Myeloablative and Reduced Intensity Conditioning for HSCT Annalisa Ruggeri, MD, Hôpital Saint Antoine Eurocord- Hôpital Saint Louis, Paris

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1 Myeloablative and Reduced Intensity Conditioning for HSCT Annalisa Ruggeri, MD, Hôpital Saint Antoine Eurocord- Hôpital Saint Louis, Paris 18th ESH - EBMT Training Course on HSCT 8-10 May 2014, Vienna, Austria

2 The preparative regimen for HSC transplantation of patients with malignant diseases should: Have sufficient immunosuppressive effect in order to avoid graft rejection Have tolerable morbidity without mortality Be capable of eradicating malignancy Finn B. Petersen and Scott I. Bearman: Preparative regimens and their toxicity. In Bone Marrow tranplantation by SJ Forman, KG Blume and E Donnall Thomas, 1994 No ideal preparative regimen currently exists

3 Background Improvement has been made in supportive care methods, such as prevention and treatment of GVHD, infections, and organ damage, resulting in marked reduction of non-relapse mortality (NRM) Most strategies to prevent relapse or decrease NRM focus mainly on modifications of the conditioning regimen

4 Biol Blood Marrow Transplant. 2009; 15: 367

5 BBMT. 2009; 15: 1628 Stem cell support required No yes Non ablative NMA Reduced intensity conditioning RIC No short long irreversible pancytopenia myeloablative MA Bacigalupo, BBMT 2009

6 GENETIC DISPARITY Conditioning Regimens by Chemo-Radiotherapy Intensity Non-Ablative Immunosuppression Reduced Intensity Ablative Haplo / UCBT MUD Matched sibling F+Cy TBI 2Gy Cy + ATG + RT FTBI FB2 FMel100 FCyTBI2Gy FB3 FB4 TBF TBI+Cy TBI+F+TT Bu16+Cy FCyTBI12Gy CLL / CML LCL/AML fcl MM Cytoreduction AGGRESSIVENESS OF MALIGNANCY

7 Myeloablative conditioning (MAC) - dose intensification Standard myeloablative conditioning (MAC) regimens generally include total body irradiation (TBI>6Gy) or busulfan (Bu>8mg/kg per os or 6.4mg/kg intravenously) associated with cyclophosphamide (Cy) More intensified MAC regimens are associated with reduction of relapse but NRM makes it prohibitive in some cases The use of fludarabine with the intent of lowering toxicity with a high immunosuppressive activity is now a common standard

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9 Bulsulfan vs TBI- Myeloablative Conditioning n=795 n=864 * 64% 61% *similar LFS when analyzing CR1 and CR2 patients separately p= % 12% p= % 21% p=0.012

10 New myeloablative conditioning regimens Improvement of Busulfan administration (targeting p.o. Bu according to its pharmacokinetics) and/or use of i.v. Bu: Reduced NRM Addition Thiotepa (potent alkylating agent, allows the routine use of lower dosed single agent (BU)) Treosulfan (less toxic profile than busulfan, promising results in the pediatric experience)

11 Reduced intensity conditioning (RIC)

12 Reduced intensity conditioning (RIC) In the late 1990s, allo HSCT using RIC was first described for the treatment of high-risk hematological diseases RIC regimen has now become standard practice allowing patients with comorbidity to benefit of HSCT Since then, several studies have demonstrated that the use of RIC is associated with a reduction of in NRM, but an increase in disease relapse

13 RIC regimens are very heterogeneous (alkylating agent and dose) FLU 150 +BU FLU 150 +TBI 200x4 FLU 150 +MEL 140 CY 120 +Thiotepa MEL100

14 The role of ATG in both MAC and RIC Most prospective and retrospective studies report a reduction of acute and chronic GVHD with ATG without a detrimental effect on survival reduction of GVHD is not associated with increased risk of relapse So why is everybody not using ATG in the unrelated donor setting, or perhaps also in sibling peripheral blood grafts? Higher risk of infections, particularly, viral infections (high risk of EBV-LPD) Increased risk of relapse, reported in some studies, but contradicted in others randomized studies Survival is not improved, despite a reduction of agvhd This is true in the short term but it may be not 10 years later Bacigalupo 2014, BBMT

15 RIC versus MAC

16 RIC versus MAC for the treatment of ALL, AML, and MDS There are no large randomized studies comparing RIC and MAC HSCT Most evidence consist of phase II studies with different types of RIC regimens and from registry based studies Single-center studies are usually affected by selection bias as allocation of patients to either MAC or RIC is based on age or comorbidity

17 RIC versus MAC HSCT for the treatment of acute leukemia

18 RIC n=93 (regimen containing 9mg/kg n=27; melphalan 150mg/m 2 n=150; TBI < 500 cgy single dose or < 800 cgy fractionated n=30) MAC n=1428 (Cy+TBI n=1037; BU±Cy n=175) Patients receiving RIC were older (median age 45y vs. 28 with MAC)

