Should patients with higher risk MDS (or AML in «early relapse») proceed directly to allo SCT without prior chemotherapy?

Should patients with higher risk MDS (or AML in «early relapse») proceed directly to allo SCT without prior chemotherapy? Pierre Fenaux Cohem 2012 Barcelona

Should patients with higher risk MDS (or AML in «early relapse») proceed directly to allo SCT without prior chemotherapy? AML in «early relapse» Higher risk MDS

AML in «early relapse»? AML in «early» hematological relapse: AML with 6 to? % marrow blasts Relapse discovered during follow up Relapse discovered upon admission in the transplant unit AML in molecular relapse APL CBF (t(8;21) and inv (16)) NPM 1 mutation or by flow cytometry

MRD >0.01%

Should patients with higher risk MDS (or AML in «early relapse») proceed directly to allo SCT without prior chemotherapy? AML in «early relapse» Higher risk MDS

Allo SCT in higher risk MDS Allo SCT is the only curative treatment in MDS Most MDS patients will receive reduced intensity conditioning (RIC) regimens Relapse after allo is the major cause of failure with RIC Relapse after allo is associated with marrow blast % and karyotype (especially with RIC)

Platzbecker et al, BBMT, 2011 Median follow-up of 20 months 3-year OS was 39% for HCT and 7% for 5-aza

Prognostic factors of treatment with AZA? French ATU program 282 patients Validation with AZA 001 patients (n=161) Cohorte d ATU (développement) low Multivariate Analisis HR 95% CI p puntuacio n Performance status 2,0 [1,4-2,9] <10-4 1 4 units RBC transfused /8w 1,9 [1,4-2,6] <10-4 1 1,0 Presence of circulanting blasts 2,0 [1,5-2,7] <10-4 1 Cytogenetics (IPSS) <10-4 0,8 p<0,0001 intermediate risk 1,4 [0,8-2,3] 1 Probabilité cumulée de survie 0,6 0,4 0,2 unfavorable 3,0 [2,0-4,3] 2 Grupo, de riesgo Score low 0 (N,%) 30 (11%) ATU (n=269) Survie médiane globale (mois) NR AZA-001 (n=152) (N,%) 23 (15%) Survie médiane globale (mois) NR 0,0 Intermediiate 1-3 191 (71%) 15,0 114 (75%) 21,4 0 6 12 18 24 30 36 42 48 54 60 Mois high 4-5 48 (18%) 6,1 15 (10%) 9,3 R. Itzykson et al.,blood, 2011

Incidence and prevalence of myelodysplastic syndromes: Data from the Düsseldorf MDS-registry. Neukirchen J, 2011 crude incidence rate 4.15/100,000/year point prevalence 7 per 100,000 persons of 7. incidence and prevalence of MDS higher in men than women increased sharply with increasing age.

RIC vs Standard RIC versus Regimen Standard (EBMT) Regimen RIC reduced TRM but is related to a significant higher risk of relapse leading to a similar DFS Martino R et al. Blood. 2006

RIC vs Standard Regimen (EBMT) Standard Regimen Various conditionings Fluda Mel Fluda Bu Fluda TBI TBI alone. Deeg J et al. Curr Opin in Hematol. 2008

RIC vs Standard Regimen RIC or (EBMT) RICs Various conditionings Fluda Mel Fluda Bu Fluda TBI TBI alone. RIC

Allo SCT in higher risk MDS Allo SCT is the only curative treatment in MDS Most MDS patients will receive reduced intensity conditioning (RIC) regimens Relapse after allo is the major cause of failure with RIC Relapse after allo is correlated with pretransplant marrow blast % and karyotype (especially with RIC)

Outcome according to FAB/blast count RA/RARS RCMD/RS RAEB-1 RAEB-2 Alessandrino Blood 2008 Sierra, Blood 2002

median 42 age, targeted BuCy, 64 % Low, INT-1 Deeg et al. Blood 2002

3 year relapse rate according to marrow blasts at transplant P=0,004 < 5% >= 5% < 5% >= 5% Experience of the SFGM TC on 462 consecutive patients, unpublished

3 year relapse rate according to the conditioning intensity in patients with marrow blasts at transplant <5% P=ns MAC RIC Experience of the SFGM TC on 462 consecutive patients, unpublished

3 year relapse rate according to the conditioning intensity in patients with marrow blasts at transplant >=5% P=0,04 MAC RIC Experience of the SFGM TC on 462 consecutive patients, unpublished

Should we try to reduce marrow blasts (tumor burden) before allo SCT? Results with intensive chemotherapy Results with Hypomethylating agents Proposals for a pragmatic approach

Intensive chemotherapy Mainly anthracycline-arac (like in AML) CR rates: 40-60% Short CR (median 1 y) response only in the absence of unfavorable karyotype

Survival with Anthracycline AraC Chemotherapy 100 80 Survival (%) 60 40 N = 99 20 0 0 20 40 60 80 100 120 140 Wattel E. et al. Br J Haematology. 1997;98:983-991.

