Stem cell transplantation for patients with AML in Republic of Macedonia: - 15 years of experience -

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1 Stem cell transplantation for patients with AML in Republic of Macedonia: - 15 years of experience - R E S E A R C H A S S O C I A T E P R O F. D - R Z L A T E S T O J A N O S K I

2 Definition Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haematopoietic progenitor cells which lose the ability to differentiate normally and to respond to normal regulators of proliferation. AML is the most common adult leukaemia, with an annual incidence of approximately 2.4 cases per 100,000 population up to the sixth decade, rising to cases in the seventh decade. The median age at presentation is approximately 68 years.

3 Incidence and Mortality Estimated new cases and deaths from AML in the United States in 2015: New cases: 20,830. Deaths: 10,460. Macedonia in 2015: New cases : 56 2,8 per population

4 FAB (1976) Classification M0 -- Undifferentiated AML M1 -- AML without maturation M2 -- AML with maturation M3 -- Acute Promyelocytic Leukemia M4 -- Acute Meylomonocytic Leukemia M5 -- Acute Monocytic Leukemia M6 -- Erythroleukemia (DiGuglielmo s) M7 -- Megakaryoblastic Leukemia

5 FAB vs WHO Classifications of Hematologic Neoplasm FAB criteria WHO criteria Morphology Cytochemistry Morphology Immunophenotyping Genetic features Karyotyping Molecular testing Clinical features

6 . High-risk acute myelogenous leukemia: treatment today and tomorrow. Gary J. Schiller

7 Treatment of AML-strategy Induction chemotherapy The aim: obtaining complete remission reduction of the blast cells in the marrow < 5% (inapparent) with normal picture of the peripheral blood Postremission therapy The aim: elimination of residual disease

8 Induction chemotherapy Gold standard 3+7 The anthracyclin drug for 3 days Cytarabine for 7 days Complete remission % Modification of standard chemotherapy High doses of Ara-C Purine analoges (fludarabina, 2-CDA) 6-TG etoposide

9 Postremission therapy The need of any post-remission therapy was established in the landmark study conducted by the ECOG in 1983 Intensification of remission High-dose cytarabine based regimens with anthracycline drug Allogeneic HSCT Autologous HSCT Maintance chemotherapy Low-dose Ara-C, 6-TG, anthracycline drug

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13 Overall Survival (%) 100 Cytogenetic and prognosis Favorable n= Intermediate n=1,072 67% 64% 62% 41% 25 Adverse n=163 0 Years % 11% D. Grimwade, et al, Blood, 1998

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17 Treatment of AML-strategy When considering who should be transplanted for acute myeloid leukemia (AML), it may be useful to consider four categories of patients. - patients who fail to achieve an initial remission with primary induction chemotherapy. - patients who achieve an initial complete remission, but subsequently relapse. - patients in first complete remission. - patients who should be transplanted at diagnosis without first undergoing standard induction therapy.

18 University clinic of Hematology Skopje, R.Macedonia The experience so far autologous 88 allogeneic sibling 351 Transplant procedures 239 PBSC 24 BM 84 PBSC 4 BM

19 Patients with AML treated with stem cell transplantation during Autologous Allogeneic sibling 52 (40%) 78 (60%) 130 AML transplants (52 pts or 40% allogeneic sibling and 78 pts or 60% autologous in CR1)

20 Allogeneic sibling transplants AML CML NHL ALL MM MPR MF AA MDS CLL 1% 4% 5% 1% 5% 1% 13% 1% 9% 60%

21 Autologous transplants % 40% 3% 33% 9% AML NHL ALL MM HD

22 Characteristics of AML allogeneic recepients 52 patients during Variables (%) Conditioning BuCy BuCy+M FlagIda 40(76%) 10 (19%) 2(5%) GVHD Acute Acute gr I/II Acute gr III/IV Chronic Disease status at Allo SCT Active disease Complete remission Sex Males Females Age at transplant 19(38%) 13(28%) 6(10%) 16(31%) 19(37%) 33(63%) 26(50%) 26(50%) 34 (12-56)

23 Characteristics of AML autologous recepients 78 patients during Variable Mean Minimum Maximum Std.Dev. age at diagnosis Months from diagnosis to SCT MNCx10(8)/kg CD34+/kg harvest (procedures) Plt transfusions Days with hospital stay Er transfusions Days with fever Engraftment (day) oral mucositis grade

24 Stem cell source in AML auto transplants PBSC 62 pts (80%) BM 16 pts (20%) Conditioning regimen for autologous transplantation BuCy 50 (62%) BuCy+M 2 (2,5%) BEAM 16 (21%) BAM 10 (12%) PBSC mobilisation regimen for autologous transplantation G-CSF 23 pts (37%) G-CSF+ VP mg/m2 39 pts (63%)

