Blood and Marrow Transplantation: State-of-the-Art

Transcription

1 Blood and Marrow Transplantation: State-of-the-Art Dr Keith Wilson Senior Clinical Lecturer in Haematology, Cardiff University Honorary Consultant Haematologist, University Hospital of Wales Director, South Wales BMT Programme 49 th EBMT (UK) NAP Group Meeting Cardiff, Wales 26 October 2018

2 Outline Historical Review Current Trends Key Challenges Lessons learnt Transplant of the future

3 Historical Review

4 The Father of Bone Marrow Transplantation E. Donnall Thomas Photo courtesy Suzie Fitzhugh

5 Early milestones 1949: Peter Bent Brigham Hospital, Boston Work of Leon Jacobson Lethally irradiated mice survived if spleen or marrow was shielded (or if marrow was infused) 1955: Mary Imogene Bassett Hospital, NY Work with Joseph Ferrebee 1957 article of BMT in humans following chemoradiotherapy 6 patients, two of whom had transient engraftment No survival beyond 100d

6 Early milestones 1963: Fred Hutchinson Cancer Research Centre, Seattle Developed canine BMT model Worked out rudimentary DLA typing 1969: (Re)started human trials 1970: Published results in leukaemia 1972: Published results in aplastic anaemia 1975: Published a survival plateau suggesting cure 2012: Millionth transplant worldwide

7 BMT at 50: Timeline of major developments Appelbaum F, NEJM 2007 (357):

8 Presentation of the Nobel Prize by the King of Sweden in 1990

9 European Milestones

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16 Current Practice

17 Introduction Haematopoietic progenitor cell transplantation (HPCT) is an established treatment and, in many instances, the only means of cure for selected patients with malignant and non-malignant disorders HPCT can be broadly divided into two categories Autologous (AUTO) where the patient is his own donor Allogeneic (ALLO) where the donor is Either a family member, typically a matched sibling (SIB) Or a matched unrelated volunteer donor (MUD)

18 International Trends in HPCT Four key trends have emerged in the past two decades of HPCT: Increase in the number of HPCT performed Preferential use of peripheral blood as the source of progenitor cells Increase in the use of RIC transplants Increase in the use of unrelated donors

19 MSD Training Day Cardiff 17 June 2009

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21 Reduced Intensity Transplants Less toxic than conventional transplants Useful for patients considered unsuitable for conventional BMT Age Co-morbidities Depends primarily on a graft-v-tumour effect Not suitable for patients with rapidly progressing malignancy

22 AML: Percent new cases by age Median Age at Diagnosis 67 SEER data, , all races, both sexes accessed

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24 Trends in BMT: v BSBMT 9 th Annual Report (2018) Parameter Allogeneic BMT by Era % Change N % > (14%) 1626 (27%) +157% MUD 2412 (52%) 3721 (62%) +54%

25 Key Challenges

26 Key challenges for the future Four key challenges for BMT services: Dealing with capacity Predicting demand Donor selection Relapse/Toxicity

27 HSCT Activity in Europe : Donor origin: 1 st HSCT Baldomero: Transplant Activity Survey Dec 2016

28 Adult Transplant Activity AUTO SIB MUD HAPLO

29 Key challenges for the future Four key challenges for BMT services: Dealing with capacity Ambulatory strategy Predicting demand Donor selection Relapse/Toxicity

30 Trends in BMT: 2004/09 v 2010/15 BSBMT 9 th Annual Report (2018) Diagnosis AUTOLOGOUS 2010/15 v 2004/09 ALLOGENEIC 2010/15 v 2004/09 Myeloma 42% 84% Hodgkin lymphoma 5% 14% Non-Hodgkin lymphoma 31% 14% Leukaemia AML in CR1 AML not in CR1 ALL in CR1 CML in CP1 62% 46% BM aplasia N/A 111% Myelodysplastic syndromes N/A 29% Myeloproliferative neoplasms N/A 132% 94% 45% 65% 37%

31 Key challenges for the future Four key challenges for BMT services: Dealing with capacity Ambulatory strategy Predicting demand Trends for established indications changing New indications (autoimmune disorders) New (advanced) cellular therapies e.g. CAR-T cells Donor selection Relapse/Toxicity

32 Allogeneic Donor Selection Key parameters: HLA matching Donor age Donor/recipient CMV status Donor/recipient sex match Donor allo-immunisation (pregnancy/transfusion) (Donor/recipient ABO match) Alternative donors (cord blood/haploidentical)

33 Likelihood of Finding a Matching Adult Donor SOURCE: National Marrow Donor Program/ Be The Match 2012 fiscal year reports.

34 Key challenges for the future Four key challenges for BMT services: Dealing with capacity Ambulatory strategy Predicting demand Trends for established indications changing New indications (autoimmune disorders) New (advanced) cellular therapies e.g. CAR-T cells Donor selection Who is the ideal donor Is an ideal donor necessary? Relapse/Toxicity

35 HPC transplantation failure The main causes of treatment failure post HPC transplantation are: Toxicity Infection Haemorrhage Organ failure Graft-v-host disease Secondary malignancy Disease recurrence

36 Relationship between T-cells, GvHD and disease control T-cell replete GvHD relapse T-cell deplete GvHD relapse

37 Relationship between GvHD, relapse and survival agvhd TRM RR OS I II III IV EBMT registry data of sibling BMT (N = 5761). All statistics given at 15y. 2. agvhd = acute graft-v-host disease; TRM = treatment related mortality; RR = relapse risk; OS = overall survival

38 Relapsed AML with FLT3 ITD post SCT Dr Hanadi Ezmigna Haematology and BMT Consultant University Hospital of Wales, Cardiff, UK #EBMTITC16

