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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 1  |  Page : 110-115

Pediatric chronic myeloid leukemia: A single-center experience


Department of Medical and Pediatric Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India

Date of Submission21-Oct-2015
Date of Decision19-Sep-2017
Date of Acceptance06-Apr-2018
Date of Web Publication24-Oct-2018

Correspondence Address:
Irappa Madabhavi
Department of Medical and Pediatric Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_833_15

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 > Abstract 


Background: The rationale of this study is to reveal the statistics of pediatric chronic myeloid leukemia (CML) patients.
Subjects and Methods: It is a retrospective analysis conducted to assess pediatric CML data from January 1998 to December 2014. There are 65 (3.2%) pediatric CML patients out of entire 2008 patients of CML. Data were analyzed regarding epidemiological characteristics, clinical presentations, response and side effects of imatinib, event-free survival, and overall survival of the pediatric CML patients.
Results: The median age of diagnosis was 11.84 years, and 76.9% patients were male and 23.07% patients were female. Sixty (92.3%) patients were in CML-chronic phase, 3 (4.6%) patients in CML-accelerated phase, and 2 (3.07%) patients in CML-blastic crisis. Most common initial symptoms and signs are weakness (60.0%), abdominal pain (55.38%), splenomegaly (100%), and hepatomegaly (86.5%). 67.3% of patients have white blood counts <100 × 109/L and 92.3% had platelets >150 × 109/L. In the initial months of 2002, imatinib was available and utilized in 54 patients. Of 54 patients, complete hematological response at 3 months, partial cytogenetic response at 6 months, complete cytogenetic response at 12 months, and major molecular response (MMR) at 18 months were 77.77%, 59.2%, 48.14%, and 40.74%, respectively. MMR at 36 months was 62.96% ( n = 34). Most common imatinib-related side effects are gastrointestinal upset and myelosuppression.
Conclusion: Pediatric CML in India is comparable with Western countries regarding epidemiological characteristic, clinical presentations, and tolerance of imatinib. As there is a paucity of universal literature regarding pediatric CML (especially data from Southeast Asian region), this article may fill up that space.

Keywords: Case series, chronic myeloid leukemia, imatinib, pediatric


How to cite this article:
Madabhavi I, Patel A, Modi G, Anand A, Panchal H, Parikh S. Pediatric chronic myeloid leukemia: A single-center experience. J Can Res Ther 2020;16:110-5

How to cite this URL:
Madabhavi I, Patel A, Modi G, Anand A, Panchal H, Parikh S. Pediatric chronic myeloid leukemia: A single-center experience. J Can Res Ther [serial online] 2020 [cited 2020 Jun 6];16:110-5. Available from: http://www.cancerjournal.net/text.asp?2020/16/1/110/243496




 > Introduction Top


Pediatric chronic myeloid leukemia (CML) comprises 3% of pediatric leukemia.[1] CML is an acquired clonal hematopoietic stem cell disorder, affecting all the hemic cells (neutrophils, basophils, eosinophils, monocytes, erythrocytes, and megakaryocytes). It is characterized by increased granulocyte pool of the whole body, elevation of the leukocyte counts, myeloid hyperplasia of the bone marrow (BM), and extramedullary hematopoiesis. The molecular pathogenesis is analogous to adult CML patients. The Philadelphia (Ph) chromosome, cytogenetic hallmark of CML, was the first specific chromosomal aberration allied with a human malignancy.[2] It is characterized by mutual translocation amid chromosome 9 and chromosome 22. The outcome is that a fusion gene is formed by juxta positioning the Abl1 (Abelson, the name of a leukemia virus) gene on chromosome 9 (region q34) to a piece of the breakpoint cluster region (BCR) gene on chromosome 22 (region q11).

