1. 2013.04.29 R2 김재민 / Prof. 윤휘중 Journal conference 1

2. Therapy-related acute myeloid leukemia (t-AML) : clinical syndrome occurring as a complication after cytotoxic and/or radiation therapy Approximately 10% of all AMLs arise after a patient’s exposure to chemotherapy and/or radiation for a primary malignancy or autoimmune disease Patients with t-AML – considered inferior outcome compared with de novo AML The latency period(Dx of primary disease and occurrence of t-AML) : months ~ years : may depend on the cumulative dose, dose intensity, and type of preceding chemotherapy and/or radiation therapy) INTRODUCTION INTRODUCTION 2

3. t-AML more frequently have abnormal cytogenetics in particular, they have an increased prevalence of adverse-risk karyotypes At present, few data exist regarding the frequency of gene mutations Chromosomal aberrations in t-AML are thought to be the consequence of mutational events induced by previous therapy Hematopoietic progenitor cells, that survive with acquired mutations caused by non-repair or mis-repair, are at risk for leukemic transformation and finally result in overt AML Some patients may have an inherited susceptibility for the development of t-AML INTRODUCTION INTRODUCTION 3

4. 2 subtypes of t-AML : depending on the pervious therapy m/c subtype - after exposure to alkylating agents and/or radiation with a latency period of 5-10 years frequently accompanied by unbalanced cytogenetic abnormalities (such as loss of all or parts of chromosomes 5 and/or 7) 2 nd m/c subtype - agents targeting topoisomerase II shorter latency period of 1-5 years balanced chromosomal rearrangements (MLL, RUNX1, and PML-RARA) However, in recent years most patients : treatment with both discrimination according to the type of previous therapy is often not feasible -> World Health Organization (WHO) classification - no longer subcategorized INTRODUCTION INTRODUCTION 4

5. Because pretreatment cytogenetic and molecular aberrations are the most powerful prognostic parameters for clinical outcome in de novo AML the question: Whether Dx of t-AML itself indicates a poor prognosis or Whether association with an adverse genetic risk profile Characteristics and clinical impact of t-AML(in particular clinical and biologic prognostic markers): only a few The objective of our study : to evaluate the characteristics and clinical impact of t-AML in a large cohort of adult AML patients treated within prospective multicenter treatment trials. INTRODUCTION INTRODUCTION 5

6. 1993.09 ~ 2008 6 prospective multicenter treatment trials of the AMLSG(German-Austrian AML Study Group) All patients : age-adapted intensive induction and consolidation therapy AML HD93; APL95;AML HD98A; AML HD98B; AMLSG 06-04, NCT00151255; AMLSG07-04; NCT00151242 patients older than 60 years of age : significantly less intensive In all trials patients with t-AML were eligible had completed therapy for the previous malignancy had no active disease were considered by their physician to be at low risk of relapse Dx of AML : French-American-British Cooperative Group criteria METHODS - Patients METHODS - Patients 6

7. METHODS – Statistical anlysis METHODS – Statistical anlysis 7

8. 8 Cytogenetic cagegorization

9. RESULTS RESULTS 9 > d/t high frequency of t-AML after Tx of breast cancer > < < 3,177 : were enrolled 3,026 : information type of AML

10. 10 > > > > < < > < <

11. 11 t-AML de novo AML

12. RESULTS RESULTS 12 Median latency period : 4.04 yrs (m/c) (2 nd m/c) (m/c) Type of primary disease Type of previous therapy

13. 13 Shorter latency a/w Younger age at Dx Intercalating agents Toposiomerase II inhibitors Intercalating agents a/w induction of cytogenetic abnormalities t(9;11) or t(v;11)(v;q23) RESULTS RESULTS

14. 14 RESULTS RESULTS Latency period, cytogenetic abnormalities, previous therapies in de novo AML 77 (3%) of the 2653 de novo AML patients : Hx of previous neoplasm who did not receive chemotherapy and/or radiation : significantly older all other de novo AML pts (60 vs 53 years; P 0.0001) prostate cancer (n 18, 23%) breast cancer (n 8, 10%) Gastrointestinal cancer (n 8, 10%) as well as bladder cancer, renal cell carcinoma, and malignant melanoma (n 7 each, 9%) Latency period to the occurrence of AML : 5.0 years The cytogenetic profile : greater frequency of adverse-risk abnormalities (19/67 [28%] vs 441/ 2314 [19%]; P.06), in particular -5 or 5q abnormalities (10/67 [15%] vs 177/2314 [8%], P.04).

