Dasatinib in pediatric Chronic Myeloid Leukemia: An overview

Vinod Gunasekaran

Consultant – Paediatric Haemato Oncology, Kauvery Hospital, Trichy, Tamil Nadu

Background

Chronic myeloid leukemia (CML) is a cancer of white blood cells, characterised by unregulated growth of myeloid cells in the bone marrow due to a characteristic chromosomal translocation called Philadelphia chromosome [t (9;22)]. This translocation leads to BCR-ABL gene fusion, leading to fusion protein with tyrosine kinase activity. In 1990s, the first targeted therapy for CML, Imatinib (a tyrosine kinase inhibitor – TKI) changed the treatment paradigm of chronic myeloid leukemia. Point mutations in kinase domain can lead to treatment resistance. Second generation tyrosine kinase inhibitors (Dasatinib, Nilotinib) were developed to over-ride the treatment resistance and to provide additional treatment options in CML. Dasatinib is now approved as a 1st-line and 2nd-line treatment in CML in both adults and children in USA and in EU. Approval in children in based on phase I and phase II trials showing early and durable responses with documented safety profile.

Dasatinib – pharmacodynamics & pharmacokinetics

It is a carboxamide derivative (structurally unrelated to Imatinib) which is 325 times more potent than Imatinib and 16 times more potent than Nilotinib (a derivative of Imatinib).  It has the ability to recognise multiple states of enzyme (inactive and active) whereas, Imatinib and Nilotinib bind only to inactive conformation. It overcomes most of the mutations causing Imatinib resistance. Dasatinib has rapid absorption, is not affected by food, and has high CNS penetration.

Half-life – 2 to 5 hr.

Dasatinib – Therapeutic efficacy

In phase I / II trials: Both in treatment-experienced & treatment-naive patients

Results: high cytogenetic response; rapid and durable.

Treatment naive Treatment experienced patients
24 monthsAt 24 months
94% CCyR 83% CCyR
70% MMR55% MMR
21% CMR 17% CMR
100% OS96% OS
At 48 months - estimated PFS - 93%At 48 months - estimated PFS - 78%
At a cut-off BCR-ABL <10% at 3 months

3y PFS 97% vs 82% (if BCR-ABL >10%)		In phase I trial - 7y OS - 82.4%

Dasatinib – Tolerability

Generally well tolerated;

  • Nausea and/or vomiting (23%)
  • Rash (18%)
  • Diarrhoea (17%)
  • Fatigue (12%)
  • Myalgia or arthralgia (12%)
  • Hemorrhage (10%)
  • Fluid retention (10%)
  • Growth / development ae (5%)

Grade 3 or 4 haematological abnormalities

  • Neutropenia (20 or 12%)
  • Anemia (10 or 5%)
  • Leukopenia (9 or 2%)
  • Thrombocytopenia (8 or 3%)

Literature Review

1). Yoo JW, Jo S, Ahn MB, Kim S, Lee JW, Kim M, Cho B, Chung N-G. Front-Line Tyrosine Kinase Inhibitors in Pediatric Chronic Myeloid Leukemia: A Study on Efficacy and Safety. Cancers. 2023; 15(15):3862. https://doi.org/10.3390/cancers15153862

Results

Fig (1): Complete cytogenetic response (CCyR) rates at 3, 6, and 12 months according to study groups.

Fig (2): Cumulative rates of molecular response over time according to study groups: (A) major molecular response (MMR) and (B) deep molecular response (DMR).

Conclusion

In conclusion, both imatinib and dasatinib are effective and safe front-line TKIs for pediatric patients with CML, providing excellent treatment outcomes in terms of survival.

Dasatinib shows faster and higher major and deep molecular responses, with a greater possibility of discontinuing TKI treatment and achieving long-term treatment-free remission in pediatric patients.

However, height decline was observed in both imatinib-treated and dasatinib-treated patients. Growth should be monitored closely in pediatric patients who have a high potential for long-term TKI exposure.

Further studies in a large cohort are needed to investigate the long-term adverse events and establish the criteria for discontinuation of TKIs in children with CML.

Dasatinib as upfront TKI – Pros and Cons

ProsCons
Faster and higher deep molecular responseslong term data on safety awaited
Safety data available in ph-I and ph-II trialswhether the long term outcome is superior to Imatinib is not proven.
Greater possibility of discontinuing TKIs
Now cost comparable to Imatinib.

Dr. Vinod Gunasekaran
Consultant – Paediatric Hematology and Oncology

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