Pediatric Acute Lymphoblastic Leukemia: Clinical Characteristics, Treatment Outcomes, and Prognostic Factors: 10 Years' Experience From a Low- and Middle-Income Country

Abstract

PURPOSE

Acute lymphoblastic leukemia (ALL) represents around 70% of pediatric leukemia. In high-income countries, the 5-year survival is above 90%, but survival in low- and middle-income countries is inferior. This study documents the treatment outcome and prognostic factors of pediatric ALL in Pakistan.

MATERIALS AND METHODS

In this prospective cohort study, all newly diagnosed patients with ALL/lymphoblastic lymphoma from age 1 to 16 years enrolled between January 1, 2012, and December 31, 2021, were included. The treatment was based on the standard arm of the UKALL2011 protocol.

RESULTS

Data from 945 patients with ALL, including 597 males (63.2%), were analyzed. The mean age at diagnosis was 5.73 ± 3.51 years. Pallor was the commonest presentation in 95.2% followed by fever in 84.2% of patients. The mean WBC count was 56.6 ± 103.4 × 10⁹/L. Neutropenic fever followed by myopathy was the most common complication during induction. In univariate analysis, the high WBC count (P ≤ 0.001), intensive chemotherapy (P ≤ 0.001), malnutrition (P = .007), poor response to induction chemotherapy (P = .001), delayed presentation (P = .004), and use of steroids before chemotherapy (P = .023) significantly adversely affected overall survival (OS). The delayed presentation was the most significant prognostic factor in the multivariate analysis (P ≤ .002). After a median follow-up of 54.64 ± 33.80 months, the 5-year OS and disease-free survival (DFS) were 69.9% and 67.8%, respectively.

CONCLUSION

In this largest cohort of childhood ALL from Pakistan, a high WBC count, malnutrition, delayed presentation, previous steroids use, intensive chemotherapy, and poor response to the induction chemotherapy were associated with decreased OS and DFS rates.

INTRODUCTION

Acute lymphoblastic leukemia (ALL) is the most common malignancy in the pediatric population. The 5-year overall survival (OS) in B-cell ALL has exceeded 90% in many clinical trials, whereas outcomes for T-cell ALL are still lagging by 5%-10% in most studies in developed countries.^1,2

CONTEXT

• Key Objective

• What are the factors resulting in inferior treatment outcome in pediatric acute lymphoblastic leukemia (ALL) in a low- and middle-income country (LMIC)?

• Knowledge Generated

• More than 6-month delay in diagnosis and treatment, high WBC count, malnutrition, infection and bleeding during induction, and poor response to induction chemotherapy result in decreased overall survival in pediatric ALL. Neutropenic sepsis and proximal myopathy are the commonest complications during induction chemotherapy. Induction mortality is significantly high with more intensive chemotherapy.

• Relevance

• Early referral to pediatric oncology services, avoidance of steroids before commencement of the treatment of leukemia, and better financial and moral support of the family can improve treatment outcomes of ALL in LMICs.

Around 80% of the children suffering from cancer live in low- and middle-income countries (LMICs), and the treatment outcomes in LMICs are suboptimal.^3-7 The main contributing factors to these reduced survival rates are late presentation, malnutrition, and suboptimal supportive and intensive care facilities, resulting in high treatment-related mortality (TRM). A high abandonment rate also contributes to decreased survival rates in LMICs.^8,9 Children with ALL usually present with signs of bone marrow failure including anemia, thrombocytopenia, and neutropenia with visceromegaly and lymphadenopathy. The intensity of chemotherapy in pediatric ALL is decided according to risk stratification on the basis of age, presenting WBC counts, immunophenotyping, cytogenetics, and molecular features.¹⁰

There is a scarcity of published data on treatment outcomes in pediatric ALL in LMICs like Pakistan. The present study was planned to document the demographics, clinical characteristics, treatment outcomes, and prognostic factors of pediatric ALL in Pakistan. This study will highlight the problems faced by the pediatric oncologists and help them to make necessary changes in their practice to improve the outcome of pediatric ALL in LMICs.

