Högdosbehandling med stamcellsstöd; andra indikationer Per Ljungman

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Högdosbehandling med stamcellsstöd; andra indikationer Per Ljungman

Andra indikationer MS; andra neurologiska sjukdomar Autoimmuna sjukdomar Solida tumörer

EBMT Activity Survey 2015: Main indications Allogeneic 1st HSCT Baldomero: Transplant Activity Survey Dec 2016 EBMT Activity Survey 2015: Main indications Allogeneic 1st HSCT Autologous Total Leukemia Lymphoma Plasma Cell disorder Solid tumor Non-malignant disorders Bone marrow failure Other Total 1st Transplants 11 743 1 574 567 38 1 985 827 123 16 030 539 8 143 11 187 1 478 223 26 21 596 12 282 9 717 11 754 1 516 2 208 149 37 626 Indication

Autologous HSCT in Europe 2015 1st HSCT JR. Passweg et al BMT (2017) March 13 Epub Baldomero: Transplant Activity Survey Dec 2016

Åldersincidens - MS

Etiologi - ärftlighet What causes MS? Risk för MS Vem som helst 0,1-0,2% Om MS hos förälder 0,25-0,5% syskon 2-4% enäggstvilling 25-30% Många gener identiferade HLA-DRB1*15 (ökadrisk) HLA-A*02 skyddar mot MS Ca 110 gene: IL7R, IL2R, IL22RA2 etc.

Typiskt sjukdomsförlopp

Disease course - prognosis MS är en mycket heterogen sjukdom. Varierande klinisk bild och prognos Naturförlopp efter 15 års sjukdom. 30% har lätt – måttlig funktionsnedsättning 50% kan gå utan hjälpmedel 15% I livet ( vs 88% av kontroller) Life expactancy: 10 års förkortning

Förlopp Skovvis 85-90 % Sekundärprogressiv (% av skovvis) Primärprogressiv 10-15 %

Autolog hematopoetisk stamcellstransplantation vid MS = Högdos cytostatika med autologt stamcellstöd Används sedan mitten av 1990-talet Bakgrund: MS patienter som genomgått denna behandling för annan sjukdom(leukemi) förbättrades även i sin MS, djurstudier Vi allogentransplanterade också några patienter med leukemi och MS 12 maj 2018

Behandling av MS Diagnos First line treatment Lågaktiv sjukdom: Högaktiv sjukdom First line treatment T Tecfidera T Aubagio Inj Interferon b InjGlatiramer acetat Second line treatment: Tysabri (Natalizumab) Gilenya (Fingolimod) Rituximab (CD20 ak) Third line treatment Lemtrada (alemtuzumab, CD52 ak) Autolog hematopoetisk stamcellstransplantation

Teori: Autoimmuniteten triggas perifert Teori: Autoimmuniteten triggas perifert. Räcker ej med genetisk defekt hos stamcellen för att trigga MS. ”Loss of tolerance”. Syfte: Eradikera befintligt autoreaktivt immunsystem Åstadkomma ett nytt , ”antigennegativt” immunsystem. ” Reset the immunsystem” Inducera tolerans

Conditioning therapy in MS Immunosuppressive Safe / low or no TRM (transplantation related mortality) Avoid further damage to injured axons and oligodendrocytes Avoid injury to tissue-specific stem cell compartments that may be important for CNS repair (irradiation) Minimize risk of fever and infections

Indikationer för HSCT vid MS 2016 Aggressiv skovvis förlöpande MS – dominans av inflammation. Svikt på annan konventionell behandling Tydlig god återhämtningsförmåga efter skov Låg grad av irreversibel skada i CNS Yngre patienter, <50 år

