received 400 mg/day.NCCN are those who received IM 400 mg/day; nilotinib, 300 mg twice daily; or dasatinib, 100 mg daily.( ** ) Clonal progression during treatment; CHR, Chronic hematological response; CCyR, Complete cytogenetic response.

Table 3 .
Presentations of the patient responses following chemotherapy treatments.