MATERIALS AND METHODS

This prospective cohort study was performed in the pediatric oncology unit at the Combined Military Hospital (CMH), Rawalpindi, Pakistan. All newly diagnosed patients with ALL/lymphoblastic lymphoma (LBL) from age 1 to 16 years enrolled for treatment, between January 1, 2012, and December 31, 2021 (10 years), were included in the study. Patients referred to CMH after receiving less than 1 week of chemotherapy at some other hospital were included in the study. Patients with mixed phenotypic leukemia, abandoning after commencement of treatment (during induction or later), and patients not willing to participate in the study were excluded. The last follow-up for the study was performed on May 31, 2022. Approval from the Institutional Review Board was acquired, and informed consent of the parents/guardians of the patients was obtained.

Detailed medical history and clinical examination were performed at the first admission. The basic demographic and clinical information including age, sex, weight, pallor, temperature, bruising, bleeding, bone pains, respiratory symptoms, lymphadenopathy, and visceromegaly was documented. Other important parameters such as reporting time, nutritional status, previous treatment details, and socioeconomic status were also recorded.

Diagnosis of Leukemia/LBL

The diagnostic workup incorporated a complete blood picture with differential blood cell counts and morphology, bone marrow aspiration, trephine biopsy, immunophenotyping, and molecular and cytogenetic findings. Patients having more than 20% blasts in bone marrow were labeled as ALL, and patients presenting primarily with involvement of nodal or extranodal sites and having <20% lymphoblasts in bone marrow were labeled as LBL. Further subtyping of B-cell lineage/T cell lineage acute lymphoblastic leukemia (B/T ALL) and LBL was made on the basis of the reports of immunophenotyping by flow cytometry and immunohistochemistry of the lymphoid mass. A lumbar puncture was performed to evaluate the CNS status. CNS involvement was classified into three categories as CNS1 (absence of blasts), CNS2 (<5 WBCs/mm³ with blasts), and CNS3 (>5 WBCs/mm³ with blasts) as per standard criteria. Patients with neurologic deficits or radiologic evidence of leukemic intracranial infiltration were also categorized as CNS3. A biochemical profile consisting of hepatic and renal function tests, uric acid, and assessment of cardiac status with echocardiography was performed before the start of chemotherapy.

Treatment and Response Assessment

The treatment was based on the standard arm of the UKALL2011 trial protocol.¹¹ The patients were stratified as standard- and high-risk as per National Cancer Institute (NCI) risk criteria. Standard risk was defined as a WBC count of <50 × 10⁹/L and age between 1 and 10 years. High risk was defined as a WBC count of >50 × 10⁹/L, older than 10 years, T-cell lineage acute lymphoblastic leukemia (T-ALL)/LBL, and patients having high-risk cytogenetics. Standard-risk patients and patients with Down syndrome (Trisomy 21) were treated with three-drug induction (regimen A), and high-risk patients were treated with four-drug (regimen B) induction. All patients received intrathecal methotrexate as per protocol.

For patients with ALL, remission status was assessed by bone marrow examination (BME) on days 15 and 29 of induction in standard-risk patients and on days 8 and 29 in high-risk patients. Patients having ≥25% blasts on day 8/15 BME were labeled as slow early responders and were shifted to regimen C. In patients with LBL, volumetric assessment of the tumor mass was performed by contrast-enhanced computed tomography scan on day 29 of induction. Patients with ≥35% reduction in tumor volume were considered good responders. After induction, B-cell lineage lymphoblastic lymphoma (B-LBL) continued regimen B, whereas T-cell lineage lymphoblastic lymphoma (T-LBL) received regimen C.

The response to chemotherapy was assessed after completing induction chemotherapy. End of induction assessment revealing >25% blasts (M3 marrow) on BME in patients with ALL and <35% volume reduction in patients with LBL were labeled as induction failure and were taken off UKALL2011 protocol treatment. Minimal residual disease assessment on marrow was not performed because of its nonavailability at our setup.

