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ORIGINAL ARTICLE
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Predictive role of neutropenia under crizotinib treatment in ALK-rearranged nonsmall cell lung cancer patients: A single-institution retrospective analysis


1 Department of Medical Oncology, Ege University School of Medicine, Tulay Aktas Oncology Hospital, Izmir, Turkey
2 Depatment of Pathology, Ege University School of Medicine, Izmir, Turkey

Date of Submission30-Jan-2020
Date of Decision31-Jan-2020
Date of Acceptance13-Jan-2021
Date of Web Publication30-Sep-2021

Correspondence Address:
Pınar Gürsoy,
Department of Medical Oncology, Ege University School of Medicine, Tulay Aktas Oncology Hospital, Izmir
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_71_20

  Abstract 


Background: Anaplastic lymphoma kinase (ALK)-rearranged nonsmall cell lung cancer (NSCLC) represents a molecular subgroup with high sensitivity to ALK inhibitors. Tyrosine kinase inhibitor crizotinib, an anticancer drug acting as an ALK inhibitor, has shown remarkable response in ALK-positive NSCLC. The aim of our study is to explore the adverse events (AEs) of patients on crizotinib therapy and analyze the predictability of AEs for better survival or response on NSCLC patients.
Methods: The medical records of our ALK-positive metastatic NSCLC patients who applied between years 2013 and 2018 had been reviewed retrospectively. ALK positivity of all patients had been detected by fluorescence in situ hybridization and no other driver mutations were present. Patient demographics, performance status, smoking history, previous treatments, metastatic sites, and AEs were recorded for further analyses.
Results: Thirty-six ALK-positive metastatic NSCLC patients were included in the study. Median follow-up was 30.1 months. Median progression-free survival (PFS) for patients who developed hepatic, cardiac, or endocrine toxicities was similar when compared to patients who did not develop. Although there was a numeric median PFS difference between patients who did develop visual disorders (18.4 months) and did not develop visual disorders (15.5 month), this was not regarded as statistically significant. However, median PFS of the patients who developed neutropenia upon crizotinib treatment (31.9 months) was found to be more favorable than the patients with normal neutrophil counts (12.8 months) (P = 0.026).
Conclusion: Neutropenia under crizotinib treatment was found to be associated with improved PFS suggesting that neutropenia might be an important determinant in treatment and survival strategies.


Keywords: Anaplastic lymphoma kinase, neutropenia, nonsmall cell lung cancer
Key Message : Patients with ALK-rearranged NSCLC under-crizotinib therapy may have a predictive role of neutropenia.



How to cite this URL:
Gürsoy P, Çakar B, Nart D, Göker E. Predictive role of neutropenia under crizotinib treatment in ALK-rearranged nonsmall cell lung cancer patients: A single-institution retrospective analysis. Indian J Cancer [Epub ahead of print] [cited 2021 Oct 27]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=327236





  Introduction Top


Lung cancer is the leading cause of cancer death worldwide in men and women.[1] Anaplastic lymphoma kinase (ALK) rearranged nonsmall cell lung cancers (NSCLCs) are observed in 3–5% of NSCLCs, and with an estimated 1.3 million new cases of NSCLC worldwide each year, this translates into more than 60,000 ALK-positive NSCLC patients annually.[2] Unfortunately, 40% of these patients present with metastatic disease at initial diagnosis, and the 5-year overall survival (OS) is less than 20% in this group despite new therapeutic strategies.[3],[4]

In cancer, tumor growth and progression depend upon the activity of cell surface membrane receptors that may regulate cell proliferation by controlling intracellular signal transduction pathways and act as a driver in cancer progression.[5] ALK is a receptor tyrosine kinase that is activated by ligand induced homodimerization and triggers multiple pathways including phospholipase C, phosphoinositide 3-kinase (PI3K-AKT), janus kinase signal transducer and activator of transcription and increases cell proliferation. The human ALK gene is located on chromosome 2p23 chromosomal segment, and different ALK fusion proteins were demonstrated to be a driver mutation in various cancers including anaplastic large cell lymphoma, diffuse large B-cell lymphoma, inflammatory myofibroblastic tumors, and NSCLC.[6] The chromosomal rearrangement involving the ALK and echinoderm microtubule-associated protein like 4 was identified in 5% of the patients with NSCLC.[7] In NSCLC, the ALK mutation rate increases in younger aged patients with never or light smoking history, signet ring, and mucinous type adenocancer, women gender, and in patients with malignant pleural effusion.[6],[8] Among patients carrying these features, the incidence of ALK positivity rise to 13%. The gold standard method to diagnose ALK positivity is fluorescence in situ hybridization (FISH).[9]

