Users Online: 1612
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
LEUKEMIAS: ORIGINAL ARTICLE
Year : 2014  |  Volume : 3  |  Issue : 4  |  Page : 203-205

Response to imatinib mesylate in childhood chronic myeloid leukemia in chronic phase


1 Department of Medical Oncology, Nizams Institute of Medical Science, Hyderabad, India
2 Department of Medical Oncology, Basavatarakam Indo American Cancer Hospital and Research Institute, Hyderabad, India
3 Director, Tata Memorial Hospital, Aganampudi, Vishakhapatnam, Andhra Pradesh, India
4 Department of Pathology, Nizams Institute of Medical Science, Hyderabad, India

Date of Web Publication15-Oct-2014

Correspondence Address:
Vijay Gandhi Linga
Department of Medical Oncology, Nizams Institute of Medical Science, Hyderabad
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-330X.142961

Rights and Permissions
  Abstract 

Introduction: Childhood chronic myeloid leukemia (CML) accounts for less than 3% of all childhood leukemias, hence, data on imatinib (IM) in adult CML patients has been largely extrapolated to children. We have analyzed our data to add to the existing literature. Aims: Primary objective is to assess the progression-free survival (PFS). Secondary objective are cytogenetic response, overall survival (OS), and toxicities. Settings and Design: This is a retrospective analysis from the case records from a single institution. Materials and Methods: Institutional ethics committee approval was obtained. All the children diagnosed CML in chronic phase (CML-CP) aged less than 18 years registered between 2000 and 2009 were enrolled. All the patients were started on IM at 260 mg/m 2 . Statistical Analysis: Kaplan-Meier curves were used to calculate the PFS and OS. Results: There were 64 children with median age of 13 years (range, 1-18) with male predominance (male:female (M: F) - 1.85:1). Sixty-one patients (95.4%) achieved complete hematological response (CHR) at median of 8 weeks. Thirty-seven (57.8%) patients had evaluation of cytogenetic response and were subjects for outcome analysis. The median time to best cytogenetic response evaluation was 13 months (range, 4-52). Twenty-nine patients (78.3%) achieved complete cytogenetic response (CCyR). At a median follow-up of 36 months (range 5-75), 21 (56.8%) remained progression free and 35 (94.5%) are alive. Adverse events were tolerable. Conclusions: PFS at a median follow-up of 36 months is 56.8% and OS 94.5%.

Keywords: Childhood chronic myeloid leukemia, cytogenetic responses, imatinib mesylate, survival


How to cite this article:
Linga VG, Ganta RR, Kalpathi KI, Gundeti S, Rajappa SJ, Digumarti R, Paul TR, Tandon A. Response to imatinib mesylate in childhood chronic myeloid leukemia in chronic phase. South Asian J Cancer 2014;3:203-5

How to cite this URL:
Linga VG, Ganta RR, Kalpathi KI, Gundeti S, Rajappa SJ, Digumarti R, Paul TR, Tandon A. Response to imatinib mesylate in childhood chronic myeloid leukemia in chronic phase. South Asian J Cancer [serial online] 2014 [cited 2019 Sep 20];3:203-5. Available from: http://journal.sajc.org/text.asp?2014/3/4/203/142961


  Introduction Top


Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the expansion of a clone of hematopoietic cells that carries the Philadelphia chromosome (Ph) t (9;22)(q34;q11) resulting in a novel fusion gene, BCR-ABL, which encodes a constitutively active tyrosine kinase. Imatinib (IM) is a relatively specific inhibitor of the BCR-ABL tyrosine kinase which revolutionized the treatment of CML resulting better outcomes than with traditional chemotherapy/interferon. [1]

CML in children is rare as it accounts less than 3% of childhood leukemias with an annual incidence of one case per 1 million children in western countries; hence, data on IM in adult CML patients has been largely extrapolated to children. In recent time, there are reports on growth and endocrine abnormalities with IM in children. [2] The aim of this study was to look for the outcomes of pediatric CML patients on IM and its tolerability.


