Sekundär AML till MPN Transplantation vid MPN Björn Andréasson Okt 2018

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

<p class="nojs"> <strong>Warning:</strong> The NCBI web site requires JavaScript to function. <a href="/guide/browsers/#enablejs" title="Learn how to enable JavaScript" target="_blank">more...</a> </p> 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/PMC4670948/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

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

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

Överlevnad efter Post-MPN AML

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

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

OS beroende på konitionering vid sekAML tx

Non-relaps morality efter tx sekAML

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

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.

DIPSS in170 MF patients (Seattle) Scott et al 2012

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

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

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.

Lille score Hb<1 ger 1p LPK <4 el >30 ger 1p Median survival: Low risk 0: 93 månader 18 patienter Intermediate risk 1: 26 månader 41 patienter High risk 2: 13 månader 31 patienter

Acute GVHD Data from EBMT data base, 3 months after transplantation. RIC gruppen 46/52 MAC gruppen 29/40 33 no GVHD 7 no GVHD. 6 had grade I 12 had grade I 2 had grade II 7 had grade II 5 had grade III–IV. 3 had grade III–IV. Difference between groups p< 0,001. Skin GVHD most frequent, liver and G-I GVHD

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

p=0.082

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

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

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

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

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

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

Kröger et al Blood 2009

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 2017 23, 1095-1101DOI: (10.1016/j.bbmt.2017.03.034) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

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 2017 23, 1095-1101DOI: (10.1016/j.bbmt.2017.03.034) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

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.

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)