Analysis of adverse drug reactions of imatinib in chronic myeloid leukemia patients: An Eastern Indian experience

Abstract

BACKGROUND:

Imatinib mesylate is the cornerstone therapy in the management of chronic myeloid leukemia (CML). Monitoring of adverse drug reactions (ADRs) of imatinib in our patients is very important to ensure their safety. Aims and Objectives: The current study aims to monitor ADRs encountered in CML patients in the chronic phase with imatinib (400 mg/day).

MATERIALS AND METHODS:

This prospective, observational study was conducted from November 2011 to May 2015 on 310 patients presented to the Departments of Clinical Hematology and Pharmacology of SCB MCH, Cuttack, diagnosed with CML at chronic phase. Collected ADRs were entered in the ADR reporting form (PvPI) and were analyzed for causality and severity.

RESULTS:

Anemia was the most common hematological ADR, whereas hyperpigmentation and nausea were the most common nonhematological ADRs reported. Maximum ADRs were mild to moderate and required no change in the treatment course.

CONCLUSION:

The study revealed that imatinib mesylate, a well tolerated drug, has very few cases of severe ADRs in Indian patients at the chronic stable phase of CML.

Introduction

Chronic myeloid leukemia (CML) is the most common hematological malignancy encountered by Indians.[1] WHO has designated BCR-ABL as the defining abnormality in Philadelphia chromosome positive CML. BCR-ABL mutation happens when a peace of BCR & ABL genes break off and switch places. Imatinib mesylate is a revolutionary molecule that has significantly altered the management of CML in recent years.[2] At present, most Indian patients are receiving generic imatinib mesylate, either through the government supply portal or through the Glivec International Patient Assistance Program (GIPAP).[3] Due to the targeted therapy and the availability of multiple forms of the drug being utilized by our patients, it is possible that the molecule may show a different spectrum of adverse events in Indian patients. Hence, the present study aims to observe different short- and long-term adverse drug reactions (ADRs) to imatinib mesylate and to ascertain both causality and severity.

Materials and Methods

Diagnosed patients of CML attending both the Outpatient Department and Indoor Clinical Hematology Department of SCB Medical College and Hospital, Cuttack, between November 2007 and May 2015 were included in the present study. Approval of the institutional ethics committee of SCB Medical College, Cuttack, was obtained before starting the study (IEC/IRB NO: 100). All the study participants provided written informed consent before inclusion in this study.

Inclusion criteria

Diagnosed adult patients (aged >18 years) of CML in the chronic phase were eligible for enrolment. Patients were considered new if the diagnosis is made for the first time and had not received any prior treatment related to CML.

Exclusion criteria

• CML in either accelerated phase/blast crisis

• Cardiac functional abnormality

• Impaired gastrointestinal (GI) function or any other serious medical conditions

• History of major surgery in the past 2 weeks

• History of taking medications having known interaction with imatinib.

Data collection and analysis

Patients were directly interviewed during their clinical visit and their case record sheets were reviewed for possible adverse reactions. Medication history was thoroughly asked and their physical, biochemical, and hematological parameters were recorded in the predesigned format. The data, thus, generated were analyzed regarding the severity of the reaction, the pattern of the reaction, and causality. All the collected ADRs were thoroughly analyzed by the causality assessment committee. The WHO-UMC Causality Assessment scale was used to reach the proper conclusion.[4] A modified Hartwig Siegel scale was used for determining the severity assessment of ADRs and was categorized as mild, moderate, and severe reactions.[5] Adverse events were monitored throughout the study treatment and for up to 28 days following the last dose of imatinib. ADRs were collected using a standard assessment form supplied by the Central Drugs Standard Control Organisation (CDSCO).[6] The data, thus, generated were entered into the MS Excel sheet and SPSS (IBM, SPSS statistics version, 20.0, Cal) was used for analyzing the data statistically.

Study design and treatments

This is a prospective, nonrandomized, open-label study. All eligible patients were evaluated as follows: general examination, systemic examination, routine complete blood count, and liver/kidney function test. Bone marrow examination was done in all the cases at the time of diagnosis for the proper staging of the disease. The diagnosis of CML was confirmed by the quantification of BCR-ABL byReverse Transcriptase - Polymerase Chain Reaction (RT-PCR) as per international scale. All patients in the chronic phase of CML have maintained 400 mg once daily of imatinib and they were followed up for 24 months. CML patients that required escalated doses of imatinib were excluded from the study. Patients with Grades 3 and 4 hematological ADRs and serious drug-related ADRs due to other factors were allowed for dose interruption.

Results

Among 310 study participants included in the study, 239 (77%) were male and the rest 71 (23%) were female. At the time of diagnosis, the median age of our patients was 58 years (18–74 years). The median time for diagnosis in our patients was found to be 8 months (1–18 months). In our entire study period, a total of 1193 ADRs were observed in the study participants. Out of all, 509 (42.6%) were hematological and 684 (57.4%) were nonhematological. Anemia was found to be the most common among hematological ADRs followed by leukopenia. The maximum number of ADRs belonged to Grades 1 and 2 according to CTCAE (v4.03).[7] Furthermore, there was significantly less number of cases belonging to Grades 3 and 4 [Table 1].

Table 1.