15. 15 RESULTS RESULTS Response to induction therapy Response to induction therapy for t-AML and de novo AML : CR 63% and 67% (P 0.21) : refractory disease 25% and 22% (P 0.38) : early/hypoplastic death 12% and 9% (P 0.20) : type of AML did not impact the achievement of CR (P 0.13, P 0.62)

16. 16 RESULTS - survival analysis RESULTS - survival analysis Median f/u for survival: 4.12 years Estimated 4-year RFS(relapse-free survival): 38.5% Estimated 4-year OS(overall survival): 37.1% 4-year OS: 37.9% 4-year OS: 25.5% 4-year RFS: 39.5% 4-year RFS: 24.5%

17. 17 RESULTS - survival analysis RESULTS - survival analysis Allogenic HSCT in first CR was performed : ≤ 60 years of age - 487/2064(24%) : > 60 years of age - 30/789(4%) Greater portion of younger pts Allogenic HSCT in first CR : t-AML - 40/89(45%) : de novo AML - 410/1445(28%) 60 세 이하 60 세 초과

18. 18 CID rates : greater in t-AML : regardless of the type of postremission therapy Chemotherapy & autologous HSCTAllogenic HSCT

19. 19 t-AML prevalence is increasing: life expectancy & survival ↑ paucity of prospective treatment data (excluded from clinical trials) t-AML pts : frequently had abnormal karyotypes(75% vs 51%-de nove AML) in particular, adverse-risk cytogenetics t(9;11), -5 or 5q, -7, 7q, abnl(17p), complex karyotypes frequency of NPM1 mutations, FLT3-ITD was significantly lower in t-AML -> indicating that t-AML leukemogenesis different from de novo AML However, focused on pts with cytogenetically normal AML -> no difference in the incidence and distribution of mutated NPM1 and FLT3- ITD between t-AML and de novo AML DISCUSSION DISCUSSION

20. 20 Median latency period(Dx of primary malig. ~ occurrence of t-AML) : 4 years Anthracyclines, topoisomerase II inhibitors : known a/w short latency period We found, Younger age at Dx of primary malignancy : a/w short latency period DISCUSSION DISCUSSION

21. 21 To evaluate whether the inferior prognosis of t-AML unfavorable genetic profile ? “t-AML” itself predict an inferior out come? -> multivariable analyses : endpoint - response to induction Tx, RFS, OS -> t-AML: adverse prognostic factor for RFS, OS but not for response to induction Tx t-AML pts( ≤ 60years) Greater CID(cumulative incidence of death in CR) regardless of therapy Whereas CIR(cumulative incidence of relapse) - not different vs. de nove AML DISCUSSION DISCUSSION

22. 22 Results after induction therapy were not different between t-AML and de novo AML -> dosage & modality of treatment during postremission therapy had a marked impact on the cumulative toxicity of cancer therapy -> therefore, intensive induction therapy should not be withheld for t-AML and dose reduce regimens for allogenic HSCT should be considered DISCUSSION DISCUSSION

23. 23 In summary our results : t-AML - adverse prognostic factor for RFS and OS, independent of other clinical and biologic variables The inferior outcome, especially in intensively treated younger adult patients, mainly attributable to an increased risk of death in CR, possibly reflecting cumulative toxicity of cancer treatmentd DISCUSSION DISCUSSION

24. 24 subgroups with specific diagnoses - relatively small → not possible to make definitive conclusion randomized phase III trial - potential confounding factor cancer types that are not markedly impacted ovary, breast, NSCLC, bladder - empiric CUP Tx = site-spicific Tx would take years to complete

25. 25

26. CONCLUSIONS CONCLUSIONS Molecular tumor profiling predict a tissue of origin in most patients with CUP median survival 12.5months for assay directed site specific Tx - longer than previous results using empirical CUP regimens more responsive tumor type - longer survival should be a part of CUP standard evaluation contributes to the management of CUP patients 26