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The effect of granulocyte colony-stimulating factors on survival parameters in pediatric patients with acute lymphoblastic leukemia: a retrospective study

Published:January 25, 2022DOI:https://doi.org/10.1016/j.transci.2022.103366

      Abstract

      Objective

      There is a paucity of data concerning the use of granulocyte colony-stimulating factors (G-CSFs) in pediatric patients with acute lymphoblastic leukemia (ALL). The aim of the present study was to evaluate the effect of G-CSF use on relapse-free and overall survival in 358 consecutive, newly diagnosed pediatric ALL patients uniformly treated at the same institution between April 2012 and April 2020.

      Materials and Methods

      Patients were evaluated in two separate periods, based on the G-CSF treatment approach. All patients who underwent ALL treatment between April 2012 and December 2016 received G-CSF (G-CSF+ arm; n: 245) in the course of the protocol for reducing the risk of febrile neutropenia and/or inducing neutrophil recovery to prevent any treatment delay. No patients after December 2016 received G-CSF, even if they belonged to the high-risk group, and these were included in the G-CSF arm (n: 113).

      Results

      Estimated mean relapse-free (106.5 months; 95 % CI 102−110.8 vs 82 months 95 % CI 75.2−88.9; p: 0.794) and overall survival (111.4 months; 95 % CI 108−114.8 vs 85 months 95 % CI 80.4−89.8; p: 0.431) rates were similar between the G-CSF+ and G-CSF groups.

      Conclusions

      Our findings indicate that G-CSF use during ALL treatment had no effect on relapse rates or overall survival.

      Keywords

      1. Introduction

      Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, accounting for almost 25 % of all childhood malignancies [
      • Ward E.
      • DeSantis C.
      • Robbins A.
      • et al.
      Childhood and adolescent cancer statistics, 2014.
      ,
      • Steliarova-Foucher E.
      • Comombet M.
      • Ries L.A.G.
      • et al.
      International incidence of childhood cancer, 2001-10: a population-based registry study.
      ]. The last four decades have witnessed remarkable progress in the treatment of pediatric ALL. Long-term survival rates are presently 85–90 % with the application of current, multidrug, risk-adapted chemotherapy regimens, making pediatric ALL treatment a genuine success in the history of modern oncology [
      • Hunger S.P.
      • Mullighan C.G.
      Acute lymphoblastic leukemia in children.
      ].
      However, despite these achievements, 2.5–5 % of patients will still die during induction or in first complete remission as a result of treatment [
      • Stary J.
      • Zimmermann M.
      • Campbell M.
      • et al.
      Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002.
      ,
      • Zawitkowska J.
      • Lejman M.
      • Drabko K.
      • et al.
      First-line treatment failure in childhood acute lymphoblastic leukemia: the Polish pediatric leukemia and lymphoma study group experience.
      ]. Infectious complications are the leading cause of treatment-related mortality. Children with ALL have a 1–2.4 % risk of infection-related mortality because of profound immunosuppression as a result of the primary disease itself and of the highly myelosuppressive chemotherapy required during all stages of treatment [
      • Afzal S.
      • Ethier M.C.
      • Dupuis L.L.
      • et al.
      Risk factors for infection-related outcomes during induction therapy for childhood acute lymphoblastic leukemia.
      ,
      • O’Connor D.
      • Bate J.
      • Wade R.
      • et al.
      Infection-related mortality in children with acute lymphoblastic leukemia: an analysis of infectious deaths on UKALL2003.
      ].
      Granulocyte-colony stimulating factors (G-CSFs) are frequently used to prevent infections, shorten hospitalization times, and avoid treatment delays in medical oncology and hematology. Recently published EORTC, ASCO, and NCCN guidelines recommend prophylactic use of myeloid growth factors to reduce the risk of febrile neutropenia (FN) in cases with an anticipated risk of at least 20 % [
      • Aapro M.S.
      • Bohlius J.
      • Cameron D.A.
      • et al.
      Update of EORTC guidelines fort he use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours.
      ,
      • Smith T.J.
      • Bohlke K.
      • Lyman G.H.
      • et al.
      Recommendations fort he use of WBC growth factors: american society of clinical oncology clinical practice guideline update.
      ,
      • National Comprehensive Cancer Network
      NCCN clinical practice guidelines in oncology: hematopoietic growth factors (version 2.2020).
      ]. Although all adult/pediatric treatment protocols for ALL are associated with a high risk of FN, data regarding the use of G-CSFs in the management of ALL patients are scarce, and there is little evidence for or against the use of G-CSFs in this patient population. On the other hand, the use of G-CSF as supportive care has been associated with an increased relapse risk in pediatric patients with acute myeloid leukemia [
      • Lohmann D.J.
      • Asdahl P.H.
      • Abrahamsson J.
      • et al.
      Use of granulocyte colony-stimulating factor and risk of relapse in pediatric patients treated for acute myeloid leukemia according to NOPHO-AML 2004 and DB AML-01.
      ]. Due to the theoretical concern that G-CSFs may induce proliferation of leukemic stem cells, resulting in treatment resistance and the scarcity of data supporting G-CSFs in terms of survival parameters, the routine use of G-CSFs in pediatric ALL is not recommended.
      The purpose of the present study was to evaluate the effect of G-CSF use on survival parameters in pediatric ALL patients receiving the same protocol Acute Lymphoblastic Leukemia Intercontinental Berlin-Frankfurth-Münster (ALL IC-BFM 2009).