Tecfidera Aubagio Mabthera? Estimated efficacy versus risks of approved and experimental therapies for MS. The plot indicates estimated, approximate risks vs. efficacy measures for some approved and experimental MS treatments. Tecfidera Aubagio Estimated efficacy versus risks of approved and experimental therapies for MS. The plot indicates estimated, approximate risks vs. efficacy measures for some approved and experimental MS treatments. Estimated risks of life threatening unwanted effects are obtained from data available in the current literature.39–50 The percent relapse suppression observed in treated patients is presented as a surrogate of efficacy. The list of treatments is not meant to be exhaustive but to only include the agents that have immediate relevance for the HSCT trial design. Abbreviations: GA, glatiramer acetate; IFN-β, interferon beta; FTY, fingolimod; Mitox., mitoxantrone; CY, cyclophosphamide, Nataliz., natalizumab; Alemt., alemtuzumab, Hi-CY, high-dose cyclophosphamide, HSCT, autologous hematopoietic stem cell transplantation. Mabthera? Saccardi R et al. Mult Scler 2012;18:825-834 Copyright © by SAGE Publications

MÄTNING AV MS RELATERADE SYMPTOM OCH HANDIKAPP

> 600 MS patienter har behandlats i Europa ( EBMT 2016) > 100 behandlade i Sverige (2016) Ca 45 behandlade på Huddinge HSCT vid MS, 2016

Fagius et al Mult Scler. 2009 Feb;15(2):229-37 Abstract BACKGROUND: During the last 15 years, high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) has globally been performed for severe multiple sclerosis (MS). Most patients have been in progressive phase with long disease duration. As a rule, treatment effect has been minor or moderate. PATIENTS: Since 2004, we have performed HSCT in nine young patients with "malignant" relapsing-remitting MS. Criteria for treatment were short duration of disease; very frequent, severe relapses; recent improvement periods indicating potential for recovery after strong immunosuppression. FINDINGS: Median age at treatment was 27 (range 9-34) years, MS duration 26 (4-100) months, and annualized relapse rate 10 (4-12). Median Disability Status Scale (extended disability status scale, EDSS) at HSCT was 7.0 (3.5-8.0). Median follow-up time April 2008 is 29 (23-47) months. Median EDSS improvement is 3.5 (1.0-7.0), clearly surpassing most previous reports. One patient relapsed mildly with rapid recovery 7 months after HSCT. All patients are otherwise stable, median EDSS being 2.0 (0-6.0). Before HSCT, 61 relapses occurred in 82 patient months; during follow-up, one relapse in 289 patient months. CONCLUSION: This small series of patients with "malignant" relapsing-remitting MS suggests HSCT to be an effective treatment option for this relatively rare disease course. It further suggests that future criteria for HSCT in MS should be close to the present ones. N=9, 2004-2008, malignant relapsing-remitting MS, 27(9-34), EDSS 7(3.5-8), FU 29 (23-47) months

Burman J, et al. J Neurol Neurosurg Psychiatry 2014;0:1–6

HSCT för MS Svenska erfarenheter fyrtioåtta patienter kunde identifieras den första patienten behandlades i maj 2004 och den sist inkluderade patienten behandlades i april 2013 de flesta har behandlats i Uppsala (n=19) eller Stockholm (n=14); övriga patienter är relativt jämnt fördelade på de olika universitetssjukhusen 21

HSCT för MS Svenska erfarenheter M:F = 22:26 RRMS, n=40; SPMS, n=5; PPMS, n=2; PRMS, n=1 BEAM, n=41; cyklofosfamid n=7

HSCT för MS Svenska erfarenheter medelålder vid HSCT var 31 år (9-52) sjukdomsdurationen före HSCT var i medeltal 75 månader (4-300) annualized relapse rate (ARR) under året föregående HSCT var i medeltal 4,1 (0-12) medianpatienten hade prövat två andra behandlingar före HSCT (0-4)

HSCT för MS Svenska erfarenheter pre-HSCT AAR 4,1 >450 Gd+ median EDSS 6 post-HSCT AAR 0,03 5 Gd+/162 patientår median EDSS 4

