Leukemia & Lymphoma, 2014; Early Online: 1–3 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.905774
LETTER TO THE EDITOR
The efficacy of generic formulations of imatinib mesylate in the treatment of chronic myeloid leukemia Ahmet Emre Eskazan1, Tugrul Elverdi1, Fevzi Firat Yalniz1, Ayse Salihoglu1, Muhlis Cem Ar1, Seniz Ongoren Aydin1, Zafer Baslar1, Yildiz Aydin1, Nukhet Tuzuner2, Ugur Ozbek3 & Teoman Soysal1 1Division of Hematology, Department of Internal Medicine and 2Department of Pathology, Cerrahpasa Faculty of Medicine,
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Istanbul University, Istanbul, Turkey and 3Department of Genetics, Institute of Experimental Medicine (DETAE), Istanbul University, Istanbul, Turkey
The treatment of chronic myeloid leukemia (CML) has changed greatly, and the outlook of patients with CML has improved dramatically, with the introduction of tyrosine kinase inhibitors (TKIs) [1]. The first TKI developed for CML was imatinib mesylate (IM) (Glivec; Novartis, Basel, Switzerland) [2], and thereafter many other TKIs became available on the market [3]. The high cost of new cancer drugs including those developed for CML is a major concern for healthcare payers, especially in countries with restricted resources. Reimbursement policies worldwide, therefore, encourage generic drug use to lower the prices. It is true that generics lead to considerable cost savings, but they also give rise to questions associated with their efficacy, safety and quality. In Turkey, there are three commercially available generics of IM (Imatis; Deva, Imatenil; Logus and Imavec; Koçak Farma), which have been licensed for the treatment of CML for more than a year. There is a price difference between Glivec and the generics, and due to the reimbursement policy, patients who prefer to receive the original molecule must pay the price difference; the price difference was the only reason for switching from Glivec to any generic among our cohort. The first issue that physicians caring for patients with CML encounter is whether the efficacy of these generics is comparable to that of the original molecule; the second issue is what the potential adverse events (AEs) are, other than those with use of Glivec, if any. To answer these questions, we retrospectively reviewed our data. One hundred and forty-five patients with chronic phase (CP) CML who were diagnosed and followed between 2000 and 2013 were enrolled in the study. Patients who had been switched to a second-generation TKI before the evaluation period were excluded. Patients’ demographics, IM dose, disease risk scores and follow-up durations were noted from the patients’ files retrospectively (Table I). IM response was evaluated according to criteria recommended by the
European LeukemiaNet [4]. Molecular response (MR) was classified based on the BCR–ABL1 to control gene transcript ratio, expressed on the International Scale. The cumulative incidence of major molecular response (MMR) during follow-up was calculated. CML phases were defined as described elsewhere [4]. There were two study groups: group A which included patients receiving Glivec throughout the entire follow-up, and group B which contained cases who started with Glivec and then were switched to one of the generics at a certain time during their follow-up. These two groups were compared regarding response rates, and for the assessment of tolerability, the real drug doses were compared. The switch to generics started in August 2012 when the first drug was approved and become available on the market. Eighty-one patients were male (57%), and the median age was 43 years. The two groups were equally balanced regarding age, gender and risk scores (Table I). The median follow-up duration of the entire cohort was 63 months, and 61 and 66 months for groups A and B, respectively. Group A consisted of 65 patients, 43 of whom had molecularly undetectable leukemia (MUL) or MMR; 40 of them maintained these responses whereas three patients lost MMR during follow-up (Table II). Ten of the remaining 22 patients had a durable complete cytogenetic response (CCyR), but any MR less than MMR. The other 10 cases achieved MMR during follow-up, while two lost their MR (Table II). The cumulative MMR rate was 77%, and patients who lost their MR were switched to second-generation TKIs. There were eighty patients in group B, and seventy-six of them started with the original molecule and then switched to a generic (63 patients were switched to Imatis, 13 patients were given Imatenil), and in four (two patients received Imatis, the remaining two were given Imatenil and Imavec) a generic IM was initiated upfront. Before the switch, the median follow-up under Glivec was 55 months (range,
Correspondence: Teoman Soysal, Istanbul University Cerrahpasa Medical Faculty, Department of Internal Medicine, Division of Hematology, Kocamustafapasa, Fatih, Istanbul, 34303 Turkey. Tel: 90-532-465-82-44. Fax: 90-212-589-79-34. E-mail: [email protected] There is an accompanying commentary that discusses this paper. Please refer to the issue Table of Contents. Received 24 January 2014; revised 8 March 2014; accepted 11 March 2014
1
2 A. E. Eskazan et al. Table I. Demographics of entire cohort and two patient groups. Total
Leuk Lymphoma Downloaded from informahealthcare.com by University of Otago on 09/08/14 For personal use only.