  Materials and Methods Top


Children less than 18 years with CML-CP, registered in Department of Medical Oncology from a period of 2000 to 2009 year were enrolled. Their hospital records were analyzed for duration of symptoms, size of spleen, complete blood picture, bone marrow aspiration, and cytogenetics or BCR-ABL quantitative PCR (real-time PCR) at the time of diagnosis. The criteria for diagnosis of CML-CP is documentation of t(9;22) or the BCR-ABL fusion gene, bone marrow blast <10%, and does not meet the criteria of accelerated phase or blast crisis. [1]

Institutional review board approval was taken and individual patient's/parent's/guardian's informed and written consent was taken before initiation of treatment. All the children were started on IM at a dose of 260 mg/m 2 . [3] All children had their hemograms done fortnightly till complete hematological response (CHR) was obtained and thereafter monthly. Karyotyping is ordered at the time of diagnosis and percentages of Ph positive cells are noted. Marrow cytogenetic testing was repeated at 6, 12, and 18 months after the initiation of therapy. Once complete cytogenetic response (CCyR) is achieved then karyotyping is requested annually. [4] Molecular response was assessed by reverse transcription PCR (RQ-PCR) whenever feasible.

For the patients who had suboptimal response to treatment, we requested for further investigations as per standard guidelines. [1] None of the patients in our study could afford for mutational analysis, second-line tyrosine kinase inhibitors (TKIs), transplant, only option left was increasing to 340 mg/m 2 . After dose hike, the response is assessed with hemogram fortnightly till CHR and cytogenetic every 6 months till CCyR. [1],[4]

End points

The primary end point was progression-free survival (PFS), which was referred as the time from the start of IM to the following events: Death from any cause during treatment, progression to the accelerated phase or blast crisis of CML, or loss of a complete hematologic or cytogenetic response.

Secondary end points were response to treatment (attainment of CHR and CCyR), overall survival (OS), and side effects to IM treatment. The CHR is defined as a leukocyte count <10 × 10 9 /l, a platelet count of <450 × 10 9 /l, <5% myelocytes plus metamyelocytes, no blasts or promyelocytes, no extramedullary involvement, and no signs of the accelerated phase or blast crisis of CML; a cytogenetic response in marrow cells, categorized as CCyR (no Ph-positive metaphases), partial (1-35% Ph-positive metaphases), major (complete plus partial responses), minor (36-65% Ph-positive metaphases), minimal (66-95% Ph-positive metaphases), and no response (100% Ph-positive metaphases) on the basis of G-banding in at least 20 cells in metaphase per sample.

Statistical methods

Patient characteristics were summarized using descriptive statistics. Inferential statistics using Kaplan-Meier curves were used for PFS and OS using GraphPad Prism software for Windows, Version 4, 2003.


  Results Top


A total of 64 children were enrolled in the present study, 42 (65.6%) were boys and 22 (34.4%) were girls. Median age at presentation was 13 years (range 1-18 years). Fifty-three (83%) children were in early chronic phase (CP) and 11 (17%) were in late CP. The median hemoglobin was 9.3 g/dl (range 5.1-13.8), median leukocyte count was 158 × 10 9 /l (range 5.9-539) and median platelet count was 380 × 10 9 /l (range 80-11,400), median basophil % was 3 (range 0-15), median eosinophil % was 2 (range 0-15), median blast % was 3 (range 0-10), and mean spleen size at presentation was 9 cm (range 0-20). Twenty-eight (43.7%), 32 (50%), and four (6.3%) children belonged to the low, intermediate, and high Hasford risk groups, respectively; while 34 (53.1%), 23 (35.9%), and seven (10.9%) belonged to the low, intermediate, and high Sokal groups.

Sixty-one patients (95.4%) achieved CHR with a median duration of 8 weeks (range, 4-16). Twenty-seven patient did not have their evaluations as per the standard guideline, 6/27 patients were in less than 6 months of follow-up, 4/27 patients were between 6 and 15 months of follow-up and not yet completed the karyotyping at the time of analysis, one was not evaluated due to prolonged hematological toxicity, 3/27 had early hematological progression and were not evaluable, and 13/27 were irregular and lost to follow-up.