25 5 years OS in AML treated with allogeneic sibling transplantation 100% 90% Cumulative Proportion Surviving 80% 70% 60% 50% 40% 30% 20% 55% 10% 0% days posttransplant

26 5 years OS in AML according to disease status before allogeneic sibling transplantation 100% 90% Cumulative Proportion Surviving 80% 70% 60% 50% 40% 30% P= % 20% 10% 15% 0% days posttransplant CR AD

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28 5 years OS in AML in CR1 treated with autologous transplantation 100% 90% 80% Cumulative Proportion Surviving 70% 60% 50% 40% 30% 44% 20% 10% 0% Survival T ime (days)

29 The most frequent cause of death ( ) HLA-identical sibling Autologous Primary Disease (43%) GVHD (20%) Primary Disease (73%) IPn (1%) Infection (5%) Organ Failure (4%) IPn *(3%) Infection (14%) Other Cause (17%) Other (12%) Organ Failure (8%)

30 Leukemia (27 November 2014) doi: /leu Comparative therapeutic value of postremission approaches in patients with acute myeloid leukemia J Cornelissen, J Versluis, J R Passweg, and on behalf of the HOVON and SAKK Time-dependent multivariable analysis of allogenic hematopoietic stem cell transplantation (allohsct) (n=337) versus chemotherapy (n=271) or autologous HSCT (autohsct) (n=152) in 760 patients aged years with AML in CR1. Patients receiving allohsct showed improved overall survival (OS) as compared with chemotherapy (respectively, 57±3% vs 40±3% at 5 years, P<0.001). Comparable OS was observed following allohsct and autohsct in patients with intermediate-risk AML 60±4 % vs 54±5%. However, allohsct was associated with less relapse (hazard ratio (HR) 0.51, P<0.001) and better relapse-free survival (RFS) (HR 0.74, P=0.029) as compared with autohsct in intermediate-risk AMLs.

31 Leukemia (27 November 2014) doi: /leu Comparative therapeutic value of postremission approaches in patients with acute myeloid leukemia J Cornelissen, J Versluis, J R Passweg, and on behalf of the HOVON and SAKK AlloHSCT resulting in less NRM, but comparable outcome with respect to OS, RFS and relapse. Collectively, these results show that allohsct is to be preferred over chemotherapy as PRT in patients with intermediate- and poor-risk AML aged years, whereas autohsct remains a treatment option to be considered in patients with intermediate-risk AML.

32 Actuarial overall survival of patients with acute myeloid leukemia in first complete remission according to donor availability. Jan J. Cornelissen et al. Blood 2007;109: by American Society of Hematology

33 Autologous Blood Cell Transplantation Versus HLA-Identical Sibling Transplantation For Acute Myeloid Leukemia In First Complete Remission: A Registry Study From The Center For International Blood And Marrow Transplantation Research Armand Keating, Gisela DaSilva, Waleska S. Pérez, Vikas Gupta, et all. Haematologica February : IN MULTIVARIATE ANALYSIS THE INCIDENCE OF TREATMENT-RELATED MORTALITY WAS LOWER AFTER AUTOLOGOUS PERIPHERAL BLOOD TRANSPLANTATION THAN AFTER ALLOGENEIC BONE MARROW/PERIPHERAL BLOOD TRANSPLANTS [P=0.001], BUT TREATMENT FAILURE (DEATH OR RELAPSE) AFTER AUTOLOGOUS PERIPHERAL BLOOD WAS SIGNIFICANTLY MORE LIKELY [ P=0.011]. THE 5-YEAR OVERALL SURVIVAL, HOWEVER, WAS SIMILAR IN PATIENTS WHO RECEIVED AUTOLOGOUS PERIPHERAL BLOOD (N=230) [ P=0.071] OR ALLOGENEIC BONE MARROW/PERIPHERAL BLOOD (N=903). In the absence of an HLA-matched sibling donor, autologous peripheral blood may provide acceptable alternative post-remission therapy for patients with acute myeloid leukemia in first complete remission.

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36 Acknowledgments Prof.dr. Peter Cernelc Prof.dr. Joze Pretnar Prof.dr. Samo Zver Prof,dr. Uros Mlakar Ass.dr. Irena Zupan Preloznik Prof.Dr.Rozman Dr.Domanovic Dr.Lukic Mrs. Cvetka Flajs.

37 Skopje 2016 Thank you for your attention!