Supportive Care

All patients were hospitalized for the initiation of chemotherapy. Subsequent chemotherapy was given as inpatient or in daycare in outpatient department (OPD). Patients getting chemotherapy in OPD were admitted immediately in the case of fever or any other problem. Patients not admitted in the hospital were reviewed at least twice weekly in outdoor clinics. No prophylactic antimicrobials and colony-stimulating factors were used during the neutropenic period. However, all patients of febrile neutropenia were treated as an inpatient with broad-spectrum intravenous antibiotics. The fever was defined as a single oral temperature of >38°C or two readings of >37.5°C at least 2 hours apart. Neutropenia was defined as an absolute neutrophil count (ANC) of <1,000 cells per microliter. Febrile patients with an ANC of <1,000 were treated with a combination of piperacillin-tazobactam and amikacin. Vancomycin or teicoplanin was added if central venous line infection was suspected. Piperacillin-tazobactam was swapped with meropenem if fever continued after 48 hours. Amphotericin B was added empirically if the fever continued beyond 96 hours. Blood and blood products transfusion was given on a regular basis. The hemoglobin transfusion threshold was 8.0 g/dL. Thresholds for platelet transfusion were 10 × 10⁹/L for asymptomatic patients and 20 × 10⁹/L for febrile patients.¹²

Statistical Analysis

SPSS 25.0 software was used for statistical analysis, and t-test and chi-square tests were used for comparison between continuous and categorical variables. Frequencies and percentages were calculated for categorical variables. The time from the date of morphological complete remission (CR) until relapse or death was defined as disease-free survival (DFS). The time from the day of diagnosis to the day of the last follow-up or death was defined as OS. Censoring was performed at the date of last contact (May 31, 2022).

The median follow-up time was 62.69 ± 36.48 months (IQR, 27.17-93.17 months). Relapses were defined by morphology, and site involvement by the presence of leukemic blasts (marrow [≥5%], CNS [≥5 × 10⁶/L]). Kaplan-Meier survival curves estimated DFS and OS and were compared using the log-rank test. The Cox proportional hazard regression model was used for univariate and multivariate analyses of prognostic factors with 95% CIs. P values of <0.05 were considered significant. The study was approved by the ethics committee and was performed according to the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All procedures followed were according to the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. All patients gave their informed consent before their inclusion in the study. Details that might disclose the identity of the patients under study were omitted. Informed consent was obtained from all patients for being included in the study.

RESULTS

Demographics and Clinical Characteristics

During the study period, a total of 970 new patients with ALL were registered at the Pediatric Oncology Department of CMH Rawalpindi. Twenty-five patients abandoned the treatment during various phases of treatment, including 10 patients during induction, 10 after induction, and five in later phases. These patients were excluded from the study. Data of 945 patients, including 597 males (63.2%) and 348 females (36.8%), were analyzed. Only 231 (24.4%) patients were children of army personnel. The mean age at diagnosis was 5.73 ± 3.51 years (ranging from 1 to 16 years). The mean time to reach the pediatric oncologist was 50.79 ± 55.95 days (ranging from 2 to 535 days).

The most common presenting symptom was pallor in 900 (95.2%) followed by fever in 796 (84.2%) and bruising/bleeding in 405 (42.9%). Physical examination revealed pallor in 900 (95.2%) and visceromegaly in 785 (83.2%) patients. The mean WBC count was 56.6 ± 103.4 × 10⁹/L (ranging from 0.29 to 996 × 10⁹/L). An initial WBC of >50 × 10⁹/L was seen in 289 (30.6%) patients. The mean hemoglobin level was 7.41 ± 2.57 g/dL, and the mean platelets count was 70.68 ± 98.94 × 10⁹/L. Pre–B-cell lineage acute lymphoblastic leukemia (B-ALL) was the most common subtype of ALL documented in 774 (81.9%) patients followed by T-ALL in 104 (11.0%) patients. Forty-three (4.6%) patients were diagnosed as ALL on the basis of morphology as immune phenotyping was missing or inconclusive. There were 24 (2.5%) patients with LBL including 20 (83.3%) T-LBL and 4 (16.7%) B-LBL. Sixteen (1.7%) patients had CNS disease. Only 2 (0.33%) boys had testicular disease. Results of the cytogenetic analysis were available in 561 (59.4%) patients. Most patients, 385 of 561 (70.4%), had normal molecular ALL panel and karyotyping. TEL-AML-1 was documented in 55, E2A-PBX1 in 38, hyperdiploidy in 49, and BCR-ABL1 translocation in 10 patients. Three patients had Down syndrome (Trisomy 21; Table 1).

TABLE 1.

Patient Characteristics and Chemotherapy Response (n = 945)

Treatment Outcome

Treatment, response assessment, and induction outcome.

