MDS patienter med potentiellt botbar sjukdom Fortbildningdagarna i hematologi Uppsala 2016 Eva Hellström Lindberg, MD PhD Karolinska Institutet Hematologiskt Centrum Karolinska Universitetssjukhuset Stockholm
Jag vill diskutera följande Molekylär epidemiologi vid MDS Hur bedömer man risk vid MDS? Vilka möjligheter finns att åstadkomma bot och när skall de användas? Fall (Maria Creignou Karolinska) Ny pan-Nordisk studie för MDS patienter som skall transplanteras
WHO klassifikation för MDS 2008 Refractory cytopenia with unilineage dysplasia Refractory anemia with RS Refractory cytopenia with multilineage dysplasia +/- RS Refractory anemia with excess blasts (RAEB-1, 5-9% / RAEB-2 ≥10%) MDS-unclassified MDS with isolated del(5q) and BM blasts <5% Cazzola et al., Hematol Clin Oncol North Am 2010
WHO klassifikation för MDS 2016 MDS GruppKommentar MDS – SLDRS < 15% / < 5%* MDS – MLDRS < 15% / < 5%* MDS – RSRS ≥ 15% / ≥ 5%* SLD MLD MDS Isolated del(5q)En ytterligare ab OK, inte -7/7q- MDS – EB EB 1 EB 2 MDS – U 1% blaster i blodet SLD och pancytopeni Baserat på cytogenetik * Om SF3B1 mutation, räcker det med 5% RS för diagnos
Riskbedömning vid MDS Förväntad överlevnad AML transformation Komplikationer till cytopeni Sannolikhet att svara på olika behandlingar Sannolikhet att överleva en allogen stamcellstransplantation
Swedish cancer and quality registry Overall survival IPSS Low and INT-1 vs INT-2 and High Lower-risk Higher-risk Ejerblad E, INCA report patients with MDS or MDS/MPN Primary and therapy-related 95% coverage against cancer registry Complete follow-up for survival
Survival in Swedish low- and INT-1 MDS population : <70 and ≥70 years absoluterelative
International Prognostic Scoring System (IPSS) Score % BM blasts <5%5- 10% % % KaryotypegoodINTPoor-- Cytopenia Karyotype: good=normal, -Y, del(5q), del(20q), poor=complex (≥abnormalities) or chromosome 7 anomalies; Intermediate = other abnormalities Cytopenias: Hgb <10g/dl, Neutrophils <1.8x10 9 /L, Platelets <100x10 9 /L Greenberg, Blood 1997 Fler negativa prognosmarkörer -Anemi -Försämringstakt -Fibros -Vissa mutationer
IPSS-R – överlevnad och AML transformation Risk groupScore valueMedian survival (years) Very low ≤1,58,8 Low Intermediate 13,5 – 4,53.0 High Very high>60.8 OS AML free survival
Mer information om diagnostik samt mall för IPSS-R calculator/
Mutationer vid MDS Papaemmanuil, Blood 2013 Funktionella gengrupper 1.Splice factors, i.e. SF3B1, SRSF2 2.Epigenetic regulators, i.e. ASXL1, TET2 3.Signalling factor, i.e. NRAS, CBL 4.Transcription factors, i.e. RUNX1 5.Cohesin factors, i.e. STAG2
Overall Survival by Mutated Gene Hazard Ratio of Death Univariate Hazard Ratios and 95% confidence intervals IPSS-R Adjusted Hazard Ratios and intervals IPSS-M konsortium 2015 Dec ASH, 1500 patienter
TP53 mutationer Lindsley & Ebert, Annu. Rev. Pathol. Mech. Dis :21–47 Ebert et al, NEJM 2011 A subset of 439 patients (Ebert et al) with either TP53 mutation and / or a complex karyotype OS of patients with Blue: complex karyotype, WT TP53 Red: complex karyotype, mut TP53 Grey: non-complex, WT TP53
Alla mutationer utom SF3B1 påverkar negativt långtidsöverlevnad vid låg och hög-risk MDS Karimi et al, Haematologica 2015 Survival Freedom from AML
Antal mutationer har prognostisk betydelse Elli Papaemmanuil et al. Blood 2013;122:
