Efficacy of Nilotinib versus Imatinib in Philadelphia Positive Patients with Chronic Myeloid Leukemia in Early Chronic Phase Who Have a Warning Molecular Response to Imatinib

Background and Objectives: Chronic myeloid leukemia (CML) accounts for approximately 15% of newly diagnosed cases of leukemia in adults. In this study, the efficacy of nilotinib at 400 mg BID is compared with imatinib at 400 mg BID in CML patients with suboptimal molecular response after at least 12 months of daily dose 400 mg of imatinib therapy. Patients and Methods: This study included a total number of 50 patients, divided into two groups (25 patients each). The first group (Group I): Patients received imatinib at 400 mg BID, second group (Group II): Patients had a suboptimal molecular response to imatinib and received nilotinib at 400 mg BID in early chronic phase. During the two years period of data collection, the primary end included median survival. The secondary end included response rate, type of response, duration of response and progression free survival. Also side effects were recorded. Patients were followed up every month by complete and differential blood counts, liver function test, renal function test and (PCR) every three months for two year. Results: Nilotinib group had significantly higher frequency of major molecular response (MMR) where 23 (92%) patients achieved it while only 16 (64%) patients in Imatinib group achieved MMR (P = 0.01). Nilotinib had better toxicities profile than Imatinib. Conclusion: Both Nilotinib and high dose Imatinib achieved response in CML patients with suboptimal response with rapid and deeper molecular response, better survival outcomes and less side effects in nilotinib. How to cite this paper: Aly, A.H.Z., Khalifa, A.S.M. and Gadallah, E.A.A. (2018) Efficacy of Nilotinib versus Imatinib in Philadelphia Positive Patients with Chronic Myeloid Leukemia in Early Chronic Phase Who Have a Warning Molecular Response to Imatinib. Journal of Cancer Therapy, 9, 883-897. https://doi.org/10.4236/jct.2018.911073 Received: September 18, 2018 Accepted: November 13, 2018 Published: November 16, 2018 Copyright © 2018 by authors and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Open Access


Introduction
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1 -2 cases per 100,000 adults.It accounts for approximately 15% of newly diagnosed cases of leukemia in adults [1].
In 2002, the approval of the BCR-ABL tyrosine kinase inhibitor (TKI) imatinib mesylate for the first line treatment of chronic myeloid leukemia revolutionized therapeutic goals and led to the introduction of novel monitoring schemes and response definitions [2].
However, many patients treated with imatinib do not meet the molecular response targets designated by the National Comprehensive Cancer Network (NCCN) and the European Leukemia Net [3].
The response to TKI can be classified as optimal and failure.The term suboptimal may be better replaced by the term "warning", meaning that between optimal and failure, there is a gray zone where the response must be monitored more carefully and that the patient may be eligible for potentially better treatments.The choice of the treatment, particularly the decision of moving from one treatment to another, strongly depends on the response to treatment, particularly on the degree of the cytogenetic response (CgR), and on the detection of BCR-ABL KD point mutations [4].
Among patients with CCyR at 12 months in the International Randomized Study of Interferon Versus STI571 (IRIS) trial of frontline imatinib, >30% of patients did not achieve MMR at 12 months [5].
Nilotinib is a highly selective BCR-ABL1 TKI approved for the treatment of patients with newly diagnosed CML-CP or imatinib-resistant or imatinib-intolerant CML-CP or CML-AP.With 5 years of follow up in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study, frontline nilotinib resulted in higher response rates and a lower risk of disease progression versus frontline imatinib for patients with Ph + CML − CP [6].
The ELN considers patients with a response level equivalent to CCyR without MMR (BCR-ABL1IS >0.1% -1%) at 12 months following initiation of frontline TKI therapy to be in a "warning zone" indicating that they may be at risk for treatment failure [7].
In this study, we compared the efficacy of nilotinib at 400 mg BID with imatinib at 400 mg BID in suboptimal molecular response patients after at least 12 months of daily dose 400 mg of imatinib therapy and we excluded patients who started late chronic phase Imatinib therapy more than 6 months, patients who had blastic or accelerated crises, patients with impaired cardiac function, im-paired gastrointestinal (GI) function or GI disease, hypersensitivity to Nilotinib or intolerance to Imatinib, severe or uncontrolled medical conditions i.e. (uncontrolled diabetes, acute or chronic liver disease, pancreatic, or severe renal disease unrelated to tumor, active or uncontrolled infection).

