Hematopoietic stem cell transplantation

Emilian Snarski M.D. Ph.D. Ver 3.1 29.09.2016

What this presentation is about:

Basic history facts about bone marrow transplantation (BMT) Basic types of BMT Techniquest of stem cell harvesting Conditioning Standard indications for transplantation Experimental BMT – diabetes, multiple sclerosis and even HIV And future beyond BMT Presentation available on www.emiliansnarski.com If you want to read more, just follow the links in pdf:

Reference: Publications and suplementary links

What is hematopoietic stem cell

transplantation?

Transplant – tissue, organ, cell suspension

Hematopoietic stem cell transplantation – medical

procedure which bases on transplantation of

hematopoietic stem cells after the conditioning

of the recipient

The first Polish bone marrow transplantation:

Ola Przybylska 24 days after allotransplantation

(28.11.84)

5 years later

25 years later

First attempts of bone marrow

transplantation in the world – King Jan

Kazimierz University in Lvov, third from the

left Jan Raszek.

History of bone marrow transplantiation

in the world

1938 Jan Raszek: first clinical attempts to infuse marrow cells;

1945 Egon Lorenz and Leon Jacobson: sparing effect of bone marrow on lethally irradiated animals

1963 Georges Mathe: first successful allogeneic transplant in man

1968 Fritz Bach, Robert A. Good, Dirk van Bekkum: first successful HLA-matched allogeneic transplants

1970 E. Donnell Thomas: first successful transplants in leukemia, development of reproducible technology including total body irradiation.

1983 George Santos: development of megachemotherapy.

1979 John Goldman: first successful transplant of cells from the peripheral blood.

1988 Eliane Gluckman: first successful cord blood transplant

1997 Shimon Slavin: first „minitransplantations”

History of bone marrow transplantation

in Poland

History of bone marrow transplantation

in Poland

1984 Wiktor-Jędrzejczak et al.: First (and first successful) transplantation of allogeneic marrow

1985 Wiktor-Jędrzejczak et al.: First (and first successful) transplantation of autologous marrow.

1996 Hołowiecki et al.: First (and first successful) transplantation of allogeneic marrow from unrelated donor

1998 Lange and Wiktor-Jędrzejczak: First (and first successful) transplantation of allogeneic cord blood.

This guy succeeded in 25. transplantation

and this is why…he got Nobel Prize and

Polish Army sabre from us!

What clinical options do we have when it

comes to hematopoietic stem cells

transplantation?

1. Autologous – patient to himself: mobilization or cord blood

2. Allogenic – related donors: a) Brothers and sisters: syngenic, HLA

identical or haploidentical, cord blood b) Parents – HLA identical or

haploidentical c) Children – HLA identical or

haploidentical

3. Allogenic – unrelated donors

AUTOLOGOUS HEMATOPOIETIC

STEM CELL TRANSPLANTATION © Wiesław Wiktor Jędrzejczak

Allogeneic hematopoietic stem cell

transplantation

Recipient

Donor

Transplantation „Cured”

Chemotherapy Radiotherapy

Immunosupression Hematologic Recovery

Online movie showing the procedure: https://www.youtube.com/watch?v=JIWW4-CTC9I

Collecting stem cells AD 2016 Prof. Wiesław Wiktor-Jędrzejczak* (left) and Dr n. med. Emilian Snarski *who performed first bone marrow transplantation in Poland in 1984

How do we obtain stem cells for transplantation?

Donor + G-CSF for 4 days

Apheresis on the 5th day

How do we obtain stem cells for transplantation?

Why we use chemotherapy and radiotherapy

prior to transplantation?

1. The first idea was destruction of cells by radiation – so the marrow was needed to save a patient after the disease was eradicated

2. Later chemotherapy was added and doses were increased – to improve the results

3. The following decades brought the toxicity down – so more patients lived longer

4. After mortality went down the perspective has been shifted to long term life quality

How to prepare a patient to HSCT?

What advantage over standard chemotherapy does

HSCT give?

Autologous HSCT?

Allogenic HSCT?

How to prepare a patient to HSCT?

Myeloablation – desctruction of whole bone marrow and

immune system

Immunoablation – destruction of the immune system but

not the stem cells

Aktualne protokoły

kondycjonowania dostępne

na stronach EBMT

Conditioning prior to transplantation

BuCy: megachemotherapy conditioning

AD 1984

Megachemotherapy BuCy2 AD 2016

Why we use chemotherapy and radiotherapy

prior to transplantation?

„Several centres evaluated the use of TBI plus more than one drug, but no consensus was reached regarding the maximum tolerated doses. None of these regimens made any significant improvements to clinical outcome. Any reduction in relapse or rejection risk was usually accompanied by an increase in TRM. OS and DFS remained unchanged or worsened. Similarly, no study with “leukaemia-specific agents” such as ARA-C or VP16, showed superiority to Cy, a drug that is not used in the conventional treatment of leukaemia. So far, no single study has shown any conditioning regimen to provide better long-term survival than Cy/TBI or Bu/Cy.” EBMT Handbook 2012

Bone marrow transplantation = infusion

AD 2000 prof. Jędrzejczak

thawing of frozen marrow at

the transplant bed directly

prior intravenous injection to

the patient

Bone marrow transplantation = infusion

Prof. Jędrzejczak dr Fabien McClanahan

McClanahan

Evolution of BMT

Prof. Jędrzejczak dr Fabien McClanahan Patient

AD 2000 AD 2011 AD …….