The natural history of CML comprises three parts, that is, chronic phase (CP), accelerated phase (AP), and blastic crisis (BC). This is comparable to adult CML; nevertheless, CML-AP is less common in pediatric age group. Pediatric patients presented with low-grade fever, weakness, and hepatosplenomegaly. Before introduction of tyrosine kinase inhibitor (TKI), before 2001, patients were treated by hydroxyurea, cytarabine, interferon-alfa, and allogeneic hematopoietic stem cell transplantation (HSCT). Discovery of imatinib (TKI) was the paradigm shift for the management of all phases of CML. Discovery and introduction of the second-generation TKI (nilotinib, dasatinib, bosutinib, and ponatinib) and their utilization in adult CML patients who are imatinib resistant or intolerant to imatinib, further shifted this paradigm to a unique altitude. Nevertheless, only Phase I data for dasatinib and nilotinib are available to use in pediatric CML patients. Historically, allogeneic HSCT was the standard of care for pediatric CML, especially when HLA (human leukocyte antigen)-identical donor is available. However, now trials are showing that imatinib is superior compared to HSCT.[3]


 > Subjects and Methods Top


This retrospective analysis was completed at a single center in India from January 1998 to December 2014. Of a total of 2008 patients of CML, 65 (3.2%) patients were pediatrics. This study was permitted by our institutional review board, and legal guardians of patients gave written informed consent in agreement with the Declaration of Helsinki. The data regarding age, sex, symptoms, signs, and laboratory parameters were extracted from the medical record department of our center and were entered into a Microsoft Excel sheet. From January 1998 to February 2002, patients were treated with non-TKI treatments including hydroxyurea (25 mg/kg/day), interferon-alfa, and cytarabine (5 million units/m2, subcutaneous daily plus cytarabine 20 mg/m2/day, 10 days/month) and palliative supportive care (including splenic irradiation for symptomatic patients). The Glivec International Patient Assistance Program, initiated by Novartis Pharmaceuticals, and school health program (the Government of India initiative) were started in February 2002 and August 2007, respectively, at our institute. Patients enrolled in the above programs got imatinib at free of cost.

Inclusion criteria

Patients who aged 18 years or less and diagnosed as Ph chromosome-positive CML (CP or AP or BC) by conventional cytogenetic, fluorescence in situ hybridization (FISH) for BCR-ABL or by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) for BCR-ABL irrespective of performance status were included in the study.

Exclusion criteria

No definite exclusion criteria were noted.

Investigations

At our tertiary care center, any suspected CML patients underwent investigations including complete hemogram with differential counts, renal function test, liver function test, lactate dehydrogenase, serum uric acid, serum electrolytes, abdominal sonography (to measure spleen size), BM aspiration, and conventional cytogenetic. BM aspiration was done through posterior superior iliac spine with aseptic precautions. Cytogenetic examination was done on BM cells by the G-banding method. If marrow cytogenetic fails, FISH or RT-qPCR was done from peripheral blood (PB). Trephine biopsy is not mandatory but mainly for fibrosis, cellularity, or transformation. Immunophenotyping was done if BC was present.

Treatment

Hydroxyurea (25 mg/kg/day) was initiated till the diagnosis was established. Subsequently, the patients were managed with imatinib (340 mg/m2). Hydroxyurea was continued before imatinib was launched. In our cohort, none of the patients had undergone HSCT. Grade of toxicity of imatinib was evaluated according to the Common Terminology Criteria for Adverse Events v4.0.

Response evaluation

The European LeukemiaNet guidelines were used to assess the response of imatinib and further monitoring of patients. Hematological response: Complete hematological response (CHR) was defined as a white blood count (WBC) count of <10 × 109/L, a platelet count of <450 × 109/L, no immature cells (blasts, promyelocytes, and myelocytes) in the PB, and disappearance of all signs and symptoms related to leukemia (including palpable splenomegaly). Cytogenetic response: Complete cytogenetic response (CCyR) (0% Ph positive), partial (partial cytogenetic response [PCyR]; 1%–35% Ph positive), minor (36%–65% Ph positive), and minimal (66%–95% Ph positive). A MCyR included CCyR plus PCyR (i.e., ≤35% Ph-positive). Molecular response: Major molecular response (MMR) has been defined as a ratio of BCR/ABL to standardized control gene of <0.1%.[4],[5],[6],[7],[8]

Cytogenetic analysis (FISH when routine cytogenetic analysis was not obtainable) was repeated every 3 months for the 1st year and every 6 months afterward. Once a patient has achieved a CCyR, RT-qPCR was done to quantify the level of BCR/ABL M-RNA in PB.