Targeting ALK rearrangement has been explored as a therapeutic strategy in metastatic/locally advanced lung cancer. The first ALK inhibitor crizotinib improved survival of ALK-positive NSCLC patients in the first- and second-line setting compared to chemotherapy.[10],[11] Subsequently, second-generation (alectinib, ceritinib, and brigatinib) and third-generation (lorlatinib, ensartinib, and entrectinib) ALK inhibitors have demonstrated their activity in the same subsets of patients. These drugs besides uniquely inhibiting ALK activity have some diverse activities on other targets. For instance, crizotinib, beyond its ALK inhibitory effect, also demonstrated inhibitory effect on ROS proto-oncogene 1 (ROS-1) receptor tyrosine kinase and c-mesenchymal epithelial transition factor (c-MET) simultaneously.[12],[13]

Although the previous studies of various ALK inhibitors demonstrated a group side-effect profile, the incidences of adverse events (AEs) varies between agents. Brigatinib demonstrated higher pneumonitis rate, and ceritinib and crizotinib presented with more gastrointestinal toxicity.[14] Visual disturbance rate of crizotinib was found in 65% of the patients in phase 2 studies, and rapid depression of serum testosterone can be seen in the patients treated with crizotinib more frequently.[15],[16],[17]

To our knowledge, none of the ALK inhibitor studies has searched the impact of AEs on treatment outcome. In our study, we planned to explore whether AEs predict any survival differences on patients with crizotinib monotherapy.


  Material and Methods Top


We retrospectively reviewed the medical records of ALK-positive metastatic NSCLC patients admitted to Ege University Medical Oncology Clinic between the years 2013 and 2018. All patients' ALK positivity had been detected by FISH, and coexistence of epidermal growth factor receptor or ROS-1 mutation was not present in any of the patients. Patient demographics, performance status, smoking history, previous treatments, metastatic sites, and AEs were taken for further analyses.

Ethical considerations

This study was approved by the ethics committee of Ege University School of Medicine (Decision number: 19-5.2T/4). All patients gave written informed consent.

Statistical methods

All data were collected and analyzed retrospectively. Statistical analyses were performed using the SPSS 25.0. The data normality and homogeneity were evaluated by Shapiro-Wilk and Levene test, respectively. Descriptive data are expressed as frequency and central tendency measures. Chi-square test or Fisher's exact test, where appropriate, was used to compare clinicopathological data among patient subgroups. Survival durations were estimated with the Kaplan–Meier method, and log-rank test was used to compare survival durations of patient subgroups. progression-free survival (PFS) was defined as the interval between treatment initiations to the date of tumor progression. OS was measured from diagnosis to death from any cause. All P values reported were two-sided, and a P value of less than 0.05 was considered significant.


  Results Top


Thirty-six patients were enrolled to the study. The median age was 51.7 (range: 32–77) years. Fifteen (41.6%) patients were women and 21 (58.3%) were men. In all patients, tumor pathology was adenocarcinoma. Thirty of 36 (83.3%) patients had de novo metastatic disease at initial presentation. Two (5.5%) patients had solitary metastasis. Fourteen (38.8%) patients, 20 (55.5%) patients, and 2 (5.5%) patients had received crizotinib treatment in the first line, second line, and third line metastatic setting, respectively. Of the eight patients who developed neutropenia, four had previously received chemotherapy and the other four patients had not received treatment. The characteristic features of the patient group are shown in [Table 1].
Table 1: Demographic data and clinical characteristics of the patients

