Abstract

Introduction:?Chronic myeloid leukemia (CML) is rare in children and constitutes 2% of all leukemia. We present our institute experience in treating pediatric CML for 20 years.

Objectives:?There is a paucity of data on pediatric CML from India, hence we would like to present treatment responses and survival rates in our pediatric population treated with tyrosine kinase inhibitors at our center.

Materials and Methods:?Patients aged less than 18 years, diagnosed with CML from 2000 to 2019, and treated with imatinib were analyzed retrospectively considering demographic features, treatment characteristics, and survival outcomes. Descriptive analysis was done for the baseline characteristics. Event-free survival (EFS) and overall survival (OS) were calculated using the Kaplan-Meier method and the factors were compared using the log-rank test.

Results:?During the study period, 95 patients were diagnosed with CML of which 54 (56.8%) were males. The most common stage at presentation was the chronic phase (CP) with 84 (88.4%) patients followed by accelerated phase (AP) and blast crisis (BC) with 6 (6.3%) and 5 (5.3%) patients respectively. The median duration of follow-up for all patients was 98 months. EFS and OS at 8 years for patients with CML-CP were 43.1% and 80.4% respectively. Complete hematological response, complete cytogenetic response, and major molecular response was documented in 91 (95.7%), 73 (76.8%), and 63 (66.3%) patients respectively.

Conclusion?Outcomes in pediatric CML are comparable to that of adults. Imatinib is well tolerated in children.

Introduction

Chronic myeloid leukemia (CML) is rare in children and constitutes 2% of all leukemia in pediatric age group younger than 15 years and 9% in adolescents aged between 15 and 19 years.[1] [2] [3] Management of CML in children is challenging due to the lifelong treatment with tyrosine kinase inhibitors (TKIs) like imatinib and long-term adverse effects of TKI.[2] [4] These challenges are amplified in resource-challenged settings in low/middle-income countries due to delayed presentation, poor compliance to treatment, treatment abandonment, and access to drugs.

The use of hematopoietic stem cell transplantation (HSCT) to treat children in the chronic phase (CP) CML is no longer recommended with the advent of TKI.[2] [5] Imatinib has been the backbone for treating CML in children and recent evidence suggests that second-generation TKIs like dasatinib and nilotinib are safe and efficacious in children with CML.[5] [6]

Our study adds to the literature from India on pediatric CML by providing details on the clinical profile, management, and outcomes of pediatric CML treated at our center.

Materials and Methods

Inclusion Criteria

Retrospective data on 95 consecutive patients aged less than 18 years and diagnosed as Philadelphia (Ph) chromosome-positive CML at our hospital from January 2000 to December 2019 treated with TKI (imatinib) were analyzed.

Exclusion Criteria

CML patients aged more than 18 years and those who did not receive TKIs were excluded.

Baseline characteristics and other clinico-pathological features were extracted from the patient records. The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional) and with the Helsinki Declaration of 1964, as revised in 2013. This being a retrospective study, informed patient consent was waivered and approved by the hospital ethics committee (Institutional Ethics Committee, Cancer Institute (WIA), Adyar, Chennai; Accreditation number: EC-CT-2020?0141; Reference Number IEC/2020/Oct 01) on October 3, 2020.

The diagnosis of CML was established by clinical examination supported by hemogram, peripheral smear, bone marrow aspiration, and demonstration of the Ph chromosome either by conventional cytogenetics or fluorescent in situ hybridization (FISH).[7] Confirmation of the presence of breakpoint cluster region-Abelson (BCR-ABL) fusion gene transcript was done by the reverse transcriptase polymerase chain reaction (RT-PCR) method.[8]

Accelerated phase (AP) was defined by any of the following features: basophils ? 20%; blasts 10 to 19% in peripheral blood or bone marrow; persistent thrombocytopenia (<100 xss=removed>9/L) unrelated to therapy or persistent thrombocytosis (>1,000???109/L) unresponsive to therapy; increasing total white blood cell (WBC) count and increasing spleen size unresponsive to therapy; megakaryocytic proliferation in sizable sheets and clusters associated with marked reticulin or collagen fibrosis and/or severe granulocytic dysplasia; and cytogenetic evolution.[9] Blast crisis (BC) was defined as blasts ? 20% in blood or bone marrow, large foci or clusters of blasts in bone marrow biopsy, or extra-medullary blast proliferation. All other patients who did not meet the criteria for AP or BC and blasts?<!--?10% in peripheral blood or bone marrow were considered as CP.[

In children weighing?<!--?40?kg, imatinib was started at 260 to 300?mg/m10] Children weighing ? 40?kg were started on imatinib 400?mg daily.[11] Dose escalation of imatinib was done if there was nonattainment or loss of response. Toxicity details were captured from the case files and were graded according to the Common Terminology Criteria for Adverse Events, version 4.03. Treatment was started after obtaining written informed consent for TKI from the parent/guardian.

Regular follow-ups included clinical examination and complete blood count. A complete hematologic response (CHR) was defined as WBC?<!--?10???1013] Cytogenetic response assessments have been replaced by real-time quantitative RT-PCR assessment at our center since 2013. A complete cytogenetic response (CCyR) was defined as the absence of the Ph chromosome in all analyzable metaphases on karyotyping. A BCR-ABL1/ABL1 transcript ratio ? 1% on the international scale by quantitative RT-PCR was considered equivalent to CCyR.[12] [13] [14] [15] A major molecular response (MMR) was defined as a BCR-ABL1/ABL1 transcript ratio ? 0.1% on the international scale by real-time quantitative RT-PCR, whereas a complete molecular response (CMR) was defined as an undetectable BCR-ABL1 transcript by two consecutive RT-PCRs with assay sensitivity of 10?4.[13] [16] [17] [18] Management of CML has evolved over the 20-year period, and this has reflected on patient care. Cytogenetic and molecular responses were assessed using FISH or quantitative PCR for BCR-ABL transcript levels from peripheral blood. Response assessment was not performed according to the guidelines due to financial constraints.

Imatinib was withheld for grade 3 or 4 toxicity and restarted at a lower dose and escalated based on tolerance. In patients who had progression of disease to AP or BC, the dose of imatinib was increased or palliative treatment with hydroxyurea initiated. More recently, with availability of second-generation TKIs these have been administered if there is no response to imatinib. Imatinib resistance mutational analysis (IRMA) was performed where feasible.

Statistical Analysis

Descriptive analysis was done for the baseline characteristics. An event in the study was defined as any loss of CHR or nonattainment at 3 months, CCyR at 6 months, and MMR at 12 months or progression to AP or BC or death due to any cause. Event-free survival (EFS) was calculated from the date of the start of therapy until the date of the first event. Overall survival (OS) was calculated from the date of the start of therapy to the date of death or last follow-up. EFS and OS were analyzed using the Kaplan-Meier method and the factors were compared using the log-rank test. Statistical analysis was done using SPSS version 17.0 (SPSS Inc, IBM, Chicago, United States).

Results

During the study period, 95 patients were diagnosed with CML, of which 54 (56.8%) were males and 41 (43.2%) were females. The median age at presentation was 13 years. The most common stage at presentation was CP with 84 (88.4%) patients followed by AP and BC with 6 (6.3%) and 5 (5.3%) respectively. Low- and intermediate-risk Sokal score (SS) was observed in 74 (78%) patients. Four patients initially received hydroxyurea for 1 to 3 years followed by imatinib after the drug was made available in India from 2002 through an initiative called the Glivec International Patient Assistance Program.[19] Baseline clinical and laboratory parameters are listed in [Table 1].

References