39 DLI for relapsed acute leukaemia PAT Dx COND MRD REL DLI Date CD /kg Add n GvHD STATUS JY AML RIC NO NO NO 23m in CR AD AML RIC NO NO YES 5m GvHD MG AML RIC NO NO NO 3m disease EA AML RIC NO IL2 NO 4m disease AG AML MAC YES IL2+Inh YES 33m in CR RM ALL MAC YES Inh YES in CR DH AML RIC YES NO YES 11m in CR CD AML RIC YES NO YES 9m in CR

40 Survival by type of relapse: Molecular versus morphological Median OS: not reached v 119 days, P =

41 Research strategy for intervention 7.6% NPM1 + /NRAS % NPM % NPM1 + /WT % NPM1 + /WT1 + /NRAS + 1.2% NPM1 + /CEBPA + /FLT3-ITD + 0.2% NPM1 + /CEBPA + /FLT3-TKD + 1.2% NPM1 + /CEBPA + 1.0% CEBPA + /FLT3-ITD + 0.4% CEBPA + /FLT3-ITD + /WT % CEBPA + /FLT3-ITD + /FLT3-TKD + /WT % CEBPA + 0.4% CEBPA + /WT1 + /NRAS + 2.5% CEBPA + /WT % CEBPA + /NRAS + 0.8% NPM1 + /FLT3-ITD/NRAS + 2.1% NPM1 + /FLT3-ITD/WT % NPM1 + /FLT3-TKD + /WT % NPM1 + /FLT3-TKD/NRAS + 0.2% NPM1 + /FLT3-ITD/WT1 + /NRAS + 0.2% NPM1 + /FLT3-ITD/FLT3-TKD + /NRAS + 0.4% NPM1 + /FLT3-ITD/FLT3-TKD % no mutation 2.7% FLT3-ITD + /WT % FLT3-ITD + /NRAS + 0.4% FLT3-ITD + /FLT3-TKD + 6.1% FLT3-ITD + Is there a window period pre-mrd during which the bone marrow stroma becomes hostile to supporting normal haematopoiesis? 4.7% NPM1 + /FLT3-TKD + Cytogenetically normal AML (7 markers; n=485) 17.4% NPM1 + /FLT3-ITD 0.4% NPM1 + /MLL + /FLT3-ITD 0.2% NPM1 + /MLL + /FLT3-TKD + 0.2% MLL + /FLT3-ITD/FLT3-TKD + 1.4% MLL + /FLT3-ITD 0.6% MLL + /FLT3-TKD + /WT % MLL + /FLT3-TKD + 0.8% MLL + /NRAS + 3.3% MLL + 0.4% FLT3-TKD + /WT % FLT3-TKD + /NRAS + 0.2% WT1 + /NRAS + 1.2% WT % NRAS + Döhner et al. Blood. 2010;115: Slides courtesy Caroline Alvares and Jo Zabkiewicz

42 Lessons Learned & Transplant of the Future

43 BMT at 60: What have we learned and achieved? 1. Regenerative potential of marrow/spleen 2. Role of HLA in histocompatibility 3. Anti-leukaemic potential of graft (T-cells) 4. Reduced intensity conditioning 5. Efficacy of DLI in relapse 6. Regenerative potential of cord blood

44 BMT at 70: What do we still need to achieve? How to separate GvL from GvHD Lessons from cord blood T-cells less immunogenic More HLA disparity tolerated less GvHD No increase in relapse Double cord transplants Engraftment time proportional to total TNC dose Only 1 cord unit engrafts (and not necessarily the larger one) Not all T-cells are the same

45 Transplant of the future? Build on paradigm of RIC transplants Achieve MRD status Effective monitoring Timely intervention Minimally ablative allograft Mixed chimaerism to induce tolerance ( GvHD) Targeted immune therapy Modified T cells Lessons learnt from UCB and CAR-T cells

46 CAR-T Cell Protocol Lymphoma Admission day Fludarabine 30 mg/m^2, IV Cyclophosphamide 500 mg/m^2, IV REST REST Rest Days CART Cellular Return

47 Summary HSCT is now an established treatment RIC and advances in HLA typing have significantly contributed to safety and allow treatment of older patients Predicting and treating relapse remains a problem CAR-T therapy may show how to separate GvL from GvHD

48 Acknowledgements Adult Transplant Team Dr Wendy Ingram/Dr Emma Kempshall Dr Saad Al-Ismail/Dr Hamdi Sati ANP Sarah Doherty/Laura Ricketts/Bethan Ingram CNS Sheri Thompson/Nia Roberts/Hannah Woodington/Sophie Thomas/Rebecca Williams Practice Educator Martin Evans Apheresis Lead Nurses Jennefer Rose/Sophie Jones Stem Cell Processing Unit Sarah Phillips Serdar Killicer Quality/Data Management/Admin Team Dr Xiujie Zhao/Rey Consolación David Davies/Andrew Simmons Therésa Watkins Pharmacy/Dietetics Staff Physiotherapy/OT/Psychology teams Referring Clinicians SWBMT catchment area Patients and Families B4 Haematology Nursing Staff Haem Day Centre Nursing Staff TCT Nursing Staff Medical Staff Senior and Junior Paediatric Transplant Team Dr Philip Connor Nicola Gilbert Specialist Laboratories Rhian White Dr Steve Austin Steve Couzens WBMDR Emma Cook Kylie Jones WTAIL Jennifer Pepperall Chris Harvey BSBMT Data Registry Staff EBMT Registry Staff

49 MSD Training Day London 21 June 2010