      2. Materials and methods

      2.1 Study design and data collection

      The data in this retrospective single-center study were obtained from patient files. The study protocol was approved by the local review board. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All parents provided written informed consent authorizing the use of their children’s personal information for research purposes.

      2.2 Study population

      The study involved 358 consecutive, newly diagnosed pediatric ALL patients uniformly treated at the same institution between April 2012 and April 2020. Patients were divided into two study periods based on the G-CSF treatment approach. In line with the local policy of our institution, all patients who underwent ALL treatment between April 2012 and December 2016 received G-CSF (G-CSF+ arm) in the course of the protocol in order to reduce the risk of FN and/or induce neutrophil recovery to prevent any treatment delay. Patients in the G-CSF arm received at least one dose of G-CSF during one or more phases of the chemotherapy protocol. However, our G-CSF use strategy changed in January 2017. No patients after that time received G-CSF, even if they belonged to the high-risk group and were scheduled to receive G-CSF according to the protocol (G-CSF arm). Eleven patients with infant leukemia and eight with a short follow-up period (<1 month) were excluded from the analysis.

      2.3 Study protocol

      All patients were treated using the ALL IC-BFM 2009 protocol []. Patients were stratified into three risk groups (standard, intermediate, and high) based on age, white blood cell count at presentation, early treatment response, cytogenetics, molecular genetic abnormalities, and multicolor flow cytometric evaluation of measurable residual disease at day 15 of induction. According to the study protocol, high-risk patients were scheduled to receive G-CSF. As previously described, after 1 January 2017, no patient received G-CSF in the full course of treatment, irrespective of risk stratification. Supportive care policies were in line with the recommendations of the study protocol.

      2.4 Statistics

      Descriptive statistics, frequency, and median (min-max) values were calculated for categorical and quantitative variables. Comparisons of the study arms were performed using the chi-square and Mann-Whitney U tests for categorical and numeric variables, respectively. Overall and relapse-free survival were estimated using the Kaplan-Meier method, differences in survival being compared using the log-rank test and Cox regression. A p value <.05 was considered statistically significant. All statistical analyses were performed on IBM SPSS Statistics for Windows, Version 21.0 software (IBM Corp, Armonk, NY, USA).

      3. Results

      The demographic, clinical characteristics, and long-term outcomes of the study cohort are summarized in Table 1. The study involved a total of 358 patients (245 G-CSF+ and 113 G-CSF). Twelve (5%) and two (1.8 %) patients presented with central nervous system involvement at diagnosis in the G-CSF+ and G-CSF- arms, respectively. The study groups were comparable in terms of sex, age, immunophenotype, white blood cell count, central nervous system involvement at diagnosis, risk classification according to the ALL IC-BFM 2009 protocol, and of numbers of members with Down syndrome. The median follow-up times of surviving patients in the G-CSF+ and G-CSF- groups were 54.9 (1−119) and 17.36 (1−91) months, respectively. Twenty-eight (11.4 %) patients from the G-CSF+ arm relapsed during the study period, and 17 (6.2 %) died. The corresponding values in the G-CSF- group were seven (6.2 %) and seven (6.2 %), respectively. Mean relapse-free and overall survival times were similar between the G-CSF+ and G-CSF- groups (Fig. 1).
      Table 1Demographic, clinical and outcome parameters of the study cohort.
      ParameterG-CSF+ (n: 245)G-CSF- (n:113)p
      Gender (male/female) (n)153/9263/500.229
      Age (median-range)5.15 (1−17.7)4.45 (1−17.9)0.45
      Immunophenotype (n)
      B-ALL20199
      T-ALL40130.362
      MPL41
      WBC (/mm3) (median-range)11000 (200−474000)11935 (1180−600056)0.959
      Risk stratification (n)
      Standard60310.08
      Intermediate11063
      High6519
      Missing10
      CNS involvement at diagnosis (n; %)12 (5%)2 (1.8 %)0.156
      Down syndrome (n; %)6 (2.4 %)5 (4.4 %)0.314
      Follow-up (months) (median-range)54.9 (1−119)17.36 (1−91)
      Relapse (n; %)28 (11.4 %)7 (6.2 %)0.121
      Death (n; %)17 (6.9 %)7 (6.2 %)
      RFS (mean) (months; 95 % CI)106.5 (102−110.8)82 (75.2−88.9)0.794
      OS (mean) (months; 95 %CI)111.4 (108−114.8)85 (80.4−89.8)0.431

