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University Hamburg Medical Center Dept of Stem Cell Transplantation

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1 University Hamburg Medical Center Dept of Stem Cell Transplantation
Allogeneic Stem Cell Transplantation for bcr/abl negative Myeloproliferative Neoplasm MPN Horizons 2016, November 2016, Belgrade, Serbia Nicolaus Kröger University Hamburg Medical Center Dept of Stem Cell Transplantation

2 Myeloproliferative Neoplasm
(Diseases of hematopoetic stem cell) CML Polycythemia vera Essent. Thrombocythemia Primary Myelofibrose bcr-abl + bcr-abl -

3

4 Treatment Options Can PV, ET or Myelofibrosis be cured? Answer:
Yes, but currently only by allogeneic stem cell transplantation

5 Treatment Options Why to treat and what is the treatment goal?
ET: Prevent thrombosis PV: Prevent thrombosis Reduce symptoms such as pruritus and symptoms of large spleen Myelofibrosis: a) Reduce symptoms such as weakness, splenomegaly, weight loss, night sweat, anemia, bone pain, b) Cure

6 Which patient should be considered for allogeneic stem cell transplantation?
PV general: no indication for allogeneic SCT ET general: no indication for allogeneic SCT Except: Transformation to post ET/PV MF Transformation to Acute Leukemia Myelofibrosis: yes : depending on status of the disease, donor availability and and also on age

7 Allogeneic Stem Cell Transplantation?
What can be achieved by Allogeneic Stem Cell Transplantation? Complete hematological remission including molecular remission Resolution of splenomegaly and constitutional symptoms Regression of bone marrow fibrosis Long-term survival (cure)

8 before allo MF-3 day +100 MF-0

9 Treatment Options for MPN: Allogeneic Stem Cell Transplantation
What is Stem Cell Transplantation?

10 Hematopoesis Bone Marrow Blood Platelets Erythrocytes Granulocyte
Megakaryocyt Platelets Multipotente Stem Cell Pluripotente Stem Cell Erythroblast Erythrocytes Granulocyte Hematopoietic Stem Cell Monocyte Myeloid Progentitor-cell T-Lymphocyte Stem Cell (neuronal, mesenchymal) Lymphoide Stem Cell prä T-Cell B-Lymphocyte prä B-Cell

11 Stem Cell Transplantation
autologous allogeneic

12 Why is Allogeneic Stem Cell-Transplantation curative and why are there complication?
T-Cells Graft versus Host (GvHD) Donor Recipient CD34+ stemcells Graft versus Myelofibrosis Effect

13 How to decide for allogeneic stem cell transplantation?
Allografting treatment related morbidity and mortality potential cure Consider also: Life expectancy without transplantation ? Cure rate with transplantation ? alternative options?

14 DIPSS: Dynamic International Prognostic Scoring System for PMF
Risk scoring system DIPSS: Dynamic International Prognostic Scoring System for PMF Factors Score Age > 65 years 1 Constitutional symptoms 1 Hb < 10 g/dL 2 Leukocytes > 25 x 109/L 1 Blood blasts > 1% 1 Risk groups Low 0 Intermediate-1 1-2 Intermediate-2 3-4 High ≥ 5 Passamonti F et al., Blood 2010, 115:1703-8

15 Survival by DIPSS category
Scott B L et al., Blood 2012;119:

16 Prerequisation for Allogeneic Stem Cell Transplantation
HLA-compatible donor

17 Need for a donor to perform allogeneic stem cell transplantation
1. Syngeneic (identical twin) 2. HLA-identical sibling 3. HLA-compatible unrelated donor

18 Hematopoietic Stem Cell Transplantation HLA-identical sibling

19 Unrelated Donor Register
Worldwide more than 20 million volunteers 80- 90% probability to find a suitable stem cell donor (for caucasian)

20 Transplant activity Europe 2013 (EBMT data base)
n= allogeneic SCT Passweg et al BMT 2015

21 How do we get the malignant cells out and the new stem cells into the patient?
Bone Marrow Blood Megakaryocyt Platelets Multipotente Stem Cell Pluripotente Stem Cell Erythroblast Erythrocytes Granulocyte Hematopoietic Stem Cell Monocyte Myeloid Progentitor-cell T-Lymphocyte Stem Cell (neuronal, mesenchymal) Lymphoide Stem Cell prä T-Cell B-Lymphocyte prä B-Cell

22 Bone Marrow Peripheral Blood Cord Blood
Hematopoietic Stem Cell Source Bone Marrow Peripheral Blood Cord Blood 1% 0,05%

23

24 Bone Marrow Peripheral Blood Cord Blood
Hematopoietic Stem Cell Source Bone Marrow Peripheral Blood Cord Blood 1% 0,05%

25

26 Allow engraftment of donor stem cells
Conditioning Three Aims: Allow engraftment of donor stem cells Reduce tumorload Immuno- suppression Anti-tumor activity Myeloablation Total Body irradiation and high dose chemotherapy

27 Engraftment of Stem Cells Provide space for new stem cells
Conditioning Three aims: Engraftment of Stem Cells Kill tumor-cells Immuno- suppression Anti-tumor activity Myeloablation Fludarabin T-lymphocyte of donor Provide space for new stem cells

28 Patient Donor Conditioning Stem Cells
Aplasia Stem Cell Transplantation

29 Immunological reconstitution
Patient Donor inpatient (ca. 4 weeks Conditioning Stem Cells Aplasia Stem Cell Transplantation Engraftment outpatient (> 1 year) Immunological reconstitution

30 Immunological reconstitution
Patient Donor inpatient (ca. 4 weeks Conditioning Stem Cells Aplasia Stem Cell Transplantation Engraftment outpatient (> 1 year) Immunological reconstitution

31 Immunological reconstitution
Patient Donor inpatient (ca. 4 weeks Conditioning Stem Cells Aplasia Stem Cell Transplantation Engraftment outpatient (> 1 year) Immunological reconstitution

32 Allogeneic SCT in PMF (Passweg et al., EBMT )
Ruxolitinib approval

33 Scenario of allogeneic SCT in Myelofibrosis
Pre-transplant strategies Transplantation strategies Post-transplant strategies 1. reduce spleen size by JAK inhibitor consider splenic irradiation or splenectomy in refractory patients with excessive spleen volume 2. improve constitutional symptoms by JAK inhibitors 3. improve iron overload by pre-transplant chelation 4. select optimal donor MRD → MUD → alternative donor 1. select patients according to DIPSS intermediate 2 / high risk 2. consider high risk molecular marker for intermediate 1 patients 3. perform conditioning with toxicity or dose-reduced regimen according to age and comorbidities 1. monitor molecular marker post transplant to assess minimal residual disease (MRD) 2. consider early discontinuation of immunosuppression or donor lymphocyte infusion in case of MRD 3. consider JAK inhibition in case of severe GvHD (within clinical trial)

34 Acknowledgement Haefaa Alchalby Tatjana Zabelina Anita Badbaran Boris Fehse Thomas Stübig Ioanna Triviai Francis Ayuk Max Christopeit Christine Wolschke Staff of the Department of Stem Cell Transplantation University Hospital Hamburg Giovanni Barosi Tiziano Barbui European Leukemia Net (ELN) Yves Chalandon Eduardo Olavarria Anja van Biezen Donal McLornan Marie Robin Kavita Raj Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation (EBMT) Dominik Wolf University Hospital Bonn Francesco Passamonti University Hospital Varese German MPN Study Group Members of the EBMT/ELN consensus panel


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