Prognostic factors in adult de novo MDS treated by intensive chemotherapy. Br J Haematol. 1991. N= 47 Median DFI 16.5 months with normal karyotype versus 4 months with abnormal findings (P = 0.018).

Intensive chemotherapy prior to all SCT in higher risk MDS? 2 prospective randomized studies: frontline allo SCT versus chemotherapy followed by allo SCT GFM study started in 1993: 3 patients included in 2 years EORTC study started in 2002: just a few patients included in 2 years

Pre transplant treatment 125 patients MAC BuCy or BuTBI 33 pts received CT before transplant taml No difference for NMR, OS, DFS RAEB/RAEB T BBMT 2005. Scott

Leukemia (2005) 19, 396 401 & 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00 www.nature.com/leu Value of chemotherapy before allogeneic hematopoietic stem cell transplantation from an HLA-identical sibling donor for myelodysplastic syndrome K Nakai 1, Y Kanda 2, S Fukuhara 1, H Sakamaki 3,SOkamoto 4, Y Kodera 5, R Tanosaki 6,STakahashi 7, T Matsushima 8,YAtsuta 9, N Hamajima 9,MKasai 10 and S Kato 11 1 2 The survival curves of the NoChemo group and CR patients in the Chemo group were superimposed (57 vs 54%, P¼0.81), whereas patients who underwent allo-sct in NR after chemotherapy showed significantly shorter survival (20%, Figure 3a). The cumulative incidence of relapse was 26.2% in the NoChemo group and 27.6% in CR patients in the Chemo total of 188 patients had received chemotherapy before allo-sct (Chemo group), whereas 95 had not (NoChemo group). Among the Chemo group, 81 underwent allo-sct in complete remission (CR), while 107 were not in remission (NR). The Chemo group included a significantly higher proportion of patients with advanced disease than the NoChemo group (Po 0.0001). In addition, the proportion of patients with a poor karyotype was significantly higher in the Chemo group (P¼0.004). Figure 3 Overall survival (a) and cumulative incidencesof relapse (b) and nonrelapse mortality (c) grouped according to the presence or absence of previous history of chemotherapy. These are compared between patients who achieved remission after chemotherapy and those who did not undergo chemotherapy. Only patients with RAEB-t or LT were included in the analyses.

Feasible to get MRD negative / CR prior to Tx? BBMT 2008 N = 49 Chemotherapy = 36

BMT FOR T-MDS AND T-AML 969 Fig 2. Kaplan-Meier estimates of overall survival, EFS, relapse, and TRM in the 70 patients, according to the disease status at BMT.

MDS Simrit et al. Seminars in Oncology 2011

Should we try to reduce marrow blasts (tumor burden) before allo SCT? Results with intensive chemotherapy Results with Hypomethylating agents Proposals for a pragmatic approach

Proportion Surviving 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 AZA 001 study : Azacitidine vs CCR ITT Population 15 months Log-Rank p=0.0001 HR = 0.58 [95% CI: 0.43, 0.77] Difference: 9.4 months 24.4 months 0.0 0 5 10 15 20 25 30 35 40 Time (months) from Randomization CCR AZA 35

Response AZA 001 study: Secondary Endpoints: IWG (2000) CR,PR and HI AZA N=17 9 (%) Overall (CR+PR) 29 CR 17 PR 12 IWG HI Major+Mino r 49

AZA 001 study :Prolonged treatment with Azacytidine improves responses in MDS response after 2 to more than 6 cycles Continuing treatment improves responses in 48% of the cases 1.0 0.9 Probabilité cumulée 0.8 0.7 0.6 0.5 0.4 0.3 0.2 50% (2 cycles) 87% (6 cycles) Extrêmes : 1-22 cycles 0.1 0 Temps (cycles) : 0 3 6 9 12 15 18 21 24 Nombre de cas : 91 34 12 6 3 1 1 1 Abs 227 CO L R SILVERMAN et al.