 > Results Top


The characteristics of patients at presentation such as age, sex, disease phase, symptoms, and signs are shown in [Table 1]. The median age at presentation and diagnosis was 11.8 years and 11.84 years (range 4–17 years), respectively. Sixty (92.3%) patients were in CML-CP. Most common initial clinical presentation was weakness (60.0%) and abdominal pain (55.38%). Splenomegaly and hepatomegaly were present as most frequent signs in 100% and 86.5% cases, respectively. At the time of diagnosis, approximately 79% ( n = 41) patients had hemoglobin (Hb) level between 8 and 12 g/dl with mean Hb of 9.9 gm/dl (range, 6–13.5). Thirty (67.3%) patients had WBCs <100 × 109/L and 17 (32.7%) patients had WBCs >100 × 109/L. Forty-eight (92.3%) patients had platelets >150 × 109/L and 4 (7.6%) patients had platelets <150 × 109/L. The mean initial WBC and platelet counts were 113.63 × 109/L (range, 39–400 × 109/L) and 247.73 × 109/L (range, 10–500 × 109/L), respectively. Three (4.6%) patients were in CML-AP and 2 (3.07%) patients were in CML-BC. Total five patients of CML expired during the study period (CML-AP = 3 and CML-BC = 2) within 5 years of diagnosis.
Table 1: Studies Evaluating Use of Specific Second- or Third-Generation TKIs in the Third-Line Setting and Beyond

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Response

Of 65 patients of pediatric CML, 11 patients were diagnosed before 2001 and imatinib was not available that time and all were managed with hydroxyurea (25 mg/kg/day), interferon-alfa (5 million units/m2, subcutaneous daily), and cytarabine (20 mg/m2/day, 10 days/month). In the initial month of 2002, imatinib was available and utilized in all the remaining 54 patients. Of 54 patients in whom imatinib was used as frontline treatment, CHR, PCyR, CCyR, and MMR were calculated. CHR at 3 months, PCyR at 6 months, CCyR at 12 months, and MMR at 18 months were 77.77% ( n = 42), 59.2% ( n = 32), 48.14% ( n = 26), and 40.74% ( n = 22), respectively. MMR at 36 months was 62.96% ( n = 34). Patients tolerated imatinib very well. Most common imatinib-related side effects are gastrointestinal upset and myelosuppression. None of the patients underwent HSCT or received nilotinib and dasatinib.

Toxicity

Fifty-four patients received imatinib. All 54 patients tolerated very well except Grade 3 neutropenia and thrombocytopenia which were seen in 6 patients (9.2%), who required temporary discontinuation of the drug. Gastrointestinal upset (33%, n = 17) and leg cramps (23%, n = 12) were the most common nonhematological toxicities.

Survival analysis

At a median follow-up of 36 months (range, 9–78), 36 (66.6%) patients remained progression free and 52 (96.29%) are alive. Of the 18 patients who progressed, 6 (33.3%) had loss of cytogenetic response only, 6 (33.3%) had hematologic progression, 3 (16.65%) had molecular progression, and 3 (16.65%) had both hematologic and cytogenetic progression.