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Treatment-related visual disturbances were seen in 8 (22.2%) patients. Hepatotoxicity developed in 8 (22.2%) patients. Seventeen (47.2%) patients had edema and pleural effusion during the treatment period. Endocrine AEs including hypothyroidism and hyperlipidemia were seen in 9 (25.0%) patients. Cardiac toxicity was seen in 3 (8.3%) patients; the most frequent AEs were bradycardia and QT prolongation. The most common hematological AEs were anemia and neutropenia, which was detected in 24 (66.6%) patients and 8 (22.2%) patients, respectively. While grade 3 neutropenia developed in the first 3 months in three patients, neutropenia began to be evident in four patients at 6 and 9 months. Patients had several episodes of neutropenia during the treatment periods. AEs are demonstrated in [Table 2].
Table 2: Adverse events related to treatment with ALK inhibitor crizotinib

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Median follow-up of the patients was 30.1 months (range: 1.2–52.3) (95% confidence interval [CI]: 23.03–37.17). The median PFS of the patients was 16.5 months (95% CI: 21.11–42.69). Although the median PFS of women (20.5 months; 95% CI: 11.6–29.2) was more favorable than men (13.4 months; 95% CI: 8–18.8), the difference did not reach a statistical significance. Median PFS of the patients with denovo metastatic and non-de novo group were 16.4 and 11.3 months, respectively (P = 0.87). There was no difference in terms of PFS between metastatic sites.

The median OS of the patients was 30.1 months (95% CI: 23.6–37.17). The OS was not different between gender groups. The median OS for women and men was 31.5 months (95% CI: 21.2–41.8) and 28.7 months, respectively (95% CI: 18.7–38.7) (P = 0.74).

When PFS was evaluated with respect to AEs, the presence or absence of hepatic, cardiac, or endocrine toxicities did not demonstrate any statistical difference. However, median PFS of the patients who developed neutropenia upon crizotinib treatment were more favorable than patients with normal neutrophil counts. Median PFS of the neutropenic patients was 31.9 months (95% CI: 21.11–42.69) and 12.8 months (95% CI: 9.8–16.7) for non-neutropenic patients (P = 0.026) [Figure 1]. None of the AEs was found to be correlated with OS [Table 3].
Figure 1: Progression-free survival (PFS) of the patients with neutropenia

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Table 3: Relationship between progression-free survival and overall survival with adverse events related to treatment with ALK inhibitor crizotinib

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  Discussion Top


Crizotinib showed promising results in the treatment of metastatic NSCLC patients with ALK rearrangements. Moreover, confirming ALK fusion in these patients, there is no present data that predicts a favorable subgroup for treatment response. The phase 3 PROFILE studies that demonstrated the crizotinib superiority over chemotherapy in the first and second-line setting established distinct AE profile of the drug.[10],[11] The most prominent AEs were vision disorders, diarrhea, nausea, and edema in PROFILE 1014 and 1007 studies.[15],[16]

The sensitivity to crizotinib drug may differ in individuals due to bioavailability. This was hypothesized as a potential reason why some patients developed more AEs. Kurata et al. demonstrated that higher crizotinib concentration is correlated with several AEs in a small subset of patients.[18] The lethal AEs due to crizotinib are a few and consist of interstitial lung disease and QT prolongation. Grade 3–4 AEs are the main restrictions in treatment discontinuation. In PROFILE studies, hepatotoxicity was reported in 13–14% and neutropenia was detected in 11–13% of patients.[10],[11] Although elevated aminotransferase levels should be managed cautiously, the neutropenia clinic is generally mild and febrile neutropenia risk is 0–1%.

In our study, we aimed to determine if AEs may predict any outcome difference in NSCLC patients. The most common grade 3–4 AE in our study was neutropenia with 19.4% frequency. The elevated aminotransferase levels were relatively less than literature. None of the neutropenic patients had required treatment cessation or had febrile neutropenia. After treatment interruption due to AEs, seven of eight patients did continue crizotinib as standard dose; one patient received 200 mg dose due to neutropenia. Treatment was continued without interruption in one patient who developed Grade 2 neutropenia. In one patient who developed grade 4 neutropenia, treatment was interrupted, and then the treatment was restarted with a dose of 200 mg, and grade 4 neutropenia was not observed during the treatment. In the remaining six patients, grade 3 neutropenia developed and the treatment of the patients was interrupted until the neutropenia levels decreased to grade 2 and then continued at the same dose.