AZA 001 study: Median overall survival per frequent cytogenetic abnormalities (Mufti, ASH 2009) karyotype Patient n Median OS AZA Median OS CCR HR Del 5q -not complex 15 25.1 17.3 0.43 -complex 29 9.9 4.9 0.55-7/ 7q- -not complex 27 24.5 8.1 0.33 -complex 30 5.3 3.9 0.45 +8 -not complex 28 26.3 8.7 0.20 -complex 18 17.3 4.9 0.43

Hypomethylating agents prior to all HSCT? In «DAC»tion instead of Induction (Lubbert,BMT, 2009) N=15 (MDS or AML) Median age 69 RIC 14 engraftment 6 alive in RC, 4 relapses, 4 TRM

Pretransplantation AZA vs Induction Chemotherapy and Posttransplantation Outcome in Patients with MDS. Gerds AT, BBMT, 2012. 68 allo HCT for MDS or AML post MDS 35 AZA and 33 IC before HCT 1 year OS 57% with AZA and 36% with IC post HCT mortality (HR, 0.68), and relapse (HR, 0.34; 95%) lower with AZA After adjustment for risk factors, rates of post HCT relapse for the 2 cohorts were similar.

Impact of azacitidine before allo SCT in MDS (Damaj,JCO, in press) G. Damaj et al.; ASH 2011; abs. 160 retrospective study SFGM-TC and GFM : 417 MDS allografted between 1999-2009 Sibling / unrelaetd excluding cord blood,classical or RIC

PATIENT CHARACTERISTICS AT DIAGNOSIS ACCORDING TO TREATMENT PRIOR TO TRANSPLANTATION

PATIENT CHARACTERISTICS AT TRANSPLANT ACCORDING TO TREATMENT PRIOR TO TRANSPLANTATION

TRANSPLANTATION MODALITIES TOTAL (n=163 ) 5 Aza (n=48 ) Induction CT (n=98 ) P Donor type, n (%) Sibling 75 (46) 20 (42) 48 (47).77 Unrelated 10/10 88 (54) 28 (58) 52 (51) Stem cell source, n (%) Marrow 21 (13) 8 (17) 11 (11).64 PBSC 142 (87) 40 (83) 87 (89) Conditioning, n (%) MAC 33 (20) 8 (17) 23 (23).41 RIC 130 (80) 40 (83) 75 (77) ATG, n (%) No 56 (34) 18 (37) 36 (37).11 YES 107 (66) 30 (63) 62 (63) TBI, n (%) No 125 (77) 38 (79) 73 (75).41 Yes 38 (23) 10 (21) 25 (25)

3y OS based on prior TTT Impact of azacitidine before allo SCT in MDS Survie Globale 1.0 0.8 0.6 0.4 0.2 p=0,10 5 Aza Chimiothérapie 5 Aza + Chimiothérapie p=0,027 Survie sans événement 1.0 0.8 0.6 0.4 0.2 p=0,11 p=0,032 3y DFS based on prior TTT 0 0 0 200 400 600 800 1000 1200 0 200 400 600 800 1000 1200 Jours Jours 3y NRM based on prior TTT Mortalité non liée àla rechute à3 ans 1.0 0.8 0.6 0.4 0.2 0 p=0,136 p=0,036 Rechute à3 ans 1.0 0.8 0.6 0.4 0.2 0 p=0,543 3y relapse based on prior TTT 0 200 400 600 800 1000 1200 0 200 400 600 800 1000 1200 Jours Jours G. Damaj et al.;jco, in press

Allo SCT: chemotherapy or hypomethylating agents before transplant? Treatment before allo based on marrow blasts, karyotype and type of transplant : Marrow blasts <5 to 10% : immediate transplant marrow blasts > 5 to 10% Normal karyotype: intensive chemo prior to transplant Unfavorable karyotype: hypomethylating agent prior to transplant

Groupe Francophone des Myélodysplasies Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland, Tunisia) Website: www. gfmgroup.org Online registry of French MDS cases Close cooperation with: - a patient support group - the International MDS Foundation - the European Leukemia Net

TYPE ADVANTAGE DISADVANTAGE POTENTIAL USE IC High CR rate Treatment related toxicity and mortality High disease burden Non adverse karyotype Little comorbidities Younger age Short interval to HCT RIC HMA Tolerability Active in adverse karyotype Late responses and lower response rates compared to IC Bridging (donor search) and/or MDS debulking Adverse karyotype Standard conditioning None No toxicity No reduction of disease burden Low disease burden PD to 1st line treatment Short interval to HCT Standard conditioning Platzbecker Seminars in hem 2012