Thirty-seven (57.8%) patients had evaluation of cytogenetic response and their results were analyzed. The median time to best cytogenetic response evaluation was 13 months (range 4-52). Twenty-nine patients (78.3%) achieved CCyR; five (13.5%) had minor cytogenetic response; and one (2.7%) each had minimal, partial, and no response.

At a median follow-up of 36 months (range 5-75), 21 (56.8%) remained progression free and 35 (94.5%) are alive [Figure 1]. Of the 16 who progressed, five (31.2%) had loss of cytogenetic response only, six (37.5%) had hematologic progression, two (12.5%) had molecular progression, and three (18.7%) had both hematologic and cytogenetic progression.
Figure 1: Progression-free survival (PFS) and overall survival (OS) of evaluable patients

Click here to view


Of the 16 who progressed, five (31.2%) had loss of cytogenetic response, six (37.5%) had hematologic progression, two (12.5%) had molecular progression, and three (18.7%) had both hematologic and cytogenetic progression. Children who progressed on IM 260 mg/m 2 , the dose was hiked to 340 mg/m 2 as they could not afford second line TKI. Out of 16, 12 (75%) achieved CHR with dose hike of IM.

Only four patients of 37 had at some point of time molecular analysis, three of them were in major molecular remission (MMR), of which two had molecular progression.

Adverse events are not infrequent. Non-hematological side effects were hypo/hyperpigmentation of skin (54%), edema/weight gain (39%), muscle cramps/musculoskeletal pain (30%), growth retardation (29%), fatigue (23%), asthenia (15%), skin rash (15%), diarrhea (9%), oral ulcers (9%), dyspepsia (7.8%), constipation (4.5%), and liver function test abnormalities (3%). Hematological side effects were anemia (65%), neutropenia (28%), and thrombocytopenia (17%). The Z-scores for height and age were lower compared to the baseline, more so in the prepubertal age group. [5]


  Discussion Top


Millot et al., reported 40 cases of CML with 38 cases of CP and one each of accelerated phase (AP) and blast phase (BP). [6] In children very few studies are available to date, Phase I study of Children's Oncology Group (COG) reported that 12 children who were previously treated with interferon-α10 had CCyR and one patient had partial cytogenetic response. [7] A case series from Memorial Sloan Kettering Cancer Center (MSKCC) reported that two children in early phase and two children in late CP achieved CCyR. [8] Millot et al., reported 12 out of 20 children in CP failed Interferon (INF) attained CCyR. [9] In the present study, out of total 64 children, 61 (95.4%) achieved CHR with a median duration of 8 weeks. In the present analysis due to parental apprehension and logistic reasons, all children did not undergo cytogenetic evaluation as per schedule. Only 37 children (57.8%) had evaluation of cytogenetic response. Among them mean time to attain best cytogenetic response was 13 months, 29 patients (78.3%) achieved CCyR. Ghadyalpatil et al., reported 89.5% CCyR at median time of 10 months (range 3-31 months) in pediatric CML. [10] These results were comparable with the COG, European, and French pediatric CML studies' data. [1]

At a median follow up of 36 months (range 5-75), 21 (56.8%) remained progression free (PFS) and 35 (94.5%) are alive. Ghadyalpatil et al., reported event-free survival (EFS) and OS was 74.1 and 100%, respectively in pediatric CML patients at a median follow-up of 29 months. [10] Lakshmaiah et al., reported EFS and OS at 43 months as 92.8 and 100%, respectively. [11] Biswajit et al., reported 3-year disease-free survival (DFS) and OS as 86.2 and 89.5%, respectively, in young CML patients. [12]

