LA LEUCEMIA SECONDARIA: QUALI OPZIONI TERAPEUTICHE. Livio Pagano Istituto di Ematologia Università Cattolica S. Cuore Roma

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1 LA LEUCEMIA SECONDARIA: QUALI OPZIONI TERAPEUTICHE Livio Pagano Istituto di Ematologia Università Cattolica S. Cuore Roma

2 saml: Incidence In USA, NCI / SEER data ,600 new patients with AML / year ~ new patients with secondary AML / year ~ new patients with secondary AML > 60 yrs / year VERY FEW ENTER CLINICAL TRIALS

3 Incidence of Therapy-Related Leukemia Hodgkin lymphoma Childhood ALL Breast cancer Patients rescued by HSCT

4 New categories at risk More and higher doses of etoposide More anthracyclines and mitoxantrone More widespread use of G-CSF More solid organ transplants More cytotoxic treatment of autoimmune disorders (lupus; multiple sclerosis) More concomitant immunosuppression, e.g. fludarabine

5 Therapy-Related Leukemogenesis Radiotherapy Ionization Free radical formation Radiotherapy Alkylating agents Cations Electron-rich rich sites on DNA DNA Breakage Anti-Topoisomerase II agents Stabilization of the covalent bonds between DNA strands

6 Patients receiving chemotherapy uniform therapy

7 But the population is heterogeneous : saml

8 Long-term goal is genetically-tailored therapy High saml risk Treat with alternate therapy Treat with standard therapy

9 Survival of 1091 de novo AML and 93 therapy-related AML patients Schoch et al. (German AMLCG) Leukemia 2004

10 Treatment options for saml: 80 years Authors N cases Trial CR (%) Bloomfield et al Preisler et al HidAra-C 73 Vaughan et al 83 8 D + HidAra-C 50 Duane et al Kamtarjian et al ROAP 29 Brusamolino et al D+Ara-C+Vp16 15 Preisler et al HidAra-C 42 Larson et al HidAra-C 47 Hoyle et al DAT 36 De Witte et al D+ HidAra-C 60 N. B.: median DFS 3 m; OS range 4-12 m

11 Treatment options for saml: the addition of G-CSF Authors Philipott 93 Ganser 93 Baer 93 Visani 94 Bernasconi 98 Steinmetz 99 N cases Trial I+HidAra-C+Vp16 I+HidAra-C+Vp16 I+HidAra-C FLAG CTX +/- G-CSF I-FLAG CR (%) Vs

12 Factors that affect the outcome of patients with saml Persistence of the primary malignant disease Prior treatment injury to organs and vascular supply Depletion of normal hematopoietic stem cells Damage to bone marrow stroma (myelofibrosis) Chronic immunosuppression (dysfunctional phagocytes) Colonization with pathogenic bacteria and fungi Refractoriness to transfusion support High frequency of unfavorable cytogenetic features Rapid emergence of chemotherapy resistance

13 Guidelines criteria for therapetical options Age Performance status Morfology Cytogenetic class

14 saml vs De Novo AML by Cytogenetics Favorable Intermediate Unfavorable De Novo AML n yr relapse risk 32% 47% 78% 3-yr survival 68% 46% 17% saml n yr relapse risk 19% 62% 67% 3-yr survival 79% 25% 14% Grimwade et al, Blood, 1998

15 Survival for therapy-related and de novo AML and the impact of karyotype Kern et al. (German AMLCG) J Clin Oncol 2004 P=0.006 Karyotype Favorable Intermediate Unfavorable t-aml (n=121) No. of pts de novo (n=1511) Months (median) t-aml de novo 27 NR

16 Therapy of Secondary Leukemia APL Favorable Cytogenetics Intermediate Cytogenetics Unfavorable Cytogenetics Standard ATRA based therapy

17 Data Center APL as second tumor G.I.M.E.M.A. APL AIDA 0493 Event-free free survival sapl 0.65 APL sapl: Total patients 31 events 7 APL: Total patients 641 events years Pulsoni et al. BLOOD 2002

18 Data Center APL as second tumor G.I.M.E.M.A. APL AIDA 0493 Survival sapl 0.85 APL sapl: APL: Total patients 31 events 4 Total patients 641 events years Pulsoni et al. BLOOD 2002

19 A more favorable outcome for saml with inv(16) or t(15;17) International Workshop in Chicago (Genes Chromos Cancer, April 2002) Inv (16) t(15;17) No of pts OS of intensively treated saml patients No. of Complete remissions (%) Continuous CR 35 (90%) 23 (59%) 26 (74%) 20 (57%) Courtesy by Larson

20 .... Characteristics and outcome of t-apl seem similar to those of de novo APL.....