Patients, n Median age, years (range) Male/female, n Eutos risk low/high, n Hasford risk low/int/ high, n Sokal risk low/int/ high, n Median follow-up, months (range) Median weekly dose of imatinib, mg
Group A
Group B
p-Value
145 65 80 43 (15–81) 44 (15–73) 42 (15–81)
— 0.562
81/64 128/17 80/52/13
36/29 55/10 37/22/6
45/35 73/7 45/28/7
0.917 0.218 0.962
63/56/26
35/19/11
36/30/14
0.390
63 (6–144) 61 (6–144) 66 (12–139)
0.196
—
0.707
2744
2814
3–126 months). Among these 76 patients, four received Glivec for less than 6 months before the switch. The median follow-up after switching was 12 months (range, 4–16 months). Responses in group B were evaluated based on the BCR–ABL1 values after switching to a generic. Before switching, 56 patients (77%) had MMR or MUL, among whom 53 maintained their responses, but MMR was lost in three (Table II). The remaining 24 had CCyR, but any MR less than MMR. After the switch, 14 of these 24 cases preserved their responses, while seven gained MMR or MUL. The remaining two patients lost their MR, and one of them lost CCyR; they were switched to second-generation TKIs. Among these 24 patients, of the four cases who had an early switch from Glivec to a generic, two achieved a MMR, and the other two had a CCyR with a median follow-up of 12.5 months (range, 11–15 months). Similarly, among four patients who started a generic, two achieved a MMR, and the other two acquired a partial CyR and CCyR, respectively, with a median follow-up of 6 months (range, 4–14 months). The cumulative MMR rate was 75%, and the response rates were not significantly different between the two groups (Table II). The starting dose of IM was 400 mg/day in all patients. There were five patients in each group who needed a dose reduction (400 → 300 mg/day) due to hematological or non-hematological AEs. In five patients, hematological AEs (thrombocytopenia in four, and neutropenia in one), and non-hematological AEs in four cases (gastrointestinal side effects in two, skin reaction in one, and myalgia in one), were the reasons for a dose reduction. Among these nine patients, the dose reduction was performed before the generics were available, and the patients who were switched to a generic (n ⫽ 4) kept receiving 300 mg daily IM. One
patient in group B had a dose reduction due to edema after switching to a generic. The median dose of IM utilized was 2744 mg and 2814 mg per week for groups A and B, respectively (p ⫽ 0.707). In the pre-IM era, the median survival of patients with CML was approximately 6 years. With TKI therapy, the annual all-cause mortality in CML declined to 2%, versus a historical rate of 10–20%, and the estimated 10-year survival increased from ⬍ 20% to ⬎ 80% [5]. Patients with CML now live close to normal life spans [6], as long as they receive the appropriate TKIs and adhere to treatment. The annual cost of IM treatment among different countries can vary between 24 and 92 thousand US dollars [2,7–9]. This may reflect the geopolitical and socioeconomic dynamics of different geographic regions. The current prices of drugs for CML are thought to be high, and the launch of generics might reduce healthcare costs. In our study, the two groups received similar IM doses, which might indicate that patients receiving a generic did not experience any AEs that would cause them to discontinue taking their medications; also the tolerability of both Glivec and the generics are inferred to be alike, since the drug doses were carefully determined. Parrillo-Campiglia et al. [10] conducted a randomized, open-label study to assess the bioequivalence of a generic formulation versus Glivec. The test and reference formulations of IM met the regulatory criteria for bioequivalence based on the rate and extent of absorption in their healthy, fasting, male volunteers. Both formulations were generally well tolerated in the population studied, which might support our findings. There are very limited data regarding generics of IM, with conflicting results [11–13]. Mattar [12] reported a case with CP-CML, who first had Glivec and achieved a complete hematologic response (CHR), and then switched to a generic and lost the CHR. Similar to this finding, Asfour and Elshazly [13] also reported two cases of CML (one in CP and the other in blast crisis) who started Glivec, which induced responses, but then lost these responses after switching to a generic. It is obvious that single case reports usually do not give sufficient information about the efficacy or inadequacy of a drug, and thus our study, which consists of approximately 150 patients, might add valuable information to the literature. In group B, 95% of patients were switched to a generic, after a median follow-up of 55 months under Glivec. At the time of the switch, all of these patients had a CCyR, and the MMR rate was 77%. After the switch, the cumulative MMR rates in groups A and B were similar (77% vs. 75%).
