journal club.pptx-dasatinib versus imatinib in ph positive ALL

PH POSITIVE ALL PEDIATRICS

1. Journal club

2. Introduction Ph chromosome – 3 to 4% cases of childhood ALL. Dismal prognosis – historically 5 yr EFS – 28-32% PCI , Allo Transplant. IMATINIB -5 Yr EFS -57%,all receive PCI,and 38 to 100% underwent transplant. Relapse and drug resistance – Imatinib 2nd generation TKI – Dasatinib and Nilotinib Dasatinib – cross the BBB So this study was planned

3. METHODS Trial design- oversight Chinese childrens cancer group study ALL-2015(CCCG-ALL-2015) Prospective,multi - institutional clinical trial Children aged 0-18 yrs ,confirmed Diagnosis of ALL MRD directed risk stratified treatment-St Jude childrens research hospital XV &XVI studies and Shanghai childrens medical centre 2005 trial. t(9,22) – Cytogenetics,FISH or RT PCR. Patients,physicians,research staff – were not aware of results.

4. Participants & Randomization Randomized to intermediate risk arm Randomly assigned to 1:1 ratio to receive imatinib vs dasatinib usually on day 8 of induction Stratified randomization was done – interactive web response system open label study Enrollment was stopped after interim analysis demonstrated that dasatinib yields a superior outcome compared with imatinib.

5. Treatments Upfront window therapy with dexamethasone for 4 days Remission induction – Prednisone,Vincristine,Daunorubicin,Pegaspargase - days 5 to 28 Cytarabine and Mercaptopurine – days 29-35 Ph positive ALL – Dasatinib (80mg/m2) or Imatinib(300mg/m2)- median of 8 days till end of therapy. Triple intrathecal therapy – Day 5,12,19,and 29 of induction therapy. Additional intrathecal treatment –days 8 and 15 – given to patients with blasts in CSF or Traumatic LP at diagnosis.

6. Consolidation- High dose MTX,MP,Triple intrathecal therapy. Intial continuation treatment – Daily MP with additional Pegaspargase,Daunorubicin,Vincristine,Dexamethasone and TIT 3weekly Subsequent continuation treatment – daily MP and weekly Methotrexate interrupted by 12 pulse therapies with cyclophosphamide,cytarabine,dexamethasone,and vincristine. Intrathecal therapy given was given only in the first cycle. None of the patients were given PCI. Allogeneic transplant was recommended only for high risk patients with MRD of atleast 1% at end of remission induction.

7. Outcome measures Primary end point – Event Free survival Secondary end point – relapse and death,overall survival. Randomization of 204 patients – 80% power – detect 8.5 to 11 %difference in EFS. Interim analysis was planned at 3.5 years – to account for slower accrual.

8. Statistical analysis EFS &OS curves – Kaplan meir survival curves. EFS – diagnosis to first treatment failure. Overall survival – time from diagnosis to death . 95% confidence intervals Fisher exact test –comparisons in contingency tables. Single & multivariate regression analysis of EFS – cox and fine gray regression models. P<0.05 – significance. Statistical analysis – R statistical software.

9. Results 5525 patients were enrolled.(Jan 2015-Sep 2018) 225 Patients – Ph positive ALL. 35 patients declined randomization,1 died before treatment. Eligible patients -189 92-Dasatinib,97-Imatinib Given daily for entire duration of therapy. Baseline demographic and disease characteristics were balanced between the 2 groups.

10. Primary outcomes INTENTION TO TREAT – 4YR EFS OS DASATINIB 71%(56.2-89.6%) 88.4%(81.3-96.1%) IMATINIB 48.9%(32-74.5%) 69.2(55.6-86.2%) P 0.005 0.04

11. 4 Year Cumulative risk of Any relapse. DASATINIB IMATINIB 19.8%(4.2-35.4%) 34.4%(15.6-53.2%) P-0.01

12. Isolated CNS Relapse – 4 year Cumulative risk DASATINIB IMATINIB 2.7%(0.0-8.1%) 8.4%(1.2-15.6%) P-0.06

13. Cumulative risk of any CNS relapse(isolated +hematologic) DASATINIB IMATINIB 10.1%(0.0-23.3%) 9.4%(1.9-19.9%) P-0.20

14. Death in Remission- 4 year Cumulative risk DASATINIB IMATINIB 5.6%(0.8-10.4%) 4.3%(0.2-8.4%) P-0.67

15. Multivariate analysis-Factors independently associated with poor EFS Treatment with Imatinib. 10 years or older Leucocyte count at least 1 lac at diagnosis T cell phenotype.

16. F actors associated with inferior event free survival DASATINIB IMATINIB Leucocyte count –at least 1 lac at diagnosis Leucocyte count – at least 1 lac at diagnosis CNS 3 10 years or older High risk T cell phenotype Increased MRD on Days 19 and 46 Increased MRD on Days 19 and 46

17. Discussion First randomized phase III trial – Dasatinib vs Imatinib. Other studies EFS 4year DASATINIB(n-92) IMATINIB(97) Intention to treat analysis 71% 48.9% In the as treated analysis 88.4% 69.2% Children s oncology group International study group EFS 62%(4yr) n - 60 66%(3yr) n- 106

18. 5year EFS/OS-60%/87%

19. 3 year EFS/OS – 66% /92,3%

20. Despite total omission of PCI ,with transplant limited to single patient the 4 year EFS -71% in Dasatinib group. Isolated CNS Relapse in Dasatinib treated patients Present study Children Oncology group International study 1 of 92 (1.08%) 4of 60(6.66%) 4of 106(3.77%)

21. 40 patients completed ALL therapy in this study. RELAPSE- Improved disease control in Dasatinib – Higher dose of Dasatinib (80mg/m2). Increased systemic drug exposure and therapeutic level in CNS IMATINIB(15) DASATINIB(25) 3-(20%) 2(8%)

22. No difference in the toxic effects between 2 arms No deaths directly attributed to either of agents 5% of patients in each arm died of fatal infection. Similar to the other study. 7% of patients in each arm had disseminated fungal infections. Dasatinib at a dosage of 80mg/m2 – allows omission of PCI. Need for transplant elimination – requires further research.

23. Conclusions Dasatinb (80mg/m2) vs Imatinib(300mg/m2) . Dasatinib more effective than Imatinib Dasatinib – excellent control of CNS Leukemia without PCI.

24. Analysis & Review Dasatinib – 2 nd generation TKI. More potent than IMATINIB(325 times). Comparing Dasatinib vs Imatinib – ?? Though this is first randomized phase III trial in paediatrics comparing Imatinib vs Dasatinib . Other trials used Dasatinib at 60 mg/m2. Rate of fatal infections with 80 mg/m2 –almost equal with 60 mg/m2 Dasatinib in paediatrics –FDA approval –Ph Positive CML-CP Ph positive ALL

25. Cumulative risk of any CNS relapse(Isolated +combined with hematologic) and Deaths in remission did not differ significantly . Showed Dasatinib is superior to Imatinib in 4 year EFS,OS,and any relapse and isolated CNS relapse. Dasatinib – CNS disease control – avoiding PCI Primary objective – achieved.

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