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