Table II. Distribution of responses to imatinib among two groups. Group A (n ⫽ 65) Patients with MMR or MUL/any MR less than MMR at time of switch, n Who maintained their response/lost MMR after switch Patients with any MR less than MMR at time of switch, n Who maintained their response after switch Who gained MMR after switch Who maintained CCyR but worsening MR Who lost CCyR after switch Cumulative number of cases with MMR, n (%)
43/22 40/3 22 10 10 2 0 50 (77)
Group B (n ⫽ 80) 56/24* 53/3 24 14 7 2 1 60 (75)
p-Value 0.622 0.827 — 0.388 0.258 0.717 0.414 0.789
CCyR, complete cytogenetic response; MR, molecular response; MMR, major molecular response; MUL, molecularly undetectable leukemia. *Four patients who started TKI treatment with a generic, and four patients who had an early switch to a generic, were added to these 24 cases.
Leuk Lymphoma Downloaded from informahealthcare.com by University of Otago on 09/08/14 For personal use only.
Letter to the Editor 3 The MMR rates among both groups are higher than the data in the published literature [4]. The reason for this finding is that our study cohort consisted of 145 patients, of whom 141 (95%) started with Glivec, and received the drug for a median of ~5 years. These patients were the responders, who maintained these responses during the entire follow-up. The majority of the non-responders were switched to secondgeneration TKIs and/or proceeded to bone marrow transplant before the generics became available. It was previously demonstrated that IM could be safely discontinued in patients with a deep molecular response (DMR) [14,15]. Since our patients received IM for a median of 5 years, possibly some of them would maintain a MR if they discontinued the original drug thereafter. On the other hand, in addition to those who preserved their responses, seven patients achieved MMRs under the generics, which might verify the efficacy of the generics in the treatment of CML. Among our cohort, there were only four patients who started with a generic, and with this study design, we cannot comment on the efficacy and tolerability of generics of IM when administered in the upfront setting. Also, after switching from Glivec to a generic, patients were followed for a median of 12 months, which makes it difficult to estimate long-term outcomes. Thus it is mandatory to follow patients for a longer period of time to gain more accurate data regarding efficacy. In conclusion, TKIs are now the mainstay of treatment of CML, and patients with CML live close to normal life spans. The current prices of TKIs are high, and the launch of generics might reduce healthcare costs. Among our patient cohort, with a median follow-up of 63 months, the generics were at least non-inferior to the original molecule regarding efficacy and tolerability when used subsequently. Prospective randomized trials are needed to address the efficacy of generics of IM in the upfront treatment setting. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Sahin F, Saydam G, Comert M, et al. Turkish chronic myeloid leukemia study: retrospective sectional analysis of CML patients. Turk J Haematol 2013;30:351–358. [2] O’Brien S, Guilhot F, Larson RA , et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348:994–1004. [3] Experts in Chronic Myeloid Leukemia. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Blood 2013;121:4439–4442. [4] Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013;122:872–884. [5] Kantarjian H, O’Brien S. The chronic leukemias. In: Goldman L, Schafer A , Arend W, et al., editors. Cecil medicine. 24th ed. Philadelphia, PA: Elsevier Saunders ; 2012. pp 1209–1218. [6] Gambacorti-Passerini C, Antolini L, Mahon FX, et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst 2011;103:553–561. [7] Red Book online database. Available from: http://www.redbook. com/redbook/ [8] Bundesministerium für Gesundheit. The act on the reform on the market for medicinal products (Gesetz zur Neuordnung des Arzneimittelmarktes - AMNOG). Available from: www.bmg.bund.de/ ministerium/english-version/amnog.html [9] The Pharma Letter. German pharma criticizes new AMNOG vetting procedure. March 2012. Available from: www.thepharmaletter.com/ file/111771/german-pharma-criticizes-new-amnog-vettingprocedure. html. [10] Parrillo-Campiglia S, Ercoli MC, Umpierrez O, et al. Bioequivalence of two film-coated tablets of imatinib mesylate 400 mg: a randomized, open-label, single-dose, fasting, two-period, two-sequence crossover comparison in healthy male South American volunteers. Clin Ther 2009;31:2224–2232. [11] Gogtay J, Chahchad S, Jadhav S, et al. Response to the case report by Mattar: generic imatinib (Imatib, Cipla) in a patient with chronic myeloid leukemia in chronic phase. Int J Hematol 2010;92:772–773. [12] Mattar M. Failure of copy imatib (CIPLA, India) to maintain hematologic and cytogenetic responses in chronic myeloid leukemia in chronic phase. Int J Hematol 2010;91:104–106. [13] Asfour IA , Elshazly SA . Changing therapy from Glivecto a “copy” imatinib results in a worsening of chronic myeloid leukemia disease status: two case reports. Cases J 2009;2:9342. [14] Mahon FX, Rea D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 2010;11:1029–1035. [15] Ross DM, Branford S, Seymour JF, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood 2013;122:515–522.