      4. Discussion

      The current study retrospectively evaluated the effect of G-CSFs on ultimate outcome parameters in pediatric patients with ALL. Patients received a uniform protocol throughout the study, and the study groups were comparable in terms of demographic and clinical parameters. No significant effect of G-CSF use on relapse-free or overall survival was observed. Mainly because of the retrospective nature of the study, we did not retrieve data regarding FN episodes, duration of hospitalization, or treatment delays.
      Myeloid colony-stimulating factors are frequently used in adult oncology practice to reduce the incidence of FN and infectious complications, shorten the length of hospital stay, and to prevent any delay in administering the planned courses of myelosuppressive chemotherapy. However, evidence-based data regarding the safety and efficacy of G-CSFs in the treatment armamentarium of pediatric ALL are scarce. A randomized, crossover study from the Children Cancer Group involving 287 newly diagnosed pediatric ALL patients evaluated the effect of G-CSFs on hematopoietic toxicities, supportive care requirements, and outcome parameters [
      • Heath J.A.
      • Steinherz P.G.
      • Altman A.
      • et al.
      Human granulocyte colony-stimulating factor in children with high-risk acute lymphoblastic leukemia: a children’s cancer group study.
      ]. Prophylactic use of G-CSFs shortened periods of neutropenia, but did not significantly reduce episodes of FN or serious infections. Neither length of hospitalization nor times to completion of induction therapy were altered using G-CSF. There was also no difference in terms of six-year event-free survival between the study arms in the context of G-CSF use. A systematic review of six studies involving a total of 333 patients presenting with pediatric ALL concluded that the use of colony-stimulating factors significantly reduced FN episodes and shortened length of hospital stay. However, there was no effect in terms of shortening the duration of neutropenia or preventing treatment delays. The authors were unable to obtain data regarding important outcome parameters such as relapse rates and overall survival [
      • Sasse E.C.
      • Sasse A.D.
      • Brandalise S.
      • et al.
      Colony stimulating factors for prevention of myelosupressive therapy induced febrile neutropenia in children with acute lymphoblastic leukemia.
      ].
      The lymphoblasts of a 20-month-old boy with ALL were shown to express receptors for G-CSF in one report, and their proliferation was induced with G-CSF [
      • Inukai T.
      • Sugita K.
      • Lijima K.
      • et al.
      Leukemic cells with 11q23 translocations express granulocyte colony-stimulating factor (G-CSF) receptor and their proliferation is stimulated with G-CSF.
      ]. The need for data regarding long-term safety of prophylactic G-CSFs is still unmet, but is of the utmost importance. As expected, the follow-up period among patients in the G-CSF arm was too short to draw definitive conclusions regarding relapse and survival. However, at the time of writing we observed no sign of an increased relapse risk or shortened survival with the use of G-CSFs.
      The main limitations of the present study are its retrospective design and relative short-follow up period, and the limited number of patients making it impossible to show any difference in outcome parameters, if these really exist. On the other hand, patients in the G-CSF+ arm not only received G-CSF on the basis of the protocol applied, but also in line with the decision of primary physicians. During the first study period, patients were treated with G-CSF based on physician discretion, irrespective of risk stratification. All patients in the G-CSF+ arm received at least one dose of the drug, but there was no uniform strategy concerning the use of G-CSF in terms of dosage, frequency, or duration of treatment. It is therefore quite possible that a standard application of G-CSF would modify our findings.
      Our findings indicate that the use of G-CSF during the treatment of ALL had no effect on relapse rates or overall survival. However, further prospective, randomized studies are now needed to confirm the safety and efficacy of G-CSF use in pediatric ALL.

      Source of funding statement

      None.

      Author contributions

      All authors have contributed in different ways to the current manuscript. All have reviewed and agreed upon the content of this manuscript. The contribution of authors are summarized below.
      Design of the study: Sibel Akpınar Tekgündüz, Ali Aycicek
      Collection and assembly of data: Sibel Akpınar Tekgündüz, Ezgi Pasli Uysalol, Ferhan Akici
      Data analysis and interpretation: Sibel Akpınar Tekgündüz, Ali Aycicek, Cengiz Bayram
      Manuscript preparation: Sibel Akpınar Tekgündüz, Gul Nihal Ozdemir
      Final review and approval of the manuscript: All authors.

      Declaration of Competing Interest

      The authors report no declarations of interest.

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