1. Sekundär AML till MPN Transplantation vid MPN
Björn Andréasson
Okt 2018

2. Risk för leukemi vid ET Svensk-fransk studie med 795 MPN-patienter
Årlig risk för ET 0,37%, PV 0,38% och MF 1,09%
Samtliga patienter i studien utvecklade AML
Medelöverlevnad 4,6 mån, oavsett MPN vid diagnos.
Abdulkarim et al
EurJHaematol 2009

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Table 4
Intrinsic risk factors for disease transformation in PV and ET
Abbreviations: ET, essential thrombocythemia; MF, myelofibrosis; PV, polycythemia vera.
<img alt="statistics" src="/stat?jsdisabled=true&ncbi_db=pmc&ncbi_pdid=art-tables&ncbi_acc=&ncbi_domain=bloodcancer&ncbi_report=objectonly&ncbi_type=table&ncbi_objectid=tbl4&ncbi_pcid=/articles/PMC /table/tbl4/?report=objectonly&ncbi_app=pmc" />
Transformation
Clinical risk factors
Genetic risk factors
Post-PV MF
Age
JAK2V617F allele burden
Leukocytosis
Disease duration
Reticulin fibrosis
Splenomegaly
Post-PV Leukemia
Abnormal karyotype
TP53
RUNX1
Post-ET MF
Absent JAK2V617F mutation
ASXL1
Anemia
Post-ET leukemia
Thrombosis
Platelets ⩾1000 × 109/l
Cerquozzi S1, Tefferi A1
Blood Cancer J. 2015

4. 30% av AHD (antecedent hematologic disease) AML har haft MPN, Hulegård el al 2014

5. Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine Thepot Blood 2010

6. Överlevnad efter Post-MPN AML

7. Azacitidine or intensive chemotherapy for older patients with secondary or therapy-related acute myeloid leukemia. Dumas et al Oncotarget. 2017

8. Behandling av AML sekundär till MPN
Till patienter som kan vara kandidater för allogentransplantation: induktionsbehandling för AML enl vårdprogram, allotx vid remission
Till patienter som inte är kandidater för allogentransplantation: Vidaza eller ev studie
Supportive care

9. OS beroende på konitionering vid sekAML tx

10. Non-relaps morality efter tx sekAML

11. Transplantation of patients with ET and PV (Ballen et al 2012)

12. Stem cell transplantation in MF
Autologous: easy to collect CD34 cells, some improvement seen in spleen size and hemoglobin.
Myeloablative regimen: usually with high dose Cy and Bu or TBI. Most studies are older and not 100% comparable with modern studies
Reduced intensity regimen: most common regimes are based on Fludarabine with Bu or Melphalan or TBI.

13. DIPSS in170 MF patients (Seattle) Scott et al 2012

14. Risk model OS in 150 RIC transplanted patients (Hamburg)
Independently predictive for OS in multivariate analysis:
JAK2 wild type
Age >57 years
Constitutional symptoms
Alchalby et al 2012

15. The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries
1982 och 2009; 92 patienter with myelofibrosis; Sverige (64), Finland (12), Danmark (10) och Norge (6).
MAC n=40
RIC n=52
Gender m/f
30/10
28/24
Age at transplantation
46±12 (5-63)
55±8 (22-66)
Diagnosis PMF/post PV or ET MF
34/6
36/16
Lille score 0/1/2
7/15/17
11/26/14
Cytogenetic abnormal/normal
8/9
14/12
Donator type relative/sibling/MUD
8/18/14
2/19/31
Stem cell source BM/PBSC/BM+PBSC
14/24/2
0/51/1

16. Conditioning The majority of RIC patients (41/52) were treated with
regimen based on:
Busulfan , fludarabine and often ATG.
Some got fludarabine only and some got fludarabine and
melphalan.
Patients with MAC were, in 30 cases out of 40, treated with
cyklofosfamid in combination with busulfan or TBI.

17. Lille score Hb<1 ger 1p LPK <4 el >30 ger 1p Median survival:
Low risk : månader 18 patienter
Intermediate risk 1: 26 månader 41 patienter
High risk : månader 31 patienter

18. Acute GVHD Data from EBMT data base, 3 months after transplantation.
RIC gruppen 46/ MAC gruppen 29/40
33 no GVHD no GVHD.
6 had grade I had grade I
2 had grade II had grade II
5 had grade III–IV had grade III–IV.
Difference between groups p< 0,001.
Skin GVHD most frequent, liver and G-I GVHD

19. Survival Transplantation related death up to 100 days:
17,5% in the MAC group and 5,8% in the RIC group (p=0,096)
5 year survival (Kaplan-Meyer)
49% in the MAC group
59% in the RIC group

22. p=0.082

24. Need for DLI/secondary transplant
Myeloablativ conditioning
n=40
RIC
n=53
DLI 11
Reinfusion of stamcells without conditioning 3
Secondary transplatation 2 6

25. DLI and second transplantation
German study of 30 RIC treated MF patients
27 relapse and 3 graft-rejection
26 patients received 1-5 DLI (median 3) escalating dose
39% achieved CR

26. DLI and second transplantation
17 (13 non-responders to DLI) underwent a second transplant
15/17 from an alternative donor
9 patients reached CR and 3 patients PR
OS 2 year was 70% for all 30 patients

27. Salvage treatment DLI, escalating dose
Second transplantation, if possible from an alternative donor
Pre-treatment with JAK2 inhibitor?

28. Overall survival according to the presence or absence of the risk factor JAK2 p.V617F allele burden >1% at day 28 after allogeneic SCT: 15 patients were grouped in the low-risk arm (continuous line), 15 patients in the high-risk arm (dashed line).
Lange et al 2013

29. MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis Rondelli et al Blood 2014

30. Kröger et al Blood 2009

31. Non-relapse mortality and progression-free survival. CalR
Figure 2
Non-relapse mortality and progression-free survival. CalR
Cumulative incidence of (A) NRM, (B) PFS, and (C) OS after allo-SCT in relation to CALR mutation status.
Kröger et al 2017
Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt )
Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

32. Non-relapse mortality and progression-free survival. ASXL1
Figure 3
Non-relapse mortality and progression-free survival. ASXL1
Kröger et al 2017
(A) Relapse incidence and (B) PFS after allo-SCT in relation to ASXL1 mutation status.
Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt )
Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

33. Impact of ruxolitinib pretreatment on outcomes after allogeneic stem cell transplantation in patients with myelofibrosis. Shahnaz et al EurJHaematol 2018
Engraftment and incidence of acute GVHD grade II to IV and III/IV did not differ between groups (37% vs 39% and 19% vs 28%, respectively)
Non-relapse mortality at 2 years (23% vs 23%).
Trend for lower risk of relapse was seen in the ruxolitinib group (9% vs 17%, P = .2), resulting in a similar 2 year DFS and OS (68% vs 60% and 73% vs 70%, respectively).
No difference in any outcome variable could be seen between ruxolitinib responders and those who failed or lost response to ruxolitinib.

34. Spleen intervention pre transplantation?
Conflicting data on survival benefits of pre-tx splenectomy
Faster hematopoietic recovery in splenectomized patients
JAK2 inhibition pre-tx could be favourable; spleen reduction and better performance status. (studies planned and on-going)