Present study results were comparable with that of previous study results in pediatric CML from India in terms of response, but the PFS and OS were lower when compared with Ghadyalpatil et al., [10] Biswajit et al., [12] and Lakshmaiah et al., [11] studies [Table 1]. The reasons for such results could be due to poor adherence to the treatment, which accounted for 25% in our center and our center caters mostly for lower socioeconomic group population.
Table 1: Survival and cytogenetic response across different studies

Click here to view


Of the 16 who progressed, five (31.2%) had loss of cytogenetic response, six (37.5%) had hematologic progression, two (12.5%) had molecular progression, and three (18.7%) had both hematologic and cytogenetic progression. Children who progressed on IM 260 mg/m 2 , the dose was hiked to 340 mg/m 2 as they could not afford second line TKI. Out of 16, 12 (75%) achieved CHR with dose hike of IM.

Adverse events are not infrequent in this study, anemia (65%), pigmentation changes (54%), and weight gain (39%) are the most common manifestation. Ghadyalpatil et al., reported hematological toxicity (Grade 4 thrombocytopenia) in 14% and hypopigmentation in 50% as common toxicities in pediatric CML patients. [10] Biswajit et al., reported hypo- or hyperpigmentation (60.0%) as the most common side effect in young CML patients and Grade 3/4 hematological toxicity accounted only 7%. [12] Rajappa et al., reported similar side effect profile in adult CML patients from our center with pigmentation changes (70%), anemia (65%), and weight gain (50%) from our center. [13] The high occurrence of anemia during follow-up in the present study might be due to low mean hemoglobin level at the time of diagnosis due to low socioeconomic group. Rest of side effect profile was similar to that of western data. [1] In the present study, the Z-scores for height and age were lower to the baseline after starting on IM; we have reported it earlier from the same Institute [5] and there are reports on growth retardation on IM from other centers. [2] The influence of malnutrition cannot be ruled out totally, but to our understanding the sudden decline in the growth rate after starting IM has major influence.

We conclude that in children with CML-CP, IM showed better cytogenetic response with the minimal toxicity, which ultimately results in prolonged OS if they are adherent to the treatment. Our survival outcome is comparable to that reported from various western populations. They should be monitored for disease response with both cytogenetic and molecular techniques as well as side effects with IM. Treatment adherence should be checked in case of suboptimal response. The healthcare provider can address most of the reasons for nonadherence with adequate counseling on the importance of adherence. More prospective studies are necessary in children to determine long-term outcomes with IM.

Limitation

It is a retrospective study, with small numbers, evaluation time points not according to guidelines, and dose intensity unknown.


  Acknowledgment Top


Max Foundation, Novartis Oncology Access for free supply of imatinib mesylate (Glivec) in India. All other supporting departments in the institute.[15]

 
  References Top

1.
Andolina JR, Neudorf SM, Corey SJ. How I treat childhood CML. Blood 2012;119:1821-30.  Back to cited text no. 1
    
2.
Rastogi MV, Stork L, Druker B, Blasdel C, Nguyen T, Boston BA. Imatinib mesylate causes growth deceleration in pediatric patients with chronic myelogenous leukemia. Pediatr Blood Cancer 2012;59:840-5.  Back to cited text no. 2
    
3.
Millot F, Baruchel A, Guilhot J, Petit A, Leblanc T, Bertrand Y, et al. Imatinib is effective in children with previously untreated chronic myelogenous leukemia in early chronic phase: Results of the French national phase IV trial. J Clin Oncol 2011;29:2827-32.  Back to cited text no. 3
    
4.
Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013;122:872-84.  Back to cited text no. 4
    
5.
Goteke VK, Maddi RN, Thota NK, Coca P, Nagalla B, Linga VG, et al. An anthropometric study in children with chronic myeloid leukemia on imatinib. J Clin Oncol 2012;30.  Back to cited text no. 5
    
6.
Millot F, Traore P, Guilhot J, Nelken B, Leblanc T, Leverger G, et al. Clinical and biological features at diagnosis in 40 children with chronic myeloid leukemia. Pediatrics 2005;116:140-3.  Back to cited text no. 6
    