 > Discussion Top


Chronic leukemia is infrequent in pediatric populations. Pediatric CML comprises 10% of all CML cases and 3% of pediatric leukemia.[1] It is extremely rare in patients aged <4 years.[9] Annual incidence is 0.1/100,000 individuals. In India, the incidence is lower compared to developed countries (age-specific incident rate is 0.04/100,000).[10] The median age of presentation is 11–12 years (range, 1–18 years).[11] No racial or hereditary inclination has been demonstrated. Ionizing radiation is proven as etiological factor in adult, but not in childhood CML. No specific risk factors are identified, except increased incidence among in vitro fertilization child.[12]

Cytogenetic signature of CML is Ph chromosome, resulting from the t (9; 22) (q34; q11) reciprocal translocation. The molecular result of this translocation is the production of a chimeric protein called BCR-ABL1, which has constitutive kinase activity. BCR-ABL1 protein imparts the key role in the pathogenesis of pediatric CML identical to adult CML. Ph chromosome is identified in conventional cytogenetic, by FISH or by RT-qPCR methods. The innate history of CML is divided into three phases consist of CP), AP, and BC. European LeukemiaNet criteria for disease phase in CML are as follows:[4]

  • CP: None of the criteria for AP or BC have been met
  • AP: (1) Blast cells 15%–29% in PB or BM. (2) Blast cells plus promyelocytes in PB or BM >30%, with blast cells <30%. (3) Basophils in blood >20%. (4) Persistent thrombocytopenia (<100 × 109/L) unrelated to therapy
  • BC: (1) Extramedullary blast involvement. (2) Blast cells 30% or more in PB or BM.


CML-CP is characterized by BM or peripheral blast count <10%, marked leukocytosis, and with thrombocytosis. It is also associated with basophilia and eosinophilia. This phase is reasonably easy to control and lasting for 3 years before it reaches to advanced phase. Non specific chief complaints like fever, night sweats, weakness, left upper quadrant discomfort, and bone pain. Most common physical findings are pallor, low-grade fever, ecchymoses, and hepatosplenomegaly. Splenomegaly is more common in patients with higher WBCs and in whom the platelets are lower.[13] Hyperleukocytosis and features suggestive of BM infiltration are seen with more advanced age.

CML-AP is less common in pediatric population. It is characterized by progressive symptoms such as fever, weight loss, night sweats, increased resistance to chemotherapy, high proportion of blasts (10%–20%), and increased basophilia. CML-BC is associated with poor prognosis (median survival is 3–9 months). It has features such as myeloid blastic (60%–70%), lymphoblastic (30%), or mixed lineage. Among lymphoblastic pre-B cell, acute lymphoblastic leukemia is more common.[14],[15] Multilineage involvement is present which is responsible for cytological heterogeneity of the BC. The p53 mutation is obvious in late CP and may be a sign of increasing genomic volatility and premature succession to BC.[16],[17]

Characteristics of pediatric CML compared to adult CML are as follows: (1) CML comprises 3% of pediatric leukemia while adult CML 15%–20% of adult leukemia. (2) CML-CP is more common and CML-AP is less common.[11] (3) The mean hematocrit in pediatrics at presentation is 25 ml/dl, which is remarkably less that seen in adults.[18],[19] (4) High median leukocyte counts (approximately 250,000/mm3) and excessive hyperleukocytosis (>500,000/mm3) are more common.[18],[20]

Pediatric CML was managed in pre-imatinib era, as in adult, by hydroxyurea, interferon-alfa, and cytotoxic chemotherapy like cytosine arabinoside. For adult CML patients there are prognostic scores like Sokal score, EUTOS score and Hasford score that guide us to estimate time to progression of CML. If matched donor was available, HSCT was the standard of care. As a matter of course, the median survival of patients diagnosed in CP had been 5–7 years, with 50%–60% alive at 5 years and 30% surviving to 10 years.