Isolate everything Isolate but be Outpatient

„vernünftig”

BMT – It only takes 14 to 28 days to

regenerate immune system

The initial engraftment

takes just few weeks

Full immune reconstitution

takes months to years

Vaccinations have to be

repeated

What is the purpose of HSCT?

Medical purpose of HSCT – cure the disease or

prolonge the life of a patient with the best possible

quality

Acute leukemia

Lymphoma

Multiple myeloma

Aplasia

MDS

Autoimmune diseases

And other

What is the advantage of HSCT compared

to chemotherapy or standard drugs?

Can BMT heal any major disease „outside”

of hematology? – case of diabetes

Approaches to treat diabetes: 1. Insulin

2. Pancreas/islet transplatation

3. Stem cells enginered to produce insulin

4. Stem cells used to built new immune system

Diabetes – stem cells form a new immune

system

Bone marrow transplantation in diabetes

Reference: Autologous HSCT for Diabetes 2015

Black bar – proportion of patients that do not take any insulin First treatment ever to cause remission of diabetes in over 90% of cases

Diabetes – stem cells form a new immune

system

Bone marrow transplantation in diabetes

Reference: Autologous HSCT for Diabetes 2015

0 6 12 18 24 30 36 42 48 54 60 66 72 78

123456789

1011121314151617181920212223

Un

iqu

e p

atie

nt n

um

be

r

Time from HSCT (months)

- without insulin – 4/20 patients in follow up - on insulin – 16/20 patients in follow up

Diabetes – stem cells can secrete insulin

Reference: Autologous versus allogenic stem cell therapy for T1DM 2015

Reduction of insulin use by 50% Secretion of insulin in patients who had no insulin secretion Unsufficient block of the immune system

Reference: Autologous versus allogenic stem cell therapy for T1DM 2015

Diabetes – stem cells can secrete insulin

Reference: Bruce Blaus Wikipedia

Can BMT heal any major disease „outside”

of hematology? – case of multiple sclerosis

The disease can be stopped by transplantation of hematopoietic stem cells – no new activity up to 12 years

Reference: Lancet 2016 MRI Changes Relapses

Multiple sclerosis – stem cell form new immune system – stop disease activity

How good is that compared to current therapy? Stem cells vs Interferon (first line treatment)

Reference: Lancet 2016

Multiple sclerosis – stem cell form new immune system – stop disease activity

Pla

ceb

o

Inte

rfero

n

Ste

m c

ells

Relapses

Multiple Sclerosis – real life stories…

Reference: http://www.youtube.com/watch?v=JU3oJEJT_yo

Reference: Wikipedia

Case of BMT and HIV

THE BERLIN PATIENT (2008) „Lucky” coincidence of: HIV, leukemia, need for bone marrow transplantation and avaliability of the donor who had genes that made him resistan to HIV

Picture: Wikimedia

HIV – after BMT stem cells regenerate resistant immune system

In most people CCR5 is needed for HIV infection Mutated gene stops HIV virus and patients cannot be infected anymore

Reference: Clinical Trial with Cord Blood 2015

How we could use this: 1. Choose donors without the CCR5 gene 2. Use cord blood without the CCR5 gene 3. Use patient own stem cells and destroy the CCR5 gene

HIV – after BMT stem cells regenerate resistant immune system

What is an ideal bone marrow

transplantation?

Conditioning

Bone marrow transplantation

Regeneration of WBC after two weeks

No complications

Lives happily ever after

Life and BMT are not ideal

Patient has other diseases: diabetes, kidney failure, heart

disease…

Complications of the underlying disease….

Complications of the treatment…

GvHD

Infections: bacterial, fungal and viral

What complications should we prevent?

What complications can we prevent?

How to make BMT better?

Procedures, SOP, procedures, improvement,

international standards (JACIE)

Adherence to the procedures

How to make people adhere to the procedures?

How to make BMT better?

– case of Staphylococcus epidemidis

Survival after BMT

No infection

Bacterial sepsis

Staphylococcus spp. –

something that can be

prevented in 60-70%...

Reference: Bogusz, Snarski et al. 2016 submited

What if complications of the procedure lead

to the death of the patient?

Medical purpose of HSCT – cure the disease or

prolong the life of a patient with the best possible

quality

Does it make sense to do hematopoietic stem

cell transplantation?

What is my dream about transplantation?

My biggest dream about bone

marrow transplantation is that we

do not make any more bone

marrow transplantations

We use the immune system

instead

The story of Emma

Reference: NY Times Reference: Vimeo

Reference: Novartis

Modified limfocytes can kill tumor cells – stem cells turned into serial killers of cancer

Limfocyte + cancer receptor = destruction of cancer cells Growing list of diseases: Acute Leukemia, Chronic Leukemia, Multiple myeloma Cheaper than bone marrow transplantation and than many drugs

What the future holds?

Predictions AD 2016

CART – limfocytes will be trained

to kill many tumors

HIV – we might see HSCT that will

cure HIV infection

Cord blood – interesting news

might be coming this way

What the future holds?

Predictions AD 2015

Haploidentical transplantation –

we will not need unrelated

donors anymore

Outpatient transplantatin

HSCT in not hematologic diseases

Not direct competition with drugs

Conclusions:

Bone marrow transplantation in basic curative treatment to many hematologic diseases There are very interesting experimental options for transplantation: diabetes, HIV, multiple sclerosis The future belongs to transplantation of cells that will kill the cancer – CAR-T cells (Chimeric antigen receptor T cells) If you want to read more visit www.emiliansnarski.com

Hematopoietic stem cell transplantation

Emilian Snarski M.D. Ph.D. Ver 3.1 29.09.2016