Arsenic trioxide for APL: Not a poison

1. Arsenic trioxide for APL:Not a poison� Sagun D. Goyal Hematology/Oncology Grand Rounds March 2nd, 2012

2. No financial disclosures

3. Outline Case Background on APL and arsenic Arsenic trioxide (ATO) in relapsed/refractory APL ATO consolidation therapy ATO as part of induction therapy ATO maintenance Conclusions Questions Our practice

4. JS 3/05 Dx with APL at age 25 WBC 7.7, plt 14, in DIC 3/05-8/06 Treatment (7+3+ATRA, Ara-C/DNR, 6-MP/MTX/ATRA) 9/06 Autologous stem cell mobilization & storage 1/07 Relapsed APL 2/07-4/07 Progress after 2 cycles of ATO salvage 5/07-9/07 Remission after salvage Mylotarg 10/07 MUD with Bu/Cy conditioning 12/07-1/08 Life-threatening GI GVHD Reinfusion of auto stem cells after Flu/Cy/TBI conditioning 10/09 Relapsed APL 10/09-11 ATO/ascorbic acid/ATRA salvage x 7 weeks 1/10 MUD with Flu/Bu/ATG conditioning 1/12 In remission

5. Acute promyelocytic leukemia 10% of all AML cases in the U.S. (t15:17) ? fusion PML-RARa gene that blocks myeloid differentiation Can present with severe coagulopathy

6. Evolution of treatment Make note of the fact that while ATRA added to chemo significantly improved outcomes, 20-40% still relapse with thatMake note of the fact that while ATRA added to chemo significantly improved outcomes, 20-40% still relapse with that

7. Arsenic 460-370 BC Used by Hippocrates to treat ulcers 263 BC Used in China for treatment of periodic fever 581-682 AD Used in China for treatment of malaria 1845 Fowler solution (potassium arsenite) described Anemia, rheumatis, psoriasis, eczema, dermatitis herpetiformis, asthma, cholera, syphilis Fowler solution used for treatment of leukemia 1931 Fowler solution rediscovered for treatment of CML Later replaced by busulfan

8. Arsenic binds thiol residues and induces formation of reactive oxygen species � affecting numerous signaling pathways. ATO targets PML, ATRA targets RARA, and thus they synergize. Both trigger catabolism of the PML-RARA protein.Arsenic binds thiol residues and induces formation of reactive oxygen species � affecting numerous signaling pathways. ATO targets PML, ATRA targets RARA, and thus they synergize. Both trigger catabolism of the PML-RARA protein.

9. ATO in relapsed APL Chinese study Multicenter American study 15 patients Treatment ATO 10mg IV QD until CR 1 cycle of consolidation CR ? 90% 40 patients Treatment ATO 0.15 mg/kg IV QD until CR 1 cycle of consolidation Maintenance for continued CR CR ? 85% 18-month DFS ? 56% 18-month OS ? 66% Mention in the American study � pts were multiply relapsed, and some had prior transplantMention in the American study � pts were multiply relapsed, and some had prior transplant

11. Retinoic acid syndrome & leukocytosis 25% developed suggestive symptoms Treated with dexamethasone Therapy interrupted for 1-5 days in 8 patients All achieved a CR

12. Other AEs Neuropathy 17 patients Majority grade I Transaminitis 10 patients Occurred with other meds or other illness (sepsis) �no significant hepatotoxicity observed� QT prolongation 16 patients 1 with a-sx 7-beat run of torsades

13. Mechanism From prior single-center studyFrom prior single-center study

14. Caspase

15. ATO consolidationNorth American Leukemia Intergroup study Stratified by ageStratified by age

16. Results

17. Disease-free survival ATO overcomes negative impact of high-risk disease; ITT analysis make results more impressive in that 20% of pts assigned to get ATO didn�t; criticism is that outcome of non-ATO group not as good as historical comparison. 97/97/77 numbers are quoted from UTD.ATO overcomes negative impact of high-risk disease; ITT analysis make results more impressive in that 20% of pts assigned to get ATO didn�t; criticism is that outcome of non-ATO group not as good as historical comparison. 97/97/77 numbers are quoted from UTD.