19 Survival curves Marks, Blood, 2010 FI n=1409 RIC n=92 FI n=1409 RIC n=92 P= % P= % 26% 32% FI n=1409 RIC n=92 41% FI n=1428 RIC n=93 43% 32% P= %

20 576 patients with ALL aged >45 years old RIC n=127 (low-dose TBI in 40 cases (32%) and chemotherapy alone in 87 cases (68%): Flu and Bu in 23 cases, Flu and Mel in 25 cases, Flu and other CT, 11 cases, and other regimens in 28 cases MAC n=449 (included cyclophosphamide and high-dose TBI in 363 cases (81%) and high-dose chemotherapy alone in 86 cases (19%)) Patients receiving RIC were older (median age 56y vs. 50 with MAC)

21 RIC vs MAC for patients with ALL- ALWP EBMT MAC n=449 RIC n= % % 31% % Relapse Incidence 2y 31% % 45% %

22 RIC n=149 MAC n=972 RIC versus MAC HSCT for the treatment of acute leukemia in patients <50 years RIC Most common conditioning regimens: MAC TBI+Flu 26% CY+TBI 71% Flu+Mel 30% BU+CY 19% BU+FLU 25% When compared to MAC, RIC group age, more recent TX, WBC at diagnosis, received PBSC more often; TBI; ATG; had previous ASCT more often HLA matching was similar in both groups Multivariate Analysis (A)Cumulative incidence of NRM; HR 0.85 (95%CI 0.57 to 1.26; p=0.41) (B) Cumulative incidence of relapse; HR 1.46 (95%CI 1.05 to 2.04; p=0.02) (C) Leukemia Free survival; HR 0.88 (95%CI 0.68 to 1.11; p=0.28)

23 RIC: blue line MAC: yellow line RIC versus MAC HSCT for the treatment of acute myeloid leukemia in pts 50 years RIC Most common conditioning regimens: MAC TBI+Flu 34% CY+TBI 47% Flu+Mel 30% BU+CY 34% BU+FLU 25% When compared to MAC, RIC group age, received PBSC more often; TBI HLA matching was similar in both groups Adjusted multivariate analysis (A)Cumulative incidence of NRM; HR 0.64 (95%CI 0.41 to 0.96; p=0.04) (B) Cumulative incidence of relapse; HR 1.34 (95%CI 09 to 2.01; p=0.16) (C) Leukemia Free survival; HR 1.04 (95%CI 0.77 to 1.40; p=0.79) Ringden, JCO, 2009

24 Conditioning Intensity in Middle Aged Patients with AML in CR1. No Advantage for Myeloablative Regimens irrespective of the risk group. An Observational Analysis by the ALWP of the EBMT JR Passweg, M Labopin, J Cornelissen, L Volin, G Socié, A Huynh, R Tabrizi, D Wu, C Craddock, N Schaap, J Kuball, P Chevallier, JY Cahn, D Blaise, A Ghavamzadeh, K Bilger, A Nagler, F Ciceri, C Schmid, S Giebel, M Mohty #EBMT2014

25 Patients and Methods Cytogenetic Risk classification of AML Reference: Doehner H et al BLOOD of 5388 eligible patients with AML in CR1 in with cytogenetic information at diagnosis HSCT: Stem cell source: PB or BM Donor: HLA id sibling, MUD Age (yrs): MAC / RIC 1638 / 1336 Reference: Bacigalupo A et al. BBMT 2009;15:1628 ALWP EBMT 25 25

26 Results: all patients 100d II-IV agvhd 3y cgvhd 3y OS 3y LFS 3y RI 3y TRM MAC 57+1% 53+1% 22+1% 23+1% 32+1% 46+1% RIC 58+1% 52+1% 33+1% 14+1% 22+1% 49+1% P <0,0001 <0,0001 <0,

27 RIC (busulfan<9mg/kg, melphalan 150mg/m 2 and TBI 500 cgy or a nonmyeloablative regimen consisted of TBI 200 cgy and fludarabine n=1448; MAC n=3731 NMA conditioning resulted in inferior DFS and OS, but there was no difference in DFS and OS between RIC and MA regimens

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29 The interaction of SC source

30 Conclusion Choice of conditioning regimen depends on different variables: disease and disease status, comorbidities, donor type, SC source With the use of reduced toxicity regimen age per se is no more a limiting factor Currently available data from retrospective-registry studies suggest: Increased relapse and decreased NRM with RIC Comparable overall results between RIC and MAC Early post HSCT immunomodulation and maintenance/target therapy are current strategies to enhance the GVL effect and eradicate residual disease

31 Acknowledgements More than 500 transplant centres in 50 countries (data managers, nurses and physicians) Eurocord, EBMT and all WP, CIBMTR, Netcord, NMDP, WMDA, SFGM-TC ESH