HSCT för MS Svenska erfarenheter Four patients experienced relapses post-HSCT; three of these patients were put on glatiramer acatete after the relapse. One of these patients went on to have another relapse. This equates to a post-HSCT annualized relapse rate of 0.03 or one relapse for every 33rd year of follow up. Progression of EDSS was defined as deterioration by at least 0.5 points sustained at subsequent follow-up visits. Eight patients progressed with this definition. Over all, relapse free survival was 87 %; MRI event free survival was 85 %; EDSS score progression free survival was 77 %; and event free survival (i e no relapses, no new MRI lesions and no EDSS progression) was 68 % 25

HSCT för MS Svenska erfarenheter Presence of Gd+ lesions prior to HSCT was associated with a favorable outcome (event free survival 79 % vs 46 %, p=0.028). Other factors such as disease duration, relapsing-remitting disease course and EDSS were analyzed, but no statistically significant differences could be demonstrated (Figure 2). No difference could be demonstrated between patients treated with the BEAM/ATG protocol vis-a-vis patients treated with the cyclophosphamide protocol (event free survival 70 % vs 56 %, p=0.76). 26

Jämförelser HSCT vs betainterferon/alemtuzumab (24 months) alemtuzumab HSCT (60 months) freedom from disease 14 % 32 % 68 %

HSCT för MS Svenska erfarenheter Mycket av den funktionsnedsättning som uppstått året före HSCT går att reversera

Resultat Myeloablativt protokoll: 77-100% relapse fria trots avsaknad av annan bromsmedicin, 3-10 års uppföljning (Fassas 2011, Nash 2003, Saccardi 2005, Kraselova 2010, Buhrman 2014) Lymfoablativt protokoll: 60- 70% relapse fria 38% fick relapse eller nya MR lesioner inom 3 år efter HSCT (Carreras 2003, Burt 2009, Buhrman 2014) Ovanligt med tillkomst av nya MR lesioner efter HSCT. SPMS: Long-term progression-free outcome: 45% 12 maj 2018 Namn Efternamn

MS patienter behåller sin benägenhet till autoimmunitet Oligoklonala band i CSF kvarstår hos många. Relapse kan komma 20 år efter HSCT. 10% av alla MS patienter som genomgått HSCT utvecklar en annan autoimmun sjukdom (hypotyreos, ITP). Ökad risk vid protokoll innehållande Alemtuzumab Harold 2013

Complications and hospitalization No mortality No CMV or EBV reactivations 22 (10-38) days of hospitalization

Gällande svenskt protokoll Cy 2g/m(2) G-CSF 5ug/kg day+6 Cy/ATG Cy 50mg/kg dag -5 till dag -2 ATG dag -5 till dag -1 MP 1g dag -5 till dag -1

Varför fortfarande låg frekvens av HSCT vid MS? Brist på randomiserade studier Brist på långtidsuppföljning Överdriven rädsla för mortalitetsrisk? Flera nya MS läkemedel på marknaden senaste tiden Pengar – läkemedelsföretag? 12 maj 2018 Namn Efternamn

Andra neurologiska sjukdomar Sjukdom n Effekt Recidiv? CIDP 20 90% förbättrades 35% NMO 16 Ej rapporterat 81% MG 8 100% 0% Burman et al 2017

Andra autoimmuna sjukdomar Systemisk scleros SLE RA Crohn

JAMA 2014

Solida tumörer Germ cell tumors Ewing sarcoma Neuroblastom Diverse tumörer ffa barntumörer

Fig 1. Kaplan-Meier estimates of (A) progression-free survival and (B) overall survival for 364 patients. Published in: Nabil Adra; Rafat Abonour; Sandra K. Althouse; Costantine Albany; Nasser H. Hanna; Lawrence H. Einhorn; JCO  2017, 35, 1096-1102. DOI: 10.1200/JCO.2016.69.5395 Copyright © 2016 American Society of Clinical Oncology

Ewing

Figure 3. Kaplan–Meier estimates. From: Primary metastatic Ewing's family tumors: results of the Italian Sarcoma Group and Scandinavian Sarcoma Group ISG/SSG IV Study including myeloablative chemotherapy and total-lung irradiation Ann Oncol. 2012;23(11):2970-2976. doi:10.1093/annonc/mds117 Ann Oncol | © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com. 45