Hematologic adverse drug reactions

Parameters	Grades 1 and 2	Grades 3 and 4	Total (%)	P
Anemia	198	12	210 (41.3)	<0.000
Leukopenia	91	18	109 (21.5)	<0.000
Lymphopenia	87	17	104 (20.4)	<0.000
Neutropenia	45	9	54 (10.6)	<0.000
Thrombocytopenia	28	4	32 (6.2)	<0.000
All total (%)	449 (37.6)	60 (5)	509 (42.6)	<0.000

The median onset lag in Grades 1 and 2 and Grades 3 and 4 were 12.5 and 17 weeks, respectively [Figure 1]. Out of nonhematological ADRs, hyperpigmentation was the most common, followed by pruritus and skin rash. The severe form of these reactions was significantly lower (except hypertension) as depicted in Table 2. When these cases were analyzed for causality assessment, the maximum cases belong to the possible category (54.7%), followed by certain (26.2%) and probable (19.1%) [Figure 2]. The severity of the observed ADRs by the modified Hartwig and Siegel scale showed that 51.6% of ADRs were mild, 38.6% were moderate, and 9.8% were severe in nature [Figure 3].

Figure 1.

Median duration of appearance of hematological ADRs from the beginning of the treatment with imatinib mesylate. ADRs: Adverse drug reactions

Table 2.

Nonhematological adverse drug reactions

Parameters	Mild/moderate	Severe	Total (%)	P
Skin rash	46	12	58 (8.4)	<0.000
Hyperpigmentation	174	8	182 (26.6)	<0.000
Hypopigmentation	13	0	13 (1.9)	-
Nausea and vomiting	76	0	76 (11.1)	-
Lid swelling	54	2	56 (8.1)	<0.000
Leg swelling	52	3	55 (8)	<0.000
Pruritus	56	12	68 (9.9)	<0.000
Abdominal pain	12	2	14 (2)	0.01
Dry skin	44	0	44 (6.4)	-
Diarrhea	20	2	22 (3.2)	<0.000
Headache and muscular pain	24	4	28 (4)	<0.000
Hyperacidity	49	1	50 (7.3)	<0.000
Hypertension	6	3	9 (1.3)	0.33
All total (%)	626 (52.4)	58 (4.8)	684 (57.3)	<0.000

Figure 2.

Causality assessment of the observed ADRs. ADRs: Adverse drug reactions

Figure 3.

Severity assessment of the observed ADRs. ADRs: Adverse drug reactions

Discussion

Currently, imatinib mesylate is the first-line therapy for CML irrespective of the disease stage. Our study was conducted on 310 participants in the chronic phase of CML. The median age in our study is 58 years which is similar to some other studies conducted in India.[8,9] Males were found to be more affected than females which corroborate with studies conducted by Bhatwadekar et al. and Deshmukh et al.[9,10]

Although imatinib is a well-tolerated molecule, Grades 1 and 2 (mild to moderate) adverse events are quite common in patients who are treated with imatinib either for the treatment of CML or Philadelphia chromosome-positive ALL patients. In our study, after the hematological system, cutaneous ADRs were the second most common system to be affected. However, this manifestation was not totally similar to other studies.[12,13,14,15] This might be due to genetic variation or environmental factors or the combined role of both components. Among hematological ADRs, anemia was the most common in our study which was in contrast to Meena et al. and Francis et al.[12,15] However, the study by Abhijit et al. favors our study.[8] The median duration of the initiation of hematological ADRs was 12.5 and 17 weeks for Grades 1 and 2 and Grades 3 and 4, respectively, which was similar to the study by Meena et al.[15]

In this study, we found only 5% of all ADRs belong to Grades 3 and 4 hematological ADRs. In a significant percentage of chronic phases, CML patients experienced hematological toxicity from the administration of imatinib at the same dose (400 mg) in the IRIS trial. However, in Grades 3 and 4, hematological toxicity was observed in fewer patients. In another Chinese study conducted on CML patients treated with imatinib in the chronic phase, thrombocytopenia was noticed in maximum patients (21.8%), followed by Grades 3 and 4 neutropenia in17.8% and anemia in only 5.9% patients as hematological ADRs. (Li Zhou et al.).[16]

In the present study for the first time, we report a sizable number of patients having hyperpigmentation. Although it had been found by other studies, the frequency of occurrence is quite high.[11]“Imatinib targets the ATP binding site of the tyrosine kinases of the C-kit. It is now clear that basal cells and melanocytes of the skin have C-kit as normal expression.”[17] Few studies have suggested that “C-kit and its ligand stem cell factor have a major role in melanogenesis, melanocyte homeostasis, and Ultra Violet-B (UVB)-induced pigmentation.”[18] The role of imatinib in hyperpigmentation was also observed in the management of GI stromal tumors.[19,20] There might be some photosensitivity reaction occurring in our study group that requires further in-depth analysis.

In this study, the maximum number of ADRs was mild in nature and only 9.8% were severe as per the severity scale. Imatinib was found to be the possible cause of the reaction in most of our CML patients as per the WHO Causality Assessment scale. Our study findings regarding causality and severity of reactions match with the observations done by Francis et al.[13]

Conclusion

After the arrival of imatinib, CML treatment has found a new direction. The success rate of imatinib is way more than any of the chemotherapeutic agents and with a significantly lower frequency of severe ADRs. Thus, ensuring adherence in the initial management of CML should be our main strategy in the management of CML in Indian patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.