LETTER TO THE EDITOR
The efficacy of generic formulations of imatinib mesylate in the treatment of chronic myeloid leukemia Ahmet Emre Eskazan1, Tugrul Elverdi1, Fevzi Firat Yalniz1, Ayse Salihoglu1, Muhlis Cem Ar1, Seniz Ongoren Aydin1, Zafer Baslar1, Yildiz Aydin1, Nukhet Tuzuner2, Ugur Ozbek3 & Teoman Soysal1 1Division of Hematology, Department of Internal Medicine and 2Department of Pathology, Cerrahpasa Faculty of Medicine,
Leuk Lymphoma Downloaded from informahealthcare.com by University of Otago on 09/08/14 For personal use only.
Istanbul University, Istanbul, Turkey and 3Department of Genetics, Institute of Experimental Medicine (DETAE), Istanbul University, Istanbul, Turkey
The treatment of chronic myeloid leukemia (CML) has changed greatly, and the outlook of patients with CML has improved dramatically, with the introduction of tyrosine kinase inhibitors (TKIs) [1]. The first TKI developed for CML was imatinib mesylate (IM) (Glivec; Novartis, Basel, Switzerland) [2], and thereafter many other TKIs became available on the market [3]. The high cost of new cancer drugs including those developed for CML is a major concern for healthcare payers, especially in countries with restricted resources. Reimbursement policies worldwide, therefore, encourage generic drug use to lower the prices. It is true that generics lead to considerable cost savings, but they also give rise to questions associated with their efficacy, safety and quality. In Turkey, there are three commercially available generics of IM (Imatis; Deva, Imatenil; Logus and Imavec; Koçak Farma), which have been licensed for the treatment of CML for more than a year. There is a price difference between Glivec and the generics, and due to the reimbursement policy, patients who prefer to receive the original molecule must pay the price difference; the price difference was the only reason for switching from Glivec to any generic among our cohort. The first issue that physicians caring for patients with CML encounter is whether the efficacy of these generics is comparable to that of the original molecule; the second issue is what the potential adverse events (AEs) are, other than those with use of Glivec, if any. To answer these questions, we retrospectively reviewed our data. One hundred and forty-five patients with chronic phase (CP) CML who were diagnosed and followed between 2000 and 2013 were enrolled in the study. Patients who had been switched to a second-generation TKI before the evaluation period were excluded. Patients’ demographics, IM dose, disease risk scores and follow-up durations were noted from the patients’ files retrospectively (Table I). IM response was evaluated according to criteria recommended by the
European LeukemiaNet [4]. Molecular response (MR) was classified based on the BCR–ABL1 to control gene transcript ratio, expressed on the International Scale. The cumulative incidence of major molecular response (MMR) during follow-up was calculated. CML phases were defined as described elsewhere [4]. There were two study groups: group A which included patients receiving Glivec throughout the entire follow-up, and group B which contained cases who started with Glivec and then were switched to one of the generics at a certain time during their follow-up. These two groups were compared regarding response rates, and for the assessment of tolerability, the real drug doses were compared. The switch to generics started in August 2012 when the first drug was approved and become available on the market. Eighty-one patients were male (57%), and the median age was 43 years. The two groups were equally balanced regarding age, gender and risk scores (Table I). The median follow-up duration of the entire cohort was 63 months, and 61 and 66 months for groups A and B, respectively. Group A consisted of 65 patients, 43 of whom had molecularly undetectable leukemia (MUL) or MMR; 40 of them maintained these responses whereas three patients lost MMR during follow-up (Table II). Ten of the remaining 22 patients had a durable complete cytogenetic response (CCyR), but any MR less than MMR. The other 10 cases achieved MMR during follow-up, while two lost their MR (Table II). The cumulative MMR rate was 77%, and patients who lost their MR were switched to second-generation TKIs. There were eighty patients in group B, and seventy-six of them started with the original molecule and then switched to a generic (63 patients were switched to Imatis, 13 patients were given Imatenil), and in four (two patients received Imatis, the remaining two were given Imatenil and Imavec) a generic IM was initiated upfront. Before the switch, the median follow-up under Glivec was 55 months (range,