21 Therapy of Secondary Leukemia APL Favorable Cytogenetics Intermediate Cytogenetics Unfavorable Cytogenetics Standard ATRA based therapy Standard Induction/ Post-remission (chemo ± auto SCT)

22 Therapy of Secondary Leukemia Studies of remission induction - pts with favorable cytogenetics: t(8;21), t(15;17), inv (16) N CR% Kantarjian,, 1985 Quensel,, 1993 Kantarjian,, % 35 80% 13 69%

23 saml with t(8;21) has a poor survival International Workshop in Chicago (Genes Chromos Cancer, April 2002) 100% 100% 80% 60% 11q23 21q22 inv(16) t(15;17) Rare Unique 80% 60% t(8;21) t(8;21), other t(3;21) t(*;21) 40% 40% 20% 20% 0% Time in month 0% Time in month Courtesy by Larson

24 Therapy of Secondary Leukemia APL Favorable Cytogenetics Intermediate Cytogenetics Unfavorable Cytogenetics Standard Induction

25 International Workshop on the Relationship of Prior Therapy to Balanced Translocations in saml 100% Chicago 2000 (Genes Chromos Cancer, April 2002) 80% 60% No treatment Non-intensive treatment Intensive treatment 40% 20% 0% Time in month No treatment (n=52) Median Survival in months (range) 2.0 ( ) 1 year survival 13.3% 2 year survival 3.5% 5 year survival <3.5% Non-intensive treatment (n=40) 13.0 ( ) 51.1% 23.2% 13.9% Intensive treatment (n=356) 11.0 ( ) 42.9% 28.4% 18.1% Log-Rank p=0.0001

26 saml N 54 De novo AML n 162 p-value CR achievement % DI Resistant Median EFS duration (months) Overall Survival (months) Survival at 2 y (%) Survival at 5 y (%) Survival at 10 y (%) 37.2 ( ) 25.5 ( ) 21.8 ( ) 34.7 ( ) 25.2 ( ) 15.1 ( ) Pagano et al, Ann Oncol 2005

27 Disease Free Survival Kaplan-Meier survival estimates, by cascont P= ns 0.25 Caso 0.00 Controllo analysis time

28 Overall Survival Kaplan-Meier survival estimates, by cas_cont P= ns Controllo analysis time Caso

29 No differenze nell ambito dei casi in esame per: Categoria di rischio genetico Patologia precedente (i.e. linfoma o Ca mammella) Tipo di chemio precedente (topo II inibitori Vs alchilanti) Unico fattore che influenza outcome: PERFORMANCE STATUS

30 Therapy of Secondary Leukemia APL Favorable Cytogenetics Intermediate Cytogenetics Unfavorable Cytogenetics CR HLA-matched donor Auto SCT Allo BMT

31 Allogeneic BMT for smds/aml Event Free Survival (%) French Study of BMT n = Years Yakoub Agha et al, J Clin Oncol, 2000

32 Allogeneic BMT for smds/aml 100 French Study of BMT Overall Survival (%) n = Years Yakoub Agha et al, J Clin Oncol, 2000

33 Percent Allogeneic Transplantation for Untreated saml n = 46 Non Relapse Mortality Relapse Disease Free Survival Years from Transplantation Anderson et al, Blood, 1997

34 Chemotherapy Stem Cell Transplantation for MDS or saml in CR1 EORTC ( ) 184 MDA 215 Induction CR Consolidation Allo / Auto - assigned Allo / Auto - actual Standard ( ICE ) 100 ( 54% ) NOVIA 36 / ( 72% ) / 36 ( 59% ) Various ( 6 regimens ) 135 ( 63% ) Various x multiple Oostervald, Leukemia, 2002

35 P a t i e n t s a l i v e % Survival from CR Logrank test: p= (years) O N Number of patients at risk : EORTC MDA

36 International Workshop on the Relationship of Prior Therapy to Balanced Translocations in saml Chicago 2000 (Genes Chromos Cancer, April 2002) 100% 80% 60% No BMT BMT 40% 20% 0% Time in month Median Survival in months (range) 1 year survival 2 year survival 5 year survival No BMT (n=289) 10.0 ( ) 40.6% 25.6% 16.2% BMT (n=67( n=67) Log-Rank p= ( ) 52.8% 39.9% 26.7%

37 Auto-SCT in saml Limited data, most commonly with short follow-up Usually reported in conjunction with primary MDS Prerequisite - CR Adequate number of stem cells for harvesting Stem cell harvested usually polyclonal Engraftment significantly more rapid with mobilized peripheral blood cells vs bone marrow.