18. Overall survival

19. Analysis by risk-groups �Patients in all risk groups benefited from the addition of ATO to the consolidation therapy.� I questioned what happened to the 29% of high-risk patients that never got into a CR, as they would have never received ATO, but 20% of these had death during inductionI questioned what happened to the 29% of high-risk patients that never got into a CR, as they would have never received ATO, but 20% of these had death during induction

20. Maintenance At time of publication �Too few events have occurred to provide the desired power to detect differences related to maintenance therapy.� ASH 2011 Abstract � follow-up �Only 5 patients who received ATO consolidation have relapsed.� �Relapse of APL is uncommon in patients who received ATO consolidation, and the need for any maintenance therapy in these patients has yet to be determined.� In all-comers (pre ATO) what was likelihood of relapseIn all-comers (pre ATO) what was likelihood of relapse

21. Moving ATO upfront

22. Single-agent ATO in newly diagnosed APL Ghavamzadeh study is best for single agent efficacy/outcome data for ATOGhavamzadeh study is best for single agent efficacy/outcome data for ATO

23. Comparison of cure rates Just mention that ATRA offers no long-term disease control in relapsed setting where ATO does, so presume that its better in frontline as wellJust mention that ATRA offers no long-term disease control in relapsed setting where ATO does, so presume that its better in frontline as well

24. Discussion Late relapses �for high-risk group of patients�appears higher than with conventional therapy� Cost ATRA + chemo ? $15-20,000 ATO ? $3-5,000

25. ATRA + ATO in newly diagnosed APL CR in 80 (94.1%) at median of 27 days Median f/u of 70 months 5-yr OS All ? 91.7% CR ? 97.4% 5 early deaths due to remission induction, 3 deaths due to disease relapse (CNS)5 early deaths due to remission induction, 3 deaths due to disease relapse (CNS)

26. Toxicity in long-term survivors Follow-up in patients while on, and at least 24 months, after last ATO dose CBC, BMP, LFTs, U/A Serum tumor markers (CEA, AFP, CA19-9, CA-125) EKG, echo CXR Dermatology consult Neurology consult and NCVs

27. Arsenic retention Arsenic has short half life in plasma, urine is better market\r Nair and hair levels reflect long-term exposure and in vivo accumulationArsenic has short half life in plasma, urine is better market\r Nair and hair levels reflect long-term exposure and in vivo accumulation

28. Conclusions ATRA/ATO-based induction show better long-term outcomes than ATRA-based regimens alone Implications for combination therapy in frontline setting No adverse long-term effects of ATO

29. Relapse at median f/u of 24 months 8 total 4 while on maintenance (3 of 4, ATO-only arm) Successful re-induction with AAA regimen in all 8 patients

30. Discussion Cumulative dose of ATO over 2 years similar to prior IV ATO studies Advantage: outpatient oral maintenance treatment Less deviation from standard treatment Patients were referred to study for maintenance Exact CR rate with the standard induction not known All risk groups enrolled Use of ATO maintenance overcame typical risk factors for relapses (i.e. WBC and plt)

31. Comparison of outcomes Outcomes comparable to previous studies Exposure to less [toxic] chemotherapy Fix tableFix table

32. Conclusions ATO is the single-most active agent in APL Combination ATO/ATRA has not been directly compared to ATRA + anthracycline-based chemo Good option At relapse For those who can�t tolerate anthracyclines Demonstrates clear benefit in consolidation Does not cause myelosuppression

33. Questions Will it have an additive role in induction with chemo and ATRA? Could it decrease early mortality? Is there a role for maintenance in patients who receive ATO consolidation? Should ATO be incorporated into maintenance? Should ATO be used in a risk-adapted manner? Is chemo even necessary in low-risk patients? Sparing chemo ? less future adverse effects� Can oral ATO replace IV ATO during all stages of treatment?

34. Our practice North American Leukemia Intergroup trial

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