Riskbedömning MDS Man född oklart men kraftigt inflammatorskt tillstånd Hyggliga blodvärden, hög cellhalt, blaster 2,5%, 46XY, trilinjär dysplasi (IPSS INT-1, IPSS-R low), 46 XY 3,5% p53 IHC+++ Huddinge 2014 – azacytidin, tveksam effekt – åter SÖS Återremitteras oktober Fortsatt <5% blaster och hyggliga blodvärden. Mår uruselt Mutationsstatus oktober 2015 TET245%patogen TET228%patogen RAD2146%oklar SRSF248%patogen TP5339%patogen ZRSR284%oklar Betydelse av NGS: Uttalad högrisk. Hade status varit känt 2014 självklar SCT kandidat. Nu död innan åb, hjärtinfarkt
Therapeutic Algorithm for Adult Patients with Primary MDS and Int-2 or High IPSS Score (European LeukemiaNet) Intermediate-2 or high IPSS risk Supportive care Azacitidine No suitable stem cell donor Poor risk cytogenetics ≥10% BM blasts Age ≥65-70 years or poor performance status Age ≥65-70 years or poor performance status Age <65-70 years and good performance status Age <65-70 years and good performance status ≥10% BM blasts, no poor risk cytogenetics Available stem cell donor Available stem cell donor <10% BM blasts Azacitidine Allo-SCT AML-like CT OR Azacitidine AML-like CT OR Azacitidine Allo-SCT AML-like CT or Azacitidine (within clinical trial or prospective registry ) AML-like CT or Azacitidine (within clinical trial or prospective registry ) Malcovati, Hellström-Lindberg, et al for the ELN network, Blood 2013
SCT är den enda botande behandlingen för MDS - fungerar inte att vänta till ytterligare progress Intermediate-2 or high IPSS risk Supportive care Azacitidine No suitable stem cell donor Poor risk cytogenetics ≥10% BM blasts Age ≥65-70 years or poor performance status Age ≥65-70 years or poor performance status Age <65-70 years and good performance status Age <65-70 years and good performance status ≥10% BM blasts, no poor risk cytogenetics Available stem cell donor Available stem cell donor <10% BM blasts Azacitidine Allo-SCT AML-like CT OR Azacitidine AML-like CT OR Azacitidine Allo-SCT AML-like CT or Azacitidine (within clinical trial or prospective registry ) AML-like CT or Azacitidine (within clinical trial or prospective registry ) Malcovati, Hellström-Lindberg, et al for the ELN network, Blood 2013 Viktiga frågor -Övre åldersgräns för SCT -SCT vid MDS med mycket hög risk -Post SCT MRD vid MDS -Förbättra pre SCT behandling -Förbättra post SCT behandling
Therapeutic Algorithm for Adult Patients with Primary MDS and Low INT-1 IPSS Risk (European LeukemiaNet) Low INT-1 IPSS risk Watchful waiting sEpo <500 mU/mL and/or RBC units <2/month sEpo <500 mU/mL and/or RBC units <2/month MDS del(5q) RBC transfusion and iron chelation therapy Age <60 years, BM blasts <5%, normal cytogenetics, transfusion- dependency (hypocellular bone marrow) Age <60 years, BM blasts <5%, normal cytogenetics, transfusion- dependency (hypocellular bone marrow) sEpo ≥500 mU/mL and RBC units ≥2/month rHuEpo +/- G-CSF rHuEpo +/- G-CSF Immunosuppressive therapy with ATG rHuEpo +/- G-CSF rHuEpo +/- G-CSF Lenalidomide (within prospective registry) Lenalidomide (within prospective registry) Asymptomatic cytopenia Symptomatic anemia sEpo <500 mU/mL and/or RBC units <2/month sEpo <500 mU/mL and/or RBC units <2/month Malcovati, Hellström-Lindberg, et al for the ELN network, Blood 2013 SCT if young / high-risk genetics