As per NCI criteria, 481 (50.9%) patients categorized as standard-risk received regimen A induction and 464 (49.1%) patients categorized as high-risk received regimen B induction. Response to chemotherapy was assessed by BME on day 8 in regimen B and day 15 in regimen A. BME was not performed in 24 patients with LBL and 36 patients with ALL including 24 patients that expired before the assessment date and 12 patients that were too critical to get the BME done. Of the 885 BME, 783 (88.5%) had <25% blasts (rapid early responder). Factors associated with slow early response were older age (19.0% in age >10 years and 9.9% in age <10 years; P = .001), high WBC count (6.8% in WBC <50 × 10⁹/L, 14.1% in WBC 50-100 × 10⁹/L, and 29.2% in WBC >100 × 10⁹/L groups; P ≤ 0.001), and high-risk group (20.6% in high-risk and 3.1% in standard-risk groups; P ≤ 0.001). During induction, 116 of 945 (12.3%) patients expired, and of the remaining 829 patients, 815 of 829 (98.3%) achieved morphological CR, 11 of 829 (1.3%) had M2 BME (5%-25% blasts), and only 3 of 829 (0.3%) had the refractory disease (RD; >25% blasts). Neutropenic fever was the most common complication documented in 764 (80.8%) patients during induction chemotherapy. Steroids-induced proximal myopathy was the second most common complication in 615 (65.1%) patients (Table 2).

TABLE 2.

Induction Outcome (n = 945)

Mortality.

During the study period, 284 (30%) patients expired including 184 of 284 (64.8%) TRM and 100 of 284 (35.2%) relapse-related mortality. The TRM was 16.6% in the standard-risk group and increased to 22.4% in the high-risk group (P = .025; odds ratio [OR] for the high-risk group 1.195; 95% CI, 1.031 to 1.384). The TRM was 18.1 in normally nourished patients and increased to 34.5% in severely malnourished patients (P = .001). The TRM was 22.1% in febrile neutropenic patients and decreased to 8.3% in patients without infection (P ≤ 0.001; OR, 3.143 for infection; 95% CI, 1.804 to 5.477).

Among the TRM patients, 116 of 184 (63.0%) deaths were recorded during induction including 50 of 481 (10.4%) in the standard-risk group and 66 of 464 (14.2%) in the high-risk group (P = .073). In univariate analysis, high WBC count, neutropenic sepsis, and malnutrition were associated with high induction mortality. The TRM was 10.2% in patients having a WBC of <10 × 10⁹/L and increased to 19.0% in patients having a WBC of >50 × 10⁹/L (P = .009). Febrile neutropenia was documented in 764 (80.9%) patients and 112 of them (14.7%) expired, whereas the TRM was 2.2% in only 4 of 181 patients without infection (P ≤ 0.001). The induction mortality was 11.6% versus 21.8% in well-nourished and severely malnourished patients, respectively (P = .014).

Age, sex, subtype of ALL, intensity of chemotherapy, delay in starting chemotherapy, and previous steroids use had no statistically significant effect on induction mortality. Neutropenic sepsis (85 of 116), bleeding (15 of 116), hepatic failure (7 of 116) were the main causes of induction mortality. Only one patient died of tumor lysis syndrome. Another 68 patients expired after induction including 16 (8.7%) during consolidation, 5 (2.7%) during interim maintenance, 20 (10.8%) during delayed intensification, and 27 (14.6%) during maintenance chemotherapy.

Relapse.

Of 761 patients (excluding 184 TRM patients), 120 (15.8%) patients relapsed, including 53 (13.2%) in the standard-risk group and 67 (18.6%) in the high-risk group (P = .041; OR for the standard-risk/high-risk group = 0.666; 95% CI, 0.450 to 0.986). Factors associated with high relapse rate were older age (23.8% in age >10 years and 13.9% in age <10 years; P = .004; OR for age group <10 years/>10 years = 0.518; 95% CI, 0.331 to 0.811), male sex (17.8% in males and 12.2% in females; P = .039; OR male/female sex = 1.565; 95% CI, 1.020 to 2.40), high WBC count (13.8% in WBC <50 × 10⁹/L; 18.3% in WBC 50-100 × 10⁹/L and 23.0% in WBC >100 × 10⁹/L; P = .038), and poor response to induction chemotherapy (100% in RD v 15.5% in CR cases; P = .005). The patients initially misdiagnosed as immune thrombocytopenic purpura and Juvenile idiopathic arthritis who used prednisone 2 mg/kg once a day for more than 4 weeks before starting chemotherapy also had a high relapse rate (35.0% v 15.2%; P = .057). The most common site of relapse was bone marrow in 65 (54.2%) patients, followed by CNS in 41 (34.2%), ocular in 7 (5.8%), testicular in 6 (5%), and lymph nodes in 1 (0.8%) patient. Of the 120 relapse patients, 85 (70.8%) relapses occurred during treatment and 100 of 120 (83.3%) expired.

