Frontline Treatment with
“Generic” Imatinib In Adult Patients with Chronic Myeloid Leukemia in
Algerian Population: A Multicenter Study
Service d’Hématologie et Thérapie Cellulaire, EHU1er Novembre, Oran,
2 Service d’Hématologie, CHU Oran, Algérie
3 Service d’Hématologie, EPH Mascara, Algérie
4 Service d’Hématologie, CHU Sidi-Bel-Abbès, Algérie
5 Service d’Hématologie, CHU Tlemcen, Algérie
6 Service d’Hématologie, CHU Béchar, Algérie
7 Service d’Hématologie, HMRU Oran, Algérie
8 Service d’Hématologie, CHU Lyon, France
Received: July 23, 2017
Accepted: September 27, 2017
Mediterr J Hematol Infect Dis 2017, 9(1): e2017062 DOI 10.4084/MJHID.2017.062
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a developing country like Algeria, such expensive therapy is not
available. Alternative approaches are needed to help these adult. In
Algeria ‘imatib’ (CIPLA-India) was introduced in 2006; but no study has
been published yet in the North Africa region regarding response and
outcome of this copy in CML patients. The goal of this multicenter
study is to characterize newly adult CML in the western region of
Algeria and to assess the effectiveness and safety of imatib (IM, copy)
as frontline therapy for patients with CML.
In Algeria ‘imatib’ (CIPLA-India) was introduced in 2006, but no study has been published yet in the North Africa region regarding the response and the outcome of this copy in CML patients. The goal of this multicenter study is to characterize newly adult CML in the western region of Algeria and to assess the effectiveness and safety of imatib as frontline therapy for patients with CML.
Patients and Methods
Patients’ characteristics. The study was carried out in all the 7 hematological services of university hospitals, in the western Algeria and data were collected using electronic medical records from patients' clinic visits. All patients aged over 15 years with de novo CML were included.
It is a longitudinal study, multicentric and retrospective. Patients, who were diagnosed to be suffering from CML between 1st January 2007 and 31st December 2014, were selected for data analysis. In all patients, the diagnosis of CML was confirmed by morphologic review of peripheral blood (PB) and by RT-PCR based BCR-ABL analysis (Applied Biosystems 7500 Real-time PCR system). Staging and evaluations of response were determined according to the current European LeukemiaNet (ELN) recommendations. The prognosis of CML patients in chronic phase was determined by either Sokal and/or EUTOS prognostic scoring systems at initial presentation, using European LeukemiaNet calculator. Patients with acceleration and blastic phase were not included in our study. All patients received a copy preparation, consisting of the alpha crystal form of imatinib, (Imatib) at an oral dose of 400 mg daily and monitored for tolerance and side effects according to the ELN recommendations adapted to our conditions and capabilities in Algeria. Doses were reduced in the presence of grade 3-4 thrombocytopenia or grade 3-4 neutropenia. Wherever it was possible the dose was maintained above 300 mg/day. Patients were treated as long as they continued to respond.
Response assessment. All patients were assessed for response to treatment by weekly physical examination, full blood count, and biochemistry for the first 6-weeks of treatment and were assessed every 3 months during their follow-up. During the treatment, quantitative, real-time PCR (RQ-PCR) for the determination of BCR/ABL1 transcripts level using the international scale, has been performed every 3 months until achievement of an MMR, then every 3 to 6 months. The complete hematologic response (CHR) at 03 months and molecular response at 03, 06, 12, 18, 24 months and more according to capabilities. At 03 months and/or 6 months we looked for a BCR/ABL1 rate <10%. At 12 months we looked for a major molecular response (MMR), defined by BCR/ABL1 ratio lower than 0,1% according to the ELN. A ratio between 0,1 to 1% is considered a good response according to GAT-LMC (the CML study Algerian group), so the Imatinib treatment is continued.