In present study among AEs, only neutropenia during crizotinib treatment was found to be associated with improved PFS and a tendency of improved OS, which did not reach a statistical significance. AEs may not be directly correlated with increased drug concentration and bioavailability. Otherwise, patients with high serum crizotinib concentration should interface all AEs together. However, in clinical practice, individual patients sometimes present with single AE during their follow-up. Among our neutropenic patients, only one patient had a grade 1 neuropathy concomitantly and others had no accompanying AEs.

When reviewing the studies with ALK inhibitors, neutropenia seems to be more frequently reported in crizotinib studies. ALEX study that had compared alectinib versus crizotinib in the first-line setting of NSCLC patients reported fewer rates of neutropenia in alectinib arm although the total rates were far more less than PROFILE studies.[19] ASCEND-4 trial also demonstrated 5.0% neutropenia in ceritinib arm.[20] In literature, there was only one case reported with grade 4 neutropenia on crizotinib treatment, after further dose decline and interruption period, switching the treatment from crizotinib to alectinib recovered this AE.[21]

In addition to ALK, crizotinib also inhibits mesenchymal epithelial growth factor/hepatocyte growth factor (HGF). HGF stimulates cell proliferation, invasion, and metastasis via its receptor c-MET activation. c-MET also regulates cancer micro-environment, and c-MET inhibition impairs the reactive recruitment of neutrophils into the tumor.[22] HGF has a role in early hematopoiesis.[23] A phase 2 study with selective c-met inhibitor tivantinib reported 6–21% severe neutropenia in two different drug doses.[24] c-MET inhibition may be the principal factor for neutropenia development; however, our current knowledge is not sufficient to define the reason of heterogeneity in neutropenia. This is mainly because c-MET concentration may vary between individuals.

Immune-related neutropenia due to crizotinib was also reported in the literature. Toyota et al. successfully managed a patient who developed neutropenia on crizotinib treatment with low-dose corticosteroids. However, in that case, the neutropenia did not recover after crizotinib interruption and improved after steroids.[25] In our study, we believe that the neutropenia was most likely not immune related, as patients whose treatment was interrupted due to grade 3–4 neutropenia, the neutrophil counts were fully recovered without any steroid intervention.

Although we demonstrated the relationship between neutropenia and PFS of ALK-positive metastatic NSCLC under crizotinib treatment for the first time in our analysis, our study had some limitations. Due to retrospective nature of the study, our data to define treatment-related symptoms as fatigue, nausea might be inefficient. As all data were explored from patient files, biochemical results were more easily accessible than symptomatic deterioration throughput. The accurate way to discover the answers to related subjects will be to design a prospective study that analyzes c-MET and crizotinib concentrations. Correlating the serum levels with the development of AEs and radiologic evaluation of the disease might more accurately define the possible relations between drug exposure and AEs.


  Conclusion Top


In our study, we demonstrated the predictive role of neutropenia under crizotinib treatment in patients with ALK-rearranged NSCLC. Crizotinib is an agent that had demonstrated survival efficacy in the both first- and second-line treatments of ALK-positive lung cancer. However, there are no clinical or laboratory parameters defining which patient group will benefit more from this drug. We believe that future randomized studies designed to determine the markers that can predict the response to treatment or to define the appropriate patient group more clearly may increase the efficacy of the treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Tanizaki J, Okamoto I, Okamoto K, Takezawa K, Kuwata K, Yamaguchi H, et al. MET tyrosine kinase inhibitor crizotinib (PF-02341066) shows differential antitumor effects in non-small cell lung cancer according to MET alterations. J Thorac Oncol 2011;6:1624-31.  Back to cited text no. 13
    
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