Chronic myeloid
leukaemia (CML) constitutes about 2–3% of
leukaemia in children and has an incidence of 0.6–1.2/million children per year in the western countries. The incidence of CML increases with age and is exceptionally rare in infancy. Because of its rarity and lack of robust clinical evidence
,management of CML in children is based on evidence from adult studies and often follows guidelines developed for adults. With the evolution of treatment of adult CML in the last few decades from the time when
stem cell transplant was the only curative treatment to the present time when
advent of tyrosine kinase inhibitors (TKIs) have provided long term control with the possibility of eventual cure, the treatment of childhood CML has also transformed. The major benefits of TKIs do not come without cost and these agents have been shown to be associated with a host of off-target toxicities which accrue with long term use of TKIs. Because children with CML may receive tyrosine kinase inhibitor
(TKI) therapy for many decades, and are exposed to TKIs during a period of active growth, morbidities in children with CMLmay
be distinct from those in adults requiring careful monitoring. Due to significant concerns about long-term toxicities of TKI use in children, some experts have argued for aggressive strategies, such as eradication of CMLstem cells with limited duration and intensive regimens of chemotherapy and stem cell transplant. This may be more advantageous in children as a way to avoid lifelong exposure to TKIs and their associated adverse effects
.Bone
marrowtransplantation in pediatric CML is currently indicated only for recurrent progressive disease
,and the acute and long-term
toxicitiesof this option should be carefully evaluated against the complications associated with lifelong use of TKIs.
Methodology:
Diagnosis, baseline work-up and stabilisation in patients newly diagnosed with CML Complete blood counts with peripheral blood film - A BM aspirate with BM biopsy; send BM Aspirate for morphology, flowcytometry (Three tubes will be used for flowcytometry to provide more than 65 immune cell subsets and their immune checkpoint proteinexpression. Tube-1 is for T cell subsets that include T-regs, TH1, TH2, TH17, TH9 and TH22, naïve and memory T cells, central memory and effector-memory T cells, LGL, gamma-delta T-cells etc. Also, for studying expression of immune checkpoint proteins like PD-1, PDL1, CTLA-4 and TIM-3 in all T cell subsets.Tube-2 For studying different B-cell subsets (precursor, transitional, naïve, memory), plasma cells, NK-cell subsets and NK-cell degranulation functions. Also, for studying expression of immune checkpoint proteins like PD-1, PDL1, CTLA-4 and TIM-3 in all T cell subsets.Tube-3 For studying immune cell subsets like plasmacytoid dendritic cells, myeloid dendritic cells and its subtypes, monocytes and its subtypes, basophils and MDSC (granulocytic & monocytic MDSC) like cells and their immune checkpoint proteins like PD-1, PDL1, CTLA-4) and cytogenetics (karyotyping &Fluorescence in situ hybridization (FISH) for bcr-abl). Baseline work-up: 1. Real-time quantitative reverse transcriptase (polymerase) chain reaction (RQ-PCR) in bone marrow for BCR-ABL transcript type (most commonly p210, rarely p190 or p230) and determination of breakpoint (commonly e13a2/ e14a2 (p210), less commonly e1a2 (p190)/e19a2 (p230), rarely e13a3) for future monitoring. 2. Human leucocyte antigen (HLA)-type patient and family 3. Biochemistry: urea and electrolytes, creatinine, urate, liver function tests, Ca/PO4 4. Virology: HBV, HCV, HIV 5. Coagulation: prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen 6. Spleen size (cm below the costal margin) 7. Height and weight 8. Pubertal development according to Tanner stage 9. Risk scoring system (Sokal, Hasford, EUTOS- significance unclear in TKI era as well as in children) Initial Management 1. Treat bleeding/infection, if present 2. Consider leukaphaeresis if evidence of leucostasis (priapism, retinopathy/papilloedema, pulmonary symptoms) 3. Start allopurinol (10 mg/kg/day; max 300 mg) and ensure good hydration. Allopurinol should only be necessary if the WBC count is >20. 4. Start hydroxycarbamide 25–50 mg/kg per day until diagnosis of CML confirmed if WBC>20 and continue till WBC <10. 