38 ASCT for smds/aml

39 ASCT for smds/aml Kroger et al.

40 ASCT for smds/aml multivariate analysis Stem cell source BM (n = 35) PBSC (n = 30) Age < 40 years (n = 33) > 40 years (n = 32) Remission status CR 1 (n = 46) Non-CR 1 (n = 19) 3-year DFS % p-value Relapse % * * p- value TRM % * p-value * * 0.5

41 Treatment options for saml particularly in elderly patients Supportive care Transfusions Antibiotics; bacterial & viral vaccines Hematopoietic growth factors Palliative chemotherapy Investigational therapies

42 Investigational Therapies Topotecan Gencitabina Gemtuzumab Ozogamicin (anti CD33) Demethilating agents

43 Topotecan Author Type of malignancy No. of patients Regimen CR/PR Death in induction Resistant Beran 1999 Sec./de novo MDS 86 Topotecan/ Cytarabine 48 (56%) 6 (7%) 32 (37%) Leoni 2001 Pagano 2001 Sec./de novo elderly AML Sec./relaps AML Fludarabine Topotecan/ Cytarabine Topotecan/ Cytarabine 12 (60%) 3 (25%) 1 (5%) / 7 (35%) 9 (75%) Guilhot 2002 MDS/sAML 238 Topotecan/ Cytarabine 48%

44 Gencitabina 10 patients, median age 71 y.o. (65-79); 2 AREB- t, 1 CMMoL, 7 sal. GEM mg/die every weeks for 8 times 1 only PR Comparing with patients treated with Low doses Ara-C similar OS with lower toxicity and supportive care Di Mario et al, Ann Oncol 2001

45 G-AraMy treatment schedules for poor prognosis elderly AML patients G-AraMY-1 INDUCTION rhg-csf: 5 g/kg/d,sc d1-8 Ara-C: 100 mg/m 2 /d CI d4-8 GO: 6 mg/m 2 /d IV d 9 CR/CRp/PR CONSOLIDATION rhg-csf 5 g/kg/d,sc d1-6 Ara-C 100 mg/m 2 /d CI d2-6 GO: 6 mg/m 2 /d IV d 9 G-AraMY MA INTENA NCE Ara-C 15 mg x 2 /d SC d 1-14 GO: 3 mg/m 2 /d IV d 15 G-AraMY-2 INDUCTION rhg-csf: 5 g/kg/d,sc d1-8 Ara- C: 100 mg/m 2 /d CI d2-8 GO: 6 mg/m 2 /d IV d 9 CR/CRp/PR CONSOLIDATION rhg-csf: 5 g/kg/d,sc d1-5 Ara-C: 1000 mg/m 2 /d x 2 IV d 2-5 GO: 6 mg/m 2 /d IV d 6 Legend: rhg-csf: recombinant human granulocyte colony-stimulating factor; Ara-C: cytarabine; GO: gentuzumab-ozogamicin; CI: continuous infusion; IV: intravenous; SC: subcutaneous; CR: complete remission; CRp: complete remission with incomplete platelets recovery.

46 DFS Kaplan-Meier survival estimates, by gruppo P-value= ns De gruppo Novo Secondary gruppo analysis time

47 DFS Kaplan-Meier survival estimates, by gruppo P-value= ns 0.50 gruppo De Novo Secondary gruppo analysis time

48 Demethilating Agents Recently approved drugs (FDA) Azacytidine May 2004: for treatment of low-risk and high-risk subtypes of MDS Lenalidomide December 2005: for treatment of patients with transfusion- dependent anemia due to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities Decitabine May 2006: for treatment of patients with MDS of all subtypes, including previously treated and untreated, de novo, and secondary MDS

49 Therapy of Secondary Leukemia APL Favorable Intermediate Unfavorable Cytogenetics Cytogenetics Cytogenetics Standard ATRA based therapy Standard Induction/ Post-remission (chemo ± auto SCT) Standard Induction CR HLA-matched donor No donor Allo BMT Young Adult Older Adult ± Auto SCT ± Experimental Therapy Consider palliative care or Experimental Therapy