OS and DFS.

After a median follow-up of 62.47 ± 36.48 months, 5-year OS and DFS rates were 69.9% and 67.8%, respectively. The OS at 2 years, 5 years, and 10 years was 74.9%, 70.6%, and 69.9%, respectively. The DFS at 2 years, 5 years, and 10 years was 74.0%, 68.3%, and 67.8%, respectively.

We also looked at various factors influencing OS and DFS. Delay in reporting to the oncologist, nutritional status, WBC count at the time of presentation, use of steroids before starting induction chemotherapy, risk group as per NCI guidelines, and end of induction remission status had a statistically significant influence on OS and DFS. Age, sex, and ALL subtypes had no statistically significant impact on OS and DFS (Table 3).

TABLE 3.

Univariate and Multivariate Cox Regression Analyses of Clinical and Laboratory Characteristics in Pediatric ALL Cases (n = 945)

Delay in reporting to the pediatric oncologist (>6 months) for treatment was associated with decreased OS. The OS was 70.8% and 51.2%, respectively, in patients getting treatment before and after 6 months of symptoms (P = .004). It was associated with a high relapse rate of 22.0% versus 12.3% (P = .069) and a high mortality of 48.8% versus 29.2% (P = .007). Malnutrition and high WBC also adversely affected survival. The OS was 72% in well-nourished children and decreased to 56.3% in severely malnourished children (P = .007; Fig 1). The OS was 73.5% in children having a WBC count of <50 × 10⁹/L and decreased to 59.9% in children having a WBC count of >100 × 10⁹/L (P = .006; Fig 2). The use of steroids before starting induction chemotherapy also resulted in decreased OS. The OS decreased from 70% in patients that had no treatment before induction to 50% in patients that used steroids (P = .023). OS was also affected by the risk groups and treatment intensity. The OS was 74.8% in the standard-risk group and decreased to 64.9% in the high-risk group (P ≤ 0.001; Fig 3). Postinduction remission status also influenced the OS. The OS was 80.5% in patients achieving CR, decreased to 52.9% in partial remission, and was 33.3% in RD patients (P = .001).

FIG 1.

OS in pediatric ALL, according to the nutritional status at presentation. ALL, acute lymphoblastic leukemia; OS, overall survival.

FIG 2.

OS of pediatric ALL, according to the WBC count at presentation. ALL, acute lymphoblastic leukemia; OS, overall survival.

FIG 3.

OS of pediatric ALL, according to the risk groups. ALL, acute lymphoblastic leukemia; OS, overall survival.

Multivariate analysis was performed for the following variables: reporting time to the oncologist, use of steroids before starting chemotherapy, nutritional status, WBC counts, risk group, and end of induction remission status. More than 6 months of delay in reporting to the oncologist for treatment was found to be the most statistically significant factor (P = .002) followed by end of induction remission status (P = .008).

DISCUSSION

The pediatric oncology department of CMH Rawalpindi is the fourth largest pediatric oncology unit of the country treating around 350 new patients with pediatric cancer annually. Although it is primarily responsible for treating army personnel and their dependents, because of the scarcity of dedicated facilities for hematology and oncology in the country, many civilians, especially from northern Pakistan, are also treated here. To our knowledge, the present study has the largest cohort of pediatric ALL consisting of patients from all over the country including more than three-quarter patients of the civilian population.

One of the major reasons for inferior outcomes in the LMICs is the abandonment of the treatment. Various studies from Pakistan, regional countries, and other LMICs have reported an abandonment rate between 12.8% and 46.1%.^5,13-16 However, in the present study, the abandonment rate was only 2.6% (these patients were excluded from data analysis for treatment outcomes). This is mainly due to detailed counseling before commencing the treatment, continuous financial and psychosocial support, and education of the families during the treatment. Moreover, traveling expenses are paid to the nonaffording families living at a significant distance from the hospital.