Vissa får är ulvar..... Low IPSS risk Watchful waiting sEpo <500 mU/mL and/or RBC units <2/month sEpo <500 mU/mL and/or RBC units <2/month MDS del(5q) RBC transfusion and iron chelation therapy Age <60 years, BM blasts <5%, normal cytogenetics, transfusion- dependency (hypocellular bone marrow) Age <60 years, BM blasts <5%, normal cytogenetics, transfusion- dependency (hypocellular bone marrow) sEpo ≥500 mU/mL and RBC units ≥2/month rHuEpo +/- G-CSF rHuEpo +/- G-CSF Immunosuppressive therapy with ATG rHuEpo +/- G-CSF rHuEpo +/- G-CSF Lenalidomide (within prospective registry) Lenalidomide (within prospective registry) Asymptomatic cytopenia Symptomatic anemia sEpo <500 mU/mL and/or RBC units <2/month sEpo <500 mU/mL and/or RBC units <2/month Malcovati, Hellström-Lindberg, et al for the ELN network, Blood 2013 Viktiga frågor -Hur kombinerar vi olika riskfaktorer -Hur bedömer vi mutationsprofil -EPO refraktär transfusionsberoende MDS -Risk vs livskvalitet
Therapeutic Algorithm for Adult Patients with Primary MDS and Low INT-1 IPSS Risk (European LeukemiaNet) Low IPSS risk Watchful waiting sEpo <500 mU/mL and/or RBC units <2/month sEpo <500 mU/mL and/or RBC units <2/month MDS del(5q) RBC transfusion and iron chelation therapy Age <60 years, BM blasts <5%, normal cytogenetics, transfusion- dependency (hypocellular bone marrow) Age <60 years, BM blasts <5%, normal cytogenetics, transfusion- dependency (hypocellular bone marrow) sEpo ≥500 mU/mL and RBC units ≥2/month rHuEpo +/- G-CSF rHuEpo +/- G-CSF Immunosuppressive therapy with ATG rHuEpo +/- G-CSF rHuEpo +/- G-CSF Lenalidomide (within prospective registry) Lenalidomide (within prospective registry) Asymptomatic cytopenia Symptomatic anemia sEpo <500 mU/mL and/or RBC units <2/month sEpo <500 mU/mL and/or RBC units <2/month Malcovati, Hellström-Lindberg, et al for the ELN network, Blood 2013 SCT if transplantable MDS 004, Fenaux et al, Blood 2011 Transfusion independency 50-60% Median response duration ≈2 years
Refractory anemia with ring sideroblasts Splice factor SF3B1 mutations in % of cases Better surivival, low risk for progression Good primary response to EPO + G- CSF Relapse in anemia usually not associated with clonal evolution Papaemmanuil, et al. N Engl J Med, 2011, Malcovati et al, 2015 Overall Survival HR.35, P=.007 HR.32, P=.005 All WHO MDS-RS Expanded erythropoieis Macrocytic anemia and transfusion dependency Ring sideroblasts
U2AF1 mutations are associated with AML progression and SF3B1 with stable disease 192 pts with MDS or high-risk AML Karimi et al, Haematologica 2015
PBSC n=16, 68% BM n=3, 33% SCT vid MDS Enda botande behandling Upp till år om “fit” Syskon mer eller mindre lika bra som MUD Haplo fortfarande inte utvärderat väl för äldre patienter Retrospektiva rapporter; DFS 35-50% Återfall huvudproblemet – Hög-risk genetik och CMML Age distribution Swedish registry
Five-group cytogenetic risk classification, monosomal karyotype, and outcome after Allo SCT for MDS or acute leukemia evolving from MDS, 1007 pts, median age 45y Deeg et al, BLOOD 2012 Monosomal karyotype RFS
Overall survival by mutational status. Bejar et al, JCO 2014, 87 patients Median age 58 (18-73) 24 RA / RCMD 42 RAEB 5 CMML
PBSC n=16, 68% Karolinska strategy for MDS SCT SCT candidate Possible SCT candidate Azacytidine ChemotherapyDonor search HLA typing Response + donorNo response Response evaluation after CT or 3 cycles aza + morbidity evaluation SCT (usually after aza cycle 4-6 or 2 CT cycles) CT or Azacytidine Experimental therapy
