blood and marrow transplantation:...

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

49th EBMT (UK) NAP Group Meeting Cardiff, Wales

26 October 2018

Outline

Historical Review

Current Trends

Key Challenges

Lessons learnt

Transplant of the future

South Wales Blood and Marrow Transplant Programme

Historical Review

The ‘Father of Bone Marrow Transplantation’

E. Donnall Thomas

1920-2012

Photo courtesy Suzie Fitzhugh

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 chemo-

radiotherapy • 6 patients, two of whom had transient engraftment • No survival beyond 100d


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


BMT at 50: 1957-2007 Timeline of major developments


Appelbaum F, NEJM 2007 (357):1472-1475

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

European Milestones

Current Practice

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)


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


MSD Training Day Cardiff – 17 June 2009

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


AML: Percent new cases by age


SEER data, 2009-2013, all races, both sexes https://seer.cancer.gov/statfacts/html/amyl.html?statfacts_page=amyl.html&x=17&y=18,

accessed 2017.02.26

Median Age

at Diagnosis

67

https://seer.cancer.gov/statfacts/html/amyl.html?statfacts_page=amyl.html&x=17&y=18

Trends in BMT: 2004-09 v 2010-15 BSBMT 9th Annual Report (2018)

Parameter Allogeneic BMT by Era

2004-2009 2010-2015 % Change

N 4665 5982 +28%

>60 632 (14%) 1626 (27%) +157%

MUD 2412 (52%) 3721 (62%) +54%


Key Challenges

Key challenges for the future

Four key challenges for BMT services: – Dealing with capacity

– Predicting demand

– Donor selection

– Relapse/Toxicity


Baldomero: Transplant Activity

Survey Dec 2016

HSCT Activity in Europe 1990-2015:

Donor origin: 1st HSCT

Adult Transplant Activity 2000-2017

0

10

20

30

40

50

60

70

80

90

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

AUTO SIB MUD HAPLO


Key challenges for the future Four key challenges for BMT services:

– Dealing with capacity • Ambulatory strategy


– Donor selection



Trends in BMT: 2004/09 v 2010/15 BSBMT 9th 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% ↑ 94% ↑ 45% ↑ 65% ↑ 37% ↓

BM aplasia N/A 111% ↑

Myelodysplastic syndromes N/A 29% ↑

Myeloproliferative neoplasms N/A 132% ↑





• Trends for established indications changing • New indications (autoimmune disorders) • New (advanced) cellular therapies e.g. CAR-T cells

– Donor selection



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)


Likelihood of Finding a Matching Adult Donor

SOURCE: National Marrow Donor Program/ Be The Match 2012 fiscal year reports.




• 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?



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


Relationship between T-cells, GvHD and disease control


T-cell replete ↑ GvHD ↓ relapse

T-cell deplete ↓ GvHD ↑ relapse

Relationship between GvHD, relapse and survival

aGvHD TRM RR OS

0 27 41 57

I 35 34 53

II 42 31 52

III 74 16 24

IV 94 19 07


1. 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

www.ebmt.org #EBMTITC16

Relapsed AML with FLT3 ITD post SCT

Dr Hanadi Ezmigna Haematology and BMT Consultant

University Hospital of Wales, Cardiff, UK

DLI for relapsed acute leukaemia PAT Dx COND MRD

REL DLI Date

CD3 107/kg

Addn GvHD STATUS

JY AML RIC NO 2011 0.5 NO NO RIP @ 23m in CR

AD AML RIC NO 2011 1.0 NO YES RIP @ 5m – GvHD

MG AML RIC NO 2012 6.4 NO NO RIP @ 3m – disease

EA AML RIC NO 2012 1.0 IL2 NO RIP @ 4m – disease

AG AML MAC YES 2013 5.0 IL2+Inh YES Alive @ 33m in CR

RM ALL MAC YES 2014 5.0 Inh YES Alive @26m in CR

DH AML RIC YES 2015 1.0 NO YES Alive @ 11m in CR

CD AML RIC YES 2015 1.1 NO YES Alive @ 9m in CR


40

Survival by type of relapse:

Molecular versus morphological

Median OS: not reached v 119 days, P = 0.013

Research strategy for intervention

15.1% NPM1+

0.8% NPM1+/FLT3-ITD/NRAS+

2.1% NPM1+/FLT3-ITD/WT1+

0.4% NPM1+/FLT3-TKD+/WT1+

0.6% 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+

4.7% NPM1+/FLT3-TKD+

17.4% NPM1+/FLT3-ITD

0.6% NPM1+/WT1+/NRAS+

0.8% NPM1+/WT1+

7.6% NPM1+/NRAS+

0.2% NPM1+/CEBPA+/FLT3-TKD+

1.2% NPM1+/CEBPA+/FLT3-ITD+

1.2% NPM1+/CEBPA+ 1.0% CEBPA+/FLT3-ITD+

0.4% CEBPA+/FLT3-ITD+/WT1+

0.2% CEBPA+/FLT3-ITD+/FLT3-TKD+/WT1+

4.2% CEBPA+

0.4% CEBPA+/WT1+/NRAS+

2.5% CEBPA+/WT1+

1.2% CEBPA+/NRAS+

14.8% no mutation

2.7% FLT3-ITD+/WT1+

0.2% FLT3-ITD+/NRAS+

0.4% FLT3-ITD+/FLT3-TKD+

6.1% FLT3-ITD+

0.4% FLT3-TKD+/WT1+

0.4% FLT3-TKD+/NRAS+

0.2% WT1+/NRAS+

1.2% WT1+

2.7% NRAS+

3.3% MLL+

0.8% MLL+/NRAS+

0.6% MLL+/FLT3-TKD+

0.6% MLL+/FLT3-TKD+/WT1+

1.4% MLL+/FLT3-ITD

0.2% MLL+/FLT3-ITD/FLT3-TKD+

0.2% NPM1+/MLL+/FLT3-TKD+

0.4% NPM1+/MLL+/FLT3-ITD

Cytogenetically

normal AML

(7 markers; n=485)

Döhner et al. Blood. 2010;115: 453-74.

Is there a window period pre-MRD during which the bone marrow stroma becomes hostile to supporting normal haematopoiesis?

Slides courtesy Caroline Alvares and Jo Zabkiewicz

Lessons Learned & Transplant of the Future

BMT at 60: 1957-2017 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


BMT at 70: 1957-2027 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


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


CAR-T Cell Protocol – Lymphoma

-6 -5 -4 -3 -2 -1 0

Admission day

Fludarabine 30 mg/m^2, IV

Cyclophosphamide 500 mg/m^2, IV

REST REST Rest Days

CART Cellular Return


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


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


MSD Training Day London – 21 June 2010

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