In LMICs, high induction mortality is a major reason for poor outcomes and has been reported from 11% to 23%.^7,17 In the present study, the induction mortality was 12.3%. Two other studies from Pakistan have reported similar induction mortality. Fadoo et al¹³ and Asim et al⁸ have reported the induction mortality of 11.5% and 12.9% from Karachi and Lahore, respectively. Malnutrition and the use of steroids were associated with high induction mortality in our study. Cancer and its treatment worsen the nutritional status of already malnourished children because of anorexia, inflammation, and increased metabolic rate. Increased morbidity and mortality in pediatric leukemia in malnourished children have been reported by various studies from LMICs.^18-21 In the present study, neutropenic sepsis followed by bleeding was the main cause of nonrelapse mortality. This is similar to other studies from LMICs.^7,13 The main reason for high induction mortality in our setup was the limited availability of intensive care facilities. Infection was also the leading cause of death during the postinduction period, mainly because of delays in commencing appropriate broad-spectrum antibiotics.

Many patients belong to rural areas with very meagre health care facilities, limited availability of broad-spectrum antibiotics, and limited transport services to reach tertiary care hospitals for optimal care. Delayed diagnosis is one of the contributing factors to decreased cure rates for cancer in low-income countries.^22-24 In the present cohort, referral to the pediatric oncologist was quite late. The mean reporting time to the pediatric oncologist was 50.79 ± 55.95 days, and 20% of patients presented after 2 months. This delayed presentation was associated with a statistically significant difference in OS and DFS. Univariate analysis revealed that the OS was 70.8% and 51.2% (log-rank P = .004) and the DFS was 68.6% and 51.2% (log-rank P = .011) in patients reported to the oncologist before and after 6 months of the onset of symptoms. Multivariate analysis also confirmed this finding. This difference in survival can be because of the following reasons: delayed presentation results in high WBC counts and worsening malnutrition. A high WBC count of >50 × 10⁹/L requires more intensive chemotherapy and is associated with high TRM, poor response to chemotherapy, and high relapse rate. This delayed presentation is multifactorial. Many patients presented initially with low platelet counts to general pediatricians and were treated as immune thrombocytopenia with steroids. Some patients presenting with joint pains were diagnosed as Juvenil idiopathic arthritis and were treated with steroids and even methotrexate as a disease-modifying agent. The mean presenting time of patients who used and did not use steroids was 134.88 ± 125.44 and 47.12 ± 47.08 days, respectively. To our knowledge, this association has not been published previously. Awareness and education of the health care providers, especially primary care pediatricians, are required. They should be sensitized to think about leukemia as a possible diagnosis in children presenting with low platelets and joint pains. An early referral will improve the outcome of ALL in children.

In conclusion, to our knowledge, in this largest cohort of childhood ALL from Pakistan, neutropenic sepsis and bleeding are the two major causes of TRM. Steroids use before starting chemotherapy, poor nutritional status, high WBC count at presentation, intensive chemotherapy, and poor response to induction chemotherapy were associated with decreased OS and DFS rates. Delay in reporting to a pediatric oncologist was the most significant prognostic factor.

DATA SHARING STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

AUTHOR CONTRIBUTIONS

Conception and design: Ishfaq Ahmad, Tariq Ghafoor, Muhammad Tahir, Awais Arshad

Financial support: Ishfaq Ahmad, Tariq Ghafoor

Administrative support: Shakeel Ahmed, Awais Arshad

Provision of study materials or patients: Tariq Ghafoor, Anwar Ullah, Shaista Naz, Muhammad Tahir, Awais Arshad, Tariq Azam Khattack

Collection and assembly of data: Ishfaq Ahmad, Shaista Naz, Muhammad Tahir, Shakeel Ahmed, Awais Arshad, Asghar Ali, Tariq Azam Khattack, Fatima Batool

Data analysis and interpretation: Ishfaq Ahmad, Tariq Ghafoor, Anwar Ullah, Muhammad Tahir, Tariq Azam Khattack

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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No potential conflicts of interest were reported.