Correspondence: Teoman Soysal, Istanbul University Cerrahpasa Medical Faculty, Department of Internal Medicine, Division of Hematology, Kocamustafapasa, Fatih, Istanbul, 34303 Turkey. Tel: 90-532-465-82-44. Fax: 90-212-589-79-34. E-mail: [email protected] There is an accompanying commentary that discusses this paper. Please refer to the issue Table of Contents. Received 24 January 2014; revised 8 March 2014; accepted 11 March 2014
1
2 A. E. Eskazan et al. Table I. Demographics of entire cohort and two patient groups. Total
Leuk Lymphoma Downloaded from informahealthcare.com by University of Otago on 09/08/14 For personal use only.
Patients, n Median age, years (range) Male/female, n Eutos risk low/high, n Hasford risk low/int/ high, n Sokal risk low/int/ high, n Median follow-up, months (range) Median weekly dose of imatinib, mg
Group A
Group B
p-Value
145 65 80 43 (15–81) 44 (15–73) 42 (15–81)
— 0.562
81/64 128/17 80/52/13
36/29 55/10 37/22/6
45/35 73/7 45/28/7
0.917 0.218 0.962
63/56/26
35/19/11
36/30/14
0.390
63 (6–144) 61 (6–144) 66 (12–139)
0.196
—
0.707
2744
2814
3–126 months). Among these 76 patients, four received Glivec for less than 6 months before the switch. The median follow-up after switching was 12 months (range, 4–16 months). Responses in group B were evaluated based on the BCR–ABL1 values after switching to a generic. Before switching, 56 patients (77%) had MMR or MUL, among whom 53 maintained their responses, but MMR was lost in three (Table II). The remaining 24 had CCyR, but any MR less than MMR. After the switch, 14 of these 24 cases preserved their responses, while seven gained MMR or MUL. The remaining two patients lost their MR, and one of them lost CCyR; they were switched to second-generation TKIs. Among these 24 patients, of the four cases who had an early switch from Glivec to a generic, two achieved a MMR, and the other two had a CCyR with a median follow-up of 12.5 months (range, 11–15 months). Similarly, among four patients who started a generic, two achieved a MMR, and the other two acquired a partial CyR and CCyR, respectively, with a median follow-up of 6 months (range, 4–14 months). The cumulative MMR rate was 75%, and the response rates were not significantly different between the two groups (Table II). The starting dose of IM was 400 mg/day in all patients. There were five patients in each group who needed a dose reduction (400 → 300 mg/day) due to hematological or non-hematological AEs. In five patients, hematological AEs (thrombocytopenia in four, and neutropenia in one), and non-hematological AEs in four cases (gastrointestinal side effects in two, skin reaction in one, and myalgia in one), were the reasons for a dose reduction. Among these nine patients, the dose reduction was performed before the generics were available, and the patients who were switched to a generic (n ⫽ 4) kept receiving 300 mg daily IM. One
patient in group B had a dose reduction due to edema after switching to a generic. The median dose of IM utilized was 2744 mg and 2814 mg per week for groups A and B, respectively (p ⫽ 0.707). In the pre-IM era, the median survival of patients with CML was approximately 6 years. With TKI therapy, the annual all-cause mortality in CML declined to 2%, versus a historical rate of 10–20%, and the estimated 10-year survival increased from ⬍ 20% to ⬎ 80% [5]. Patients with CML now live close to normal life spans [6], as long as they receive the appropriate TKIs and adhere to treatment. The annual cost of IM treatment among different countries can vary between 24 and 92 thousand US dollars [2,7–9]. This may reflect the geopolitical and socioeconomic dynamics of different geographic regions. The current prices of drugs for CML are thought to be high, and the launch of generics might reduce healthcare costs. In our study, the two groups received similar IM doses, which might indicate that patients receiving a generic did not experience any AEs that would cause them to discontinue taking their medications; also the tolerability of both Glivec and the generics are inferred to be alike, since the drug doses were carefully