Transplantace krvetvorných buněk
u hematologických malignit přehled
problematiky a současné trendy
Transplantace krvetvorných buněk
u hematologických malignit přehled
problematiky a současné trendy
Marta Krejčí
Department of Internal Medicine, Hematology and Oncology,
University Hospital Brno and School of Medicine, Masaryk University
15.3.2019
Autologous and allogeneic hematopoietic stem cell
transplantations: introduction, contemporary
indications and trends
Autologous and allogeneic hematopoietic stem cell
transplantations: introduction, contemporary
indications and trends
HEMATOPOIESIS
• Complicated and highly regulated
process of production of all blood
elements (erythrocytes, leukocytes,
platelets)
• All peripheral blood elements arise
from hematopoietic stem cells
(HSCs), these immature cells are
situated in microenvironment of
bone marrow
• HSC = 1 : 10 000 – 100 000
mononuclear cells of bone marrow;
HSC - ability of continuous
restoration
• HSC – ability to reproduce and to
differentiate to various blood lines
•
 Hematopoiesis – very complicated process, it arises from small
group of pluripotent stem cells of bone marrow.
These immature cells are able to reproduce and to
differentiate to various blood lines with production of mature
blood cells - leukocytes, erythrocytes and thrombocytes.
 Immature hematopoietic stem cells have got on their surface
antigen structure CD34, this is very important and typical sign
for these cells.
 Special flowcytometric examination of bone marrow or
peripheral blood – easy identification of these immature
hematopoietic cells according to the surface antigen CD34
Adam Z et al. Special Oncology. Galen 2010, 417 pages.
Hematopoiesis, hematopoietic cells of bone
marrow, peripheral blood stem cells – I
 Open communication between bone marrow (BM) and
peripheral blood (PB); in bone marrow are mostly immature
or partially mature cells, in peripheral blood mostly mature
cells.
 Peripheral blood stem cells (PBSC) – hematopoietic cells – can
be present in peripheral blood in some specific cases, such as
regeneration of BM after administration of chemotherapy or
application of leukocyte growth factor (filgrastim, G-CSF)
 Mobilization and harvest of PBSC – using for transplantation of
hematopoietic cells
Hematopoiesis, hematopoietic cells of bone
marrow, peripheral blood stem cells – II
Adam Z et al. Special Oncology. Galen 2010, 417 pages.
Hematopoietic stem cell transplantation (HCT)
 refers to any procedure where haematopoietic stem cells of any
donor type and any source are given to recipient with the intention
of repopulating and replacing the haematopoietic system in total or
in part.
 Sources of hematopoietic cells – bone marrow, peripheral blood,
cord blood
 Two main types of HCT:
 autologous (donor = recipient)
 allogeneic (donor = HLA identical sibling or matched unrelated
donor)
(Ljungman P et al., BMT 2010)
Definition of transplantation ( HCT)
1891 - Sequard a D’Arsenoval - BM perorally in anemia
1937 - Schretzenmayer - BM subcutaneously in some infectious diseases
1944 - Bernard – application of allogeneic bone marrow to bone marrow cavity
1948-1950 – first experiments about transplantations after radiation and
chemotherapy
1950-1966 - 417 transplantations of bone marrow were performed, but only
three patients were alive
1969 – the first “modern“ allogeneic HSCT from HLA identical sibling,
in Leiden, Netherland
1974 – establishment of European Society for Blood and Marrow
Transplantation, EBMT – start of new transplant era
1978 – the first transplantation of peripheral blood stem cells
1990 – start of HCT program in Czech Republic
2019 – HCT – still very actuall topic, the increasing of HCT procedures in Europe
and in Czech Republic
Hematopoietic stem cell transplantation (HCT)
– history in Europe
 Hematopoietic stem cell transplantation –intravenous
application of PBSC or BM graft to recipient, application
to central vein catheter ( mostly in vena subclavia)
 Administration of conditioning – preparative regimen
before HCT –usually combination of cytostatic drugs or
combination of cytostatics and total body irradiation (TBI)
 Main indications for HCTs: hematological malignancies
(90%), but HCTs are performed in many other diseases, such as
aplastic anemia, solid tumors and others
HCT – introduction - I
 Application of high-dose chemotherapy is toxic, there are two
main types of treatment toxicity: hematologic and nonhematologic
(main toxicity examples: bleeding, infections,
mucositis – involvement of oral cavity and GIT tract, organ
failure).