5. Start imatinib once diagnosis confirmed. The starting dose of imatinib is: 1. CP: 260–340 mg/m2 (maximum absolute dose 400 mg) 2. AP: 400 mg/m2 (maximum absolute dose 600 mg) 3. BC: 500 mg/m2 (maximum absolute dose 800 mg) Patients Presenting in Chronic Phase Patient should be started on Imatinib as soon as diagnosis is confirmed by cytogenetics. The standard starting dose in children is 340 mg/m2 /day (starting dose between 260-340mg/m2 rounded off to nearest 100mg; maximum 400 mg/day). Drug interactions: because of the inherent risk of either reduced activity or enhanced toxicity of the concomitant medication and/or imatinib, drugs known to interact with the same CYP450 isoenzymes (2D6 and 3A4) as imatinib should be used with caution (drug list to be attached with patient file). Grade 3/4 adverse effects are relatively rare with standard dose imatinib but lower grades of toxicity are not uncommon. They include rashes, bone pain, fluid retention, anorexia, depression, weight gain and other symptoms. Monitoring of disease response and TKI toxicity Patients in chronic phase who achieved complete haematological remission would be monitored for BCR/ABL by FISH on peripheral blood (PB) every 3 months until negative (FISH is not standardised for monitoring treatment response and ELN recommends BM cytogenetics for monitoring purpose till CCyR is attained, whereas NCCN 2018 does not recommend monitoring for cytogenetic response except whenever RQ-PCR is unavailable or there is sub-optimal molecular response). RQ PCR should be done on peripheral blood every 6 months until negative on 4 visits and then once a year. If the level of BCR-ABL transcripts appears to be rising, the test would be repeated as soon as convenient (preferably 4 weeks) and compliance check, imatinib levels, and mutation analysis will be done as appropriate. Imatinib Response and Failure Institution of TKI therapy for CML leads to haematological, cytogenetic and molecular response in that order and various studies have now provided guidance on the optimum time specific response which correlates well with long term outcome of these patients. Indications for TKD mutational studies (check with consultant before ordering): 1. At diagnosis: AP/BC patients only 2. First line imatinib therapy: treatment failure or suboptimal response 3. Second line dasatinib or nilotinib therapy: haematological or cytogenetic failure Patients with documented resistance to imatinib would get dasatinib/nilotinib based on availability of funds/patient support programmes at that time. Alternatively, imatinib dose will be escalated based on tolerance. Patients Presenting in Advanced Phase: Patients presenting with blastic transformation will be started on appropriate antileukemic therapy along with Dasatinib or Imatinib 400 mg/m2 /day (maximum 600mg) in accelerated phase and 500mg/m2(maximum 800 mg/ day) in blast crisis. Patients progressing during TKI treatment have significantly worse prognosis than those who present with advanced stage disease. Patients will also be counselled for allogenic stem cell transplant at this time. Patients would be induced with acute leukemia (ALL/AML) like chemotherapy and taken for transplant once in remission. When transplant is not feasible, patients would be started on oral chemotherapy (6Thioguanine and etoposide along with an appropriate TKI with prophylactic intrathecal chemotherapy). Stopping TKIs in children with CML Discontinuation of imatinib will be offered to patients satisfying the following eligibility criteria (adapted from existing ELN and NCCN guidelines) and consenting for the discontinuation trial: 1. On imatinib for more than 3 years 2. Persistent DMR4 (<0.01%) transcript level for more than 2 years 3. Willingness to come for follow-up and transcript level testing every 3 monthly for at least 2 years following discontinuation. During discontinuation trial, patients with rising transcript levels over the level of MMR (>0.1%) repeated on 2 occasions 1 month apart would be considered as failure of trial and will be restarted on imatinib. Following resumption of imatinib the patients would be followed up with transcript levels every 3 months twice followed by response based frequency of monitoring. Monitoring for long-term imatinib toxicity Patients on imatinib for >2 years will undergo assessment for growth, puberty, bone health, endocrine, cardiac, auditory, ophthalmic health at regular intervals as per the following table.