determined. Parrillo-Campiglia et al. [10] conducted a randomized, open-label study to assess the bioequivalence of a generic formulation versus Glivec. The test and reference formulations of IM met the regulatory criteria for bioequivalence based on the rate and extent of absorption in their healthy, fasting, male volunteers. Both formulations were generally well tolerated in the population studied, which might support our findings. There are very limited data regarding generics of IM, with conflicting results [11–13]. Mattar [12] reported a case with CP-CML, who first had Glivec and achieved a complete hematologic response (CHR), and then switched to a generic and lost the CHR. Similar to this finding, Asfour and Elshazly [13] also reported two cases of CML (one in CP and the other in blast crisis) who started Glivec, which induced responses, but then lost these responses after switching to a generic. It is obvious that single case reports usually do not give sufficient information about the efficacy or inadequacy of a drug, and thus our study, which consists of approximately 150 patients, might add valuable information to the literature. In group B, 95% of patients were switched to a generic, after a median follow-up of 55 months under Glivec. At the time of the switch, all of these patients had a CCyR, and the MMR rate was 77%. After the switch, the cumulative MMR rates in groups A and B were similar (77% vs. 75%).
Table II. Distribution of responses to imatinib among two groups. Group A (n ⫽ 65) Patients with MMR or MUL/any MR less than MMR at time of switch, n Who maintained their response/lost MMR after switch Patients with any MR less than MMR at time of switch, n Who maintained their response after switch Who gained MMR after switch Who maintained CCyR but worsening MR Who lost CCyR after switch Cumulative number of cases with MMR, n (%)
43/22 40/3 22 10 10 2 0 50 (77)
Group B (n ⫽ 80) 56/24* 53/3 24 14 7 2 1 60 (75)
p-Value 0.622 0.827 — 0.388 0.258 0.717 0.414 0.789
CCyR, complete cytogenetic response; MR, molecular response; MMR, major molecular response; MUL, molecularly undetectable leukemia. *Four patients who started TKI treatment with a generic, and four patients who had an early switch to a generic, were added to these 24 cases.
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Letter to the Editor 3 The MMR rates among both groups are higher than the data in the published literature [4]. The reason for this finding is that our study cohort consisted of 145 patients, of whom 141 (95%) started with Glivec, and received the drug for a median of ~5 years. These patients were the responders, who maintained these responses during the entire follow-up. The majority of the non-responders were switched to secondgeneration TKIs and/or proceeded to bone marrow transplant before the generics became available. It was previously demonstrated that IM could be safely discontinued in patients with a deep molecular response (DMR) [14,15]. Since our patients received IM for a median of 5 years, possibly some of them would maintain a MR if they discontinued the original drug thereafter. On the other hand, in addition to those who preserved their responses, seven patients achieved MMRs under the generics, which might verify the efficacy of the generics in the treatment of CML. Among our cohort, there were only four patients who started with a generic, and with this study design, we cannot comment on the efficacy and tolerability of generics of IM when administered in the upfront setting. Also, after switching from Glivec to a generic, patients were followed for a median of 12 months, which makes it difficult to estimate long-term outcomes. Thus it is mandatory to follow patients for a longer period of time to gain more accurate data regarding efficacy. In conclusion, TKIs are now the mainstay of treatment of CML, and patients with CML live close to normal life spans. The current prices of TKIs are high, and the launch of generics might reduce healthcare costs. Among our patient cohort, with a median follow-up of 63 months, the generics were at least non-inferior to the original molecule regarding efficacy and tolerability when used subsequently. Prospective randomized trials are needed to address the efficacy of generics of IM in the upfront treatment setting. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
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