Imatinib is an oral TKI which competes with adenosine triphosphate for BCR-ABL protein binding, There by preventing phosphorylation of substrate and subsequently it abrogates and inhibits down grade signaling pathways. Imatinib was approved by the Food and Drug Administration in 2003 for pediatric population. The International Randomized Study of Interferon and STI571 phase 3 trial revealed efficacy of imatinib maculate (STI 571, Gleevec).[21] This randomized study enrolled adult newly diagnosed CML-CP patients who were compared imatinib (400 mg) with interferon plus low-dose cytarabine. The 6-year event-free survival, PFS, and overall survival were 83%, 93%, and 88%, respectively. The 6-year OS is 95% if CML-associated deaths were only incorporated. Five percent patients had discontinued imatinib owing to side effects. The initial dose of imatinib in CP, AP, and BC is 260–300 mg/m2 (maximum absolute dose 400 mg), 400 mg/m2 (maximum absolute dose 600 mg), and 500 mg/m2 (maximum absolute dose 800 mg), respectively.[22]

The data regarding the use of TKI in pediatric CML patients are limited and are shown in [Table 1].[23],[24],[25],[26],[27],[28],[29],[30] The Children's Oncology Group (COG) studied 31 pediatric patients in phase 1 trial who received imatinib at doses ranging from 260 to 570 mg/m2. Pediatric doses of 260 and 340 mg/m2 were comparable with adult doses of 400 and 600 mg, respectively. Although ceiling-tolerated dosage could not be identified, imatinib was exceptionally well tolerated with above dose ranges. Hence, the most commonly suggested initial dose for children is in the range of 340 mg/m2. French National Phase IV trial studied 44 pediatric CML-CP patients prospectively with imatinib dose of 260 mg/m2. CHR, CCyR, and MMR rates were 98% (at 3 months), 61% (at 1 year), and 31% (at 1 year), respectively.

Roeder et al . explained biphasic molecular response by imatinib in which brisk initial slump in the level of BCR ABL1, revealing the clearance of mature CML descendants and the subsequent second phase showed shallow slope as precursor pool are less sensitive to imatinib and depleted gradually. Since active metabolites of imatinib have a shorter half-life in children compared to adults, patients with low plasma levels are less likely to achieve CCyR.[31]

Various animal studies, clinical cases, and prospective studies showed that imatinib has deleterious effect on bone metabolism and longitudinal growth.[32],[33],[34],[35],[36] Although the precise means are yet to be clearly identified, growth failure is an important key exclusive toxicity to consider when using TKIs in pediatric patients.[37] Imatinib, dasatinib, and bosutinib showed noteworthy insulin-like growth factor-1 (IGF-1) deficiencies and decrease IGF-binding protein 3 levels in an animal model study.[38] There are enough data available that if imatinib is used in prepubertal period, it may result in growth retardation or arrest.[23] Adverse effects in children happen with the equal or fewer occurrences and are less severe than in adults.[28],[39]

Information regarding the utilization of nilotinib in children is inadequate. While nilotinib had a safety profile akin to adults, it adds miniature advantage for those who failed Imatinib and dasatinib.[30] Dasatinib can traverse the blood–brain barrier and has durable response in central nervous system disease of BC.[39] Both CA180-038 and CA180-018 are phase 1 trials of dasatinib and have shown good tolerability in pediatric population.[29],[40]


 > Conclusion Top


Pediatric CML data at our center are comparable with Western countries regarding epidemiological characteristics and clinical presentations. As there is universal paucity of literature regarding pediatric CML (especially data from Southeast Asian region), this article may fill up that need. Imatinib has renovated the treatment of pediatric CML akin to the adult CML.

Learning points (highlights)

  • Pediatric CML consists of 3% of pediatric leukemia. Its median age of diagnosis is 11–12 years
  • Cytogenetic hallmark is Ph chromosome (t[9; 22] [q34; q11] reciprocal translocation) similar to occur as in adult
  • There are three phases of CML as in adult CML: (1) CP (most common), (2) AP, and (3) BC
  • Imatinib is well tolerated in pediatric populations but long-term use may impaired bone metabolism
  • Only phase 1 data, albeit successful, are available for second-generation TKI (nilotinib and dasatinib) and further trial warranted to use it in frontline setting
  • No role of upfront HSCT in pediatric CML-CP, even if matched donor is available.


Acknowledgment

We would like to acknowledge all the patients of pediatric CML, without them it is not possible to write this article.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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