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 -

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%

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

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