PBSC n=16, 68% BM n=3, 33% Post SCT Grad I-II GVHD troligen av godo Återfall inträffar upp till 3 år post SCT Sedvanlig chimerism mycket otillräcklig relapsmakör Behov av bättre MRD markörer som triggers för intervention
Individual molecular MRD monitoring for patients with MDS treated with allogeneic stem cell transplantation; the NMDSG14B study Magnus Tobiasson, NMDSG14B
Salvage therapy after relapse Aza + DLI (n=154; AML=124 MDS=28) Schroeder et al, BBMT 2015 Molecular relapse Chimerism / FISH PCR (TET2,NPM1,FLT3,MLL,WT1) n=19 Hematological relapse +/- 13% blasts n=135
Aim of study To develop molecular (MRD) markers for early detection of relapse, enabling pre-emptive treatment and reduced relapse rate. Initiated September 2016 Magnus Tobiasson, NMDSG14B
Splicing Factors (~50%) SF3B1 SRSF2 U2AF1 ZRSR2 Epigenetic regulators (~45%) ASXL1 ATRX1 EZH2 KDM6A SETBP1 DNMT3A IDH1 IDH2 TET2 Transcription Factors ETV6 BCOR BCORL1 CUX1 GATA1 GATA2 IKZF1 NPM1 TP53 PHF6 RUNX1 WT1 Kinase signaling BRAF CALR CBL CBLB CBLC CSF3R HRAS JAK2 JAK3 KRAS KIT MPL NRAS MYD88 PTPN11 RAD21 Cohesin complex RAD21 SMC1A SMC3 STAG2 Recurrently Mutated genes in MDS captured byTruSight Panel TruSight Panel Klinisk Genetik UU Svarstid: 3-4 veckor Pris: 9500 SEK
Pilot data based on ddPCR – Marios Dimitriou, KI, HERM ddPCR MNC from bone marrow 8/9 relapsed patients showed pos MRD >0.1% as the lowest MRD post SCT 12/14 remission patients showed neg MRD at some timepoint post SCT HEALTHY CONTROLMDS months 0.05%
Study design Two phases: Phase I – Observational study: collect MRD data and define trigger levels predictive for clinical relapse Ethical approval available (Dnr 2015/ ). Phase II – Interventional study: use trigger-levels to initiate pre-emptive treatment. Clone dynamics will be studied. New ethical approval need. Accredited lab for ddPCR needed Also: understand when pre-SCT treatment can be improved. Magnus Tobiasson, NMDSG14B
Study design, phase I Magnus Tobiasson, NMDSG14B
Handläggning av MDS med ålder och risk profil som gör SCT till ett behandlingsalternativ Vid diagnos: multiprofessionell konferens. Tänk ”SCT” för samtliga patienter NGS (TruSight eller motsvarande) för att stödja riskbedömning / identifiera eventuella mål för behandling Induktions CT eller azacytidine enligt MDS riktlinjer Enstaka fall SCT utan förbehandling Inkludera i NMDSG14B före sista BM före SCT. All NGS efter inklusion täcks av studiebudget TruSight panel – Uppsala – accredited method ddPCR analyseras på HERM, KI under phase I ddPCR – accrediterad metod under phase II Magnus Tobiasson, NMDSG14B
Acknowledgements Oxford – KI Sten-Eirik Jacobsen Petter Woll University of Pavia Mario Cazzola Luca Malcovati Funding King´s, London Ghulam Mufti Kyoto Seishi Ogawa Hannover Brigitte Schlegelberger Gudrun Göring Karolinska Institutet Martin Jädersten Magnus Tobiasson Mohsen Karimi Marios Dimitriou Leonie Saft Teresa Mortera Blanco Simona Conte Edda Elvarsdottir Monika Jansson Gunilla Walldin Asmaa Ben Azenkoud Ramin Tehranchi Maryam Nikpour Birgitta Sander Johanna Ungerstedt Julian Walfridsson Oxford Jackie Boultwood Andrea Pellagatti EU MDS Theo de Witte David Bowen Alex Smith, et al Hege Garelius