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Avichai Shimoni, MD

Allogeneic Hematopoietic Stem-Cell Transplantation in AML and MDS Using Myeloablative Versus Reduced Intensity Conditioning: The Role of Dose-Intensity. Avichai Shimoni, MD Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel. Introduction.

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Avichai Shimoni, MD

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  1. Allogeneic Hematopoietic Stem-Cell Transplantation in AML and MDS Using Myeloablative Versus Reduced Intensity Conditioning: The Role of Dose-Intensity Avichai Shimoni, MD Division of Hematology and Bone Marrow Transplantation,Chaim Sheba Medical Center, Tel-Hashomer, Israel

  2. Introduction • Allogeneic stem-cell transplantation with both myeloablative and reduced intensity conditioning is effective therapy in AML and MDS. However their relative merits may be different in different settings. • The relative role of intensive chemotherapy and GVL may be different in these settings. • Prior studies with myeloablative regimens showed that more intensive regimens are associated with less relapses but with higher NRM rates resulting in equivalent survival.

  3. Introduction – cont. • However, this may change in the era of RIC and more tolerable myeloablative regimens. • To better define the role of dose-intensity we analyzed SCT outcomes of 112 consecutive patients with AML/MDS transplanted over a 5-year period.

  4. Patient Characteristics No. 112 patients Gender 58 male, 54 female Median age 50 (range, 18-70) Diagnoses: AML85 patients Secondary 39 patients MDS 20 patients MPD (Other than CML) 6 patients Prior chemotherapy 12 patients kidney transplant 1 patient MDS (all with excess of blasts) 17 patients

  5. Donor characteristics HLA matched sibling - 58 1-Ag mismatched related - 6 Matched unrelated - 48

  6. Patient characteristics – cont. • Status at transplantation CR1 - 27 untreated 1 relapse - 7 CR2 – 19 induction failure - 29 untreated – 19 refractory relapse - 11 • Disease activity active disease - 58 (>10% marrow blasts) remission - 54

  7. Conditioning regimens • 45 pts meeting standard eligibility criteria • Median age 42 (range, 22-58) • 28 pts in remission, 17 pts with active disease • 30 sibling donor, 15 unrelated or 1 Ag mismatched related • Conditioning iv Busulfan 12.8 mg/kg iv CTX 120 mg/kg

  8. 67 pts not eligible for standard SCT advanced age (n=56) organ dysfunction (n=8) poor performance status (n=8) recent fungal infection (n=7) extensive prior therapy (n=9, including 4 prior autoSCT) Median age 55 (18-70). More had unrelated donor.

  9. Conditioning regimens • Reduced-intensity conditioning iv Busulfan 6.4 mg/kg iv fludarabine 150 mg/m2 FB2 n= 41 • Modified myeloablative conditioning iv Busulfan 12.8 mg/kg iv fludarabine 160 mg/m2 FB4 n= 26 ATG only for unrelated and mismatched SCT

  10. Outcomes • 105 engrafted • Median follow-up 22 months (2-62), 63 pts alive, 49 died. • 34 died of relapse, 15 died of treatment-related complications. • cumulative incidence of TRM 14% (9-22%) (GVHD-9, organ toxicities-4, sepsis-1, graft rejection-1). • cumulative incidence of acute GVHD grade II-IV 36% , grade III-IV 14% • Cumulative incidence of chronic GVHD 47%

  11. Overall Survival 48% (37-59%)

  12. Prognostic factors • The most significant factor predicting survival was the status of disease at SCT

  13. Disease status p=0.0001 Remission; 69% Active disease; 31%

  14. To define the prognostic significance of chemotherapy intensity we compared outcome after the 3 different regimens used. ivBuCy Vs FB4 Vs FB2 (myeloablative, modified myeloablative, reduced-intensity)

  15. ivBuCy FB4 FB2

  16. p=0.05 FB4 8% ivBuCy 22% FB2 8%

  17. Toxicity and TRM

  18. FB4 FB2 ivBuCy

  19. ivBuCy FB4 FB2

  20. Active disease ivBuCY FB4 p=0.01 FB2 P=0.01 FB2

  21. Pts in remission FB2 FB4 ivBuCy p=NS p=NS

  22. Effect of chronic GVHD: Pts with active disease chronic GVHD no chronic GVHD

  23. Age < 50 years > 50 years

  24. Donor source Sib; 55% Unrelated; 37% p=NS

  25. Secondary origin AML MDS/ 2AML

  26. Cytogenetics other Poor p=0.01

  27. Prognostic factors - summary • Multivariable analysis shows that active disease is the most significant factor for adverse outcome. HR 4.5 (p=0.001) • Unrelated donor (HR 1.8, p=0.08) • Poor cytogenetics (HR 2.2, p=0.04)

  28. Conclusions • Disease status at SCT is the most important predicting factor of outcome. Conditioning regimen can be selected by disease status. • With new advances in SCT such as RIC and new conditioning regimens age is no longer an adverse risk factor. • The added risk of unrelated donor SCT is reduced.

  29. Conclusions – cont. • Patients in remission at SCT have similar outcome with the different regimens. • RIC has very good results in CR1 • Randomized study needed.

  30. Conclusions – cont. • RIC is associated with poor outcome in patients with active disease at SCT. • Patients should be conditioned with myeloablative or modified myeloablative regimens. • Patients ineligible for myeloablative regimens can tolerate FB4 well. • Randomized is warranted to compare BuCy and FB4 in eligible patients.

  31. Acknowledgments Izhar Hardan Moshe Yeshurun Noga Shem-Tov Ronit Yerushalmi Abraham Avigdor Isaac Ben-Bassat Arnon Nagler Nursing, laboratory, data management and coordinating staff

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