Statistical Analysis. The statistical analysis used the calculation of averages and the Khi2 test. Overall survival (OS) was calculated from the time of diagnosis to the date of death or last follow-up. The Kaplan–Meier method was used to estimate survival rates and the log-rank test to determine differences between subgroups. For all tests, a p-value of less than 0.05 was considered statistically significant. Statistical calculations were performed using the software package SPSS 20 (SPSS, Inc., Chicago, IL). The median follow-up of patients in December 2014 is 46 months (13-107 months).
|Table 1. Pretreatment characteristics of the study population with CML.|
|Figure 1. Overall survival of patient with CML Imatib copy therapy.|
|Figure 2. Overall survival according to Sokal scoring system.|
|Figure 3. Overall survival according to EUTOS scoring system.|
Side effects of imatib (copy) in this study are shown in Table 2, and no adverse effects related deaths have occurred. At a median follow-up duration of at least 48 months (12-84 months), 81% of patients are alive and are still taking imatib, 10% of patients relapsed among them 50% because of low adherence, 42% because of resistance and only 8% developed intolerance to imatib. 9% of patients died after developing blastic phase disease. 6% of patients discontinued their follow-up, and 4% of patients died due to other reasons.
|Table 2. Incidence of grade 3-4 side effects with imatib copy therapy.|
Our multicenter study of patients with newly diagnosed CML is unique in Northern Africa. Regarding the clinical and biological feature, CML of Algerian patients seems to be frequently aggressive with anemia and a massive splenomegaly associated in a majority of cases with a high-risk Sokal.
After ITK therapy, results were very well known and described regarding Glivec®/Gleevec® used in multiple clinical trials showing cumulative OS rates of 86%, after 7-years of follow-up.
In low-income countries like Algeria, such expensive treatment is not available, and physicians in charge of adult CML patients are obliged to use a copy form, which could appear as less effective therapy in this setting. To our knowledge, there are only a few data regarding generic forms or imatib for Algerian patients with CML. A.H. Goubran, Z. Chouffai, I.A. Asfour and M. Mattar published only case reports and showed outcomes failure with Imatib copy. Ostojic A, showed that when taken at equivalent doses, imatinib generics are bioequivalent, comparable in clinical efficacy and have the potential for substantial savings in the treatment cost for CML. In a prospective, multicenter clinical trial to evaluate the early clinical efficacy and safety of a generic imatinib in treating patients with CP of CML in China, the authors showed that among 107 patients at 3-month, the CHR rate was 98.1%（105/107). The BCR-ABL transcript was ≤10% in 77/106 patients (72, 6%), 11 of them （10, 4%）achieved MMR (BCR-ABL≤0,1%). At 6-month, the CHR rate was 100%; BCR-ABL was ≤1% in 68,5%, and 33% of them achieved MMR. Grade 3 leukopenia, thrombocytopenia and anemia rates were 19,5%, 23% and 13,8%, respectively. No patient experienced grade 4 non-hematologic toxicity. No adverse effects related deaths have occurred.
Our study is the first study concerning a large cohort of patients receiving Imatib for CML and which has analyzed the safety, efficacy, OS at short, medium and long-term. With a median follow-up of 46 months (range: 13–107), we found 83% of CHR with 67% of MMR at 2 years, and 34% of CMR. The IRIS trial at 7-years has demonstrated better overall survival rate of 86%. At 5-years and 9-years, OS in our study was 83% and 67% respectively. Respect to literature data we observed a larger group of patients (17%) who have never achieved a CHR probably related to the existence of higher proportion (42%) with high-risk Sokal score and it was demonstrated that there was a relationship between prognosis and disease response. In parallel, the delayed diagnosis is one of the arguments in favor of the disease extension.
Side effects of imatib in our study were similar to those reported previously for the imatinib mesylate treatment study and only 8% of patients showed intolerance to imatib and switch to the second generation of ITK. There was a previous report from Canada with similar conclusions about the efficacy and tolerability of generic imatinib, although they used a different source of generic imatinib from our study.
Scarce compliance in CML patients treated with BCR-ABL inhibitors is common and associated with critical outcomes. Poor adherence to therapy was associated with a negative impact on both clinical and economic outcomes. In our study, more than 15% of patients presented poor adherence to CML treatment, and they had a lower CHR response at 3 months and MMR at 6 months. The estimated 5-year OS in our patients was comparable to the 72% reported in the study from Côte d’Ivoire and the 80% in the study from Nepal, whom patients were treated with imatinib mesylate (Gliveec®).
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