7.
Champagne MA, Capdeville R, Krailo M, Qu W, Peng B, Rosamilia M, et al. Children′s Oncology Group phase I study. Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: Results from a Children′s Oncology Group phase I study. Blood 2004;104:2655-60.  Back to cited text no. 7
    
8.
Kolb EA, Pan Q, Ladanyi M, Steinherz PG. Imatinib Mesylate in Philadelphia chromosome- positive leukemia of childhood. Cancer 2003;98:2643-50.  Back to cited text no. 8
    
9.
Millot F, Guilhot J, Nelken B, Leblanc T, De Bont ES, Békassy AN, et al. Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase and in relapse after stem cell transplantation. Leukemia 2006;20:187-92.  Back to cited text no. 9
    
10.
Ghadyalpatil N, Banawali S, Kurkure P, Arora B, Bansal S, Amare P. Efficacy and tolerability of imatinib mesylate in pediatric chronic myeloid leukemia in a large cohort: Results from a tertiary care referral center in India. J Clin Oncol 2009;27:15s.  Back to cited text no. 10
    
11.
Lakshmaiah KC, Bhise R, Purohit S, Abraham LJ, Lokanatha D, Suresh TM, et al. Chronic myeloid leukemia in children and adolescents: Results of treatment with imatinib mesylate. Leuk Lymphoma 2012;53:2430-3.  Back to cited text no. 11
    
12.
Biswajit D, Rejiv R, Manjunath N, Prasad G, Lakshmi S, Devika P, et al. Imatinib mesylate experience of young patients with chronic myeloid leukemia in chronic phase-Care to cure. J Clin Oncol 2009;27:15.  Back to cited text no. 12
    
13.
Rajappa S, Varadpande L, Paul T, Jacob R, Digumarti R. Imatinib mesylate in early chronic phase chronic myeloid leukemia: Experience from a developing country. Leuk Lymphoma 2008;49:554-8.  Back to cited text no. 13
    
14.
Agarwal MB, Agarwal UM, Rathi SS, Masurkar S, Zaveri B. Report of chronic myeloid leukemia in chronic phase from Ashirwad Hematology Centre, Mumbai, 2002-2009. Indian J Med Paediatr Oncol 2013;34:199-203.  Back to cited text no. 14
[PUBMED]  Medknow Journal  
15.
Andreas H, Timothy PH, Jerald PR, O′Brien SG, Guilhot F, Goldman JM, et al. International randomized study of interferon versus STI571 (IRIS) 7-year follow-up: Sustained survival, low rate of transformation and increased rate of major molecular response (MMR) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib (IM) Blood 2008;112:186.  Back to cited text no. 15
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1]


This article has been cited by
1 Front-line imatinib treatment in children and adolescents with chronic myeloid leukemia: results from a phase III trial
Meinolf Suttorp,Philipp Schulze,Ingmar Glauche,Gudrun Göhring,Nils von Neuhoff,Markus Metzler,Petr Sedlacek,Eveline S. J. M. de Bont,Adriana Balduzzi,Birgitte Lausen,Olga Aleinikova,Sabina Sufliarska,Günter Henze,Gabriele Strauss,Angelika Eggert,Bernhard Kremens,Andreas H. Groll,Frank Berthold,Christoph Klein,Ute Groß-Wieltsch,Karl Walter Sykora,Arndt Borkhardt,Andreas E. Kulozik,Martin Schrappe,Christina Nowasz,Manuela Krumbholz,Josephine T. Tauer,Alexander Claviez,Jochen Harbott,Hans H. Kreipe,Brigitte Schlegelberger,Christian Thiede
Leukemia. 2018;
[Pubmed] | [DOI]
2 Chronic Myeloid Leukemia in India
Prasanth Ganesan,Lalit Kumar
Journal of Global Oncology. 2017; 3(1): 64
[Pubmed] | [DOI]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Materials and Me...
Results
Discussion
Acknowledgment
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed1368    
    Printed26    
    Emailed0    
    PDF Downloaded230    
    Comments [Add]    
    Cited by others 2    

Recommend this journal