Patients and Methods
This comparative prospective study was carried out after approval of the local ethics committee, where we included a total number of 50 patients, fulfilling the after-coming inclusion and exclusion criteria, who divided into two groups.The first group (Group I): included 25 patients who received imatinib at 400 mg BID, second group (Group II): included 25 patients and they received nilotinib at 400 mg BID in early chronic phase that had a suboptimal molecular response to imatinib.
Patients included were male or female patients with a performance status (ECOG): 0 -2, diagnosis of phladelphia positive chronic myeloid leukemia in chronic phase, patients with suboptimal molecular response defined as patients not achieving a complete cytogenic response at 12 months and must maintain complete cytogenic response until study entry (0% pheladephia +ve chromosome).Patients should receive at least 18 months and up to 24 months of treatment with Imatinib as first line therapy at a dose of 400 mg daily without achieving a major molecular response (<0.1% IS of Pcr-Apl transcript by RQ-PCR), no renal or hepatic impairment.
Exclusion criteria included late chronic phase patients who started Imatinib more than 6 months after diagnosis, prior accelerated phase or blast phase CML, hypersensitivity to Nilotinib or intolerance to Imatinib, previous treatment with interferon or any other tyrosine kinase inhibitor except Imatinib, patients treated with Imatinib more than 400 mg/day who achieved prior major molecular or complete cytogenic response on Imatinib and lost response to enter the study, impaired cardiac or GIT functions, severe or uncontrolled medical conditions (uncontrolled diabetes mellitus, uncontrolled acute or chronic liver disease, pancreatic or severe renal disease unrelated to tumor, or uncontrolled infection), any other malignancy that is clinically significant or requiring medical interventions.
During the two years period of data collection, the primary end point included median survival.The secondary end points included response rate, type of response, duration of response and progression free survival.
Also side effects including nausea, vomiting, diarrhea, fatigue, myalgia and Q-T interval abnormalities were recorded.
Patients' follow up: Patients followed up for two year by complete blood count with differential count every month, liver function test, renal function test and (PCR) every three months.
A data entry file, using EXCEL ® 2016 program, was prepared.Data were processed and analyzed using SPSS ® ver.20.The frequencies, percentages, mean and standard deviation were computed.Independent samples t-test was used to compare quantitative data between the two groups.Chi-square test was used to compare qualitative data between two groups.P-value of < 0.05 was considered as significant.

Results
During the two years of follow up period of the study, 25 patients were enrolled in Nilotinib group and 25 patients were enrolled Imatinib group.No deaths or patients losses during study period.

Demographic data were equally distributed among both groups.
There was male predominance in both groups, but this was not a significant difference between the two groups (P = 0.09) (Table 1).
In contrast, frequency of diarrhea was higher in Nilotinib group; a total of 8 (32%) and 3 (12%) patients had G1 and G2 diarrhea respectively while only 7 (28%) patients from Imatinib group had G1 diarrhea but this there was insignificant difference between both groups regarding occurrence of diarrhea (P = 0.19) (Table 5, Figure 6).Figure 6.Frequency of diarrhea in both groups where data were expressed in form of percentage.

Survival analysis in the current study: (Was done by Kaplan Meier test)
Progression free survival: median of disease free progression was 23.44 months in case of Nilotinib group (97.6%) patients with median of disease free progression was 19.2 ( 80%) months (P = 0.01) (Figure 7).
Median survival analysis: Median survival in the current for nilotinib group was significantly higher than Imatinib group (30 months versus 25 months for Nilotinib group and imatinib group respectively; P = 0.01) (Figure 8).

Duration of response after MMR
Mean duration of response after MMR was significantly higher in Nilotinib group (19 months) in comparison to Imatinib group (16 months) with P = 0.03 (Figure 9).

Discussion
Our study was a 24-months, randomized, phase 3 study designed to compare high dose imatinib (800 mg bid) with nilitonib 400 mg bid in patients with chronic myeloid leukemia who had suboptimal response.All of the twenty-five patients participating in each group (Nilotinib 800 mg group, and Imatinib 400 mg group) have completed the 24-months period of treatment in the study.No patients in either arm progressed to accelerated phase/blast crisis by 24 months.No deaths or missing during period of study.
Our study showed that Nilotinib group had significantly higher frequency of MMR at 12 th month of therapy where 18 (72%) patients achieved it while only 16 (64%) patients in Imatinib group achieved it (P = 0.04).This is similar to a study done by Goh et al.where MMR at 12 th month was significantly higher in nilotinib arm compared to imatinib dose-escalation arm 7/13 (53.85%) and 2/11 (18.18%) [8].
At 24 months MMR were 23 (92%) in Nilotinib arm versus 16 (64%) in Imatinib arm Also the same results were obtained by Choi and his colleagues in their study where over 3 years the MMR was higher in Nilotinib group than in Imatinib group (81.0%vs 64.6% in groups 1, and 2 respectively) (P = 0.01) [9].Moreover, García-Gutiérrez et al. found in their study that MMR by 24 months in Nilotinib group was 64%, and in Imatinib group 43% [10].
Contradicting that, Bang and his colleagues in 2017 found that MMR was not significantly different in between treatment arms (41% vs 29% of patients) [11].
Regarding types of response, in our study, early molecular response within 3 to 6 months occurred in 12 patients (48%) of Nilotinib arm and 10 patients (40%) in imatinib arm.Agreeing with us, Koh et al. documented in their study the occurrence of early molecular response within 6 months in 40% of patients receiving 800 mg Imatinib [12].
On the contrary, Goh et al. have reported that early molecular response had occurred only in patients with nilotinib.[8] Moreover, Ail Awadhi and colleagues documented that 59% of patients received Nilotinib achieved early molecular response within 3 months [5].
Optimal response, in our study, occurred within 9 to 12 months in 11 (44%) and 6 (24%) patients in Nilotinib and Imatinib groups, respectively.This is similar to the findings of García-Gutiérrez and colleagues, where after 12 months 42% of patients achieved optimal response in Nilotinib versus 24% in Imatinib arm [10].
Similarly, Choi et al. reported the occurrence of optimal response after 12 months in 35% of patients who received Nilotinib versus only 28% of those who received Imatinib [9].Remarkably, Ail Awadhi et al. showed that nine of 12 (75%) patients who received Nilotinib achieved MMR at 12 months [5].
In our study, only 2 (8%) and 9 (36%) patients in Nilotinib and Imatinib groups respectively had warning response.Our results are the same and slightly better than those obtained by Hughes et al.where 84 (30%), and 128 (45%) patients had warning response in nilotinib (400 mg twice daily), and imatinib groups, respectively [13].
Regarding non-hematological adverse events in our study, renal impairment in the form of increased creatinine level was higher in the Imatinib group in comparison to Nilotinib group (2 (8%) versus 3 (12%) patients, respectively) P = 0.03 Furthermore, no patients developed acute renal failure.This is better than results obtained by [17] 7% of patients developed ac acute kidney injury; creatinine levels returned to baseline in only one of them in patients taking high dose imatinib [17].
Regarding diahrrea was higher in Nilotinib group; a total of 8 (32%) and 3 (12%) patients had G1 and G2 diarrhea respectively while only 7 (28%) patients from Imatinib group had G1 diarrhea but this there was insignificant difference between both groups regarding occurrence of diarrhea (P = 0.19).but in contrary results had occurred with Saglio et al., no diarrhea had occur with Nilotinib arm and only 3(1%) in.Imatinib arm [15].
Regarding fluid retention in our study we noticed that it occurred only in Imatinib group 8 (32%) and 4 (16%) patients had G1 and G2 fluid retention respectively (P = 0.01).
Our survival analysis By using Kaplan Meier survival analysis: The estimated rate of median survival for Nilotinib group was significantly higher than Imatinib group (30 months versus 25 months for Nilotinib group and Imatinib group, respectively) this is consisted with study by Wang et al.
showed median survival arm was 22.3 months in the nilotinib arm and 22.6 months in the imatinib arm [14].Unfortunately, we could not calculate the overall survival, as we had no deaths among our patients.
The estimated progression free survival rate occurred in Nilotinib a median of disease free progression of 23.44 months (97.6%) in case of Nilotinib group, while in case of Imatinib group with a median of disease free progression of 19.2 ( 80%) months.This is in contrary to García-Gutiérrez et al. that found PFS rate in both groups were similar 92.6% [10].Also Wang et al. showed PFS in both groups was 95.6% [14].
Finally, mean duration of response after MMR was significantly higher in Nilontinib group (19 months) than in Imatinib group (16 months).This is nearly similar to a study done by Ishikawa and his colleagues that showed duration of response after MMR 26 months in Nilontinib group versus 23.8 months in Imatinib group [20].

Conclusion
In conclusion, both Nilotinib and high dose Imatinib achieved response in CML patients with suboptimal response with rapid and deeper molecular response, better survival outcomes and less side effects in nilotinib.

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper.

Figure 1 .
Figure 1.Type of major molecular response.Data was expressed in form of percentage.

Figure 2 .
Figure 2. Frequency of myalgia in both groups where data was expressed in form of percentage.

Figure 3 .
Figure 3. Frequency of rash in both groups where data was expressed in form of percentage.

Figure 4 .
Figure 4. Frequency of fatigue in both groups where data was expressed in form of percentage.

Figure 5 .
Figure 5. Frequency of nausea in both groups where data was expressed in form of percentage.

Figure 9 .
Figure 9. Duration of response after MMR.

Table 1 .
Demographic data of both groups.
VariablesNilotinib group (n = 25) Imatinib group (n = 25)Data was expressed in form of frequency (percentage) or mean ± SD.P value was significant if <0.05.n: number.

Table 2 .
Response of therapy in each group.

Table 3 .
Hematological adverse effects of therapy in both groups.

Table 4 .
Frequency of hepatic and renal impairment.
Data was expressed in form of frequency (percentage).P value was significant if <0.05 (*).

Table 5 .
Non haematological adverse effects of therapy in both groups during course of therapy.
Data was expressed in form of frequency (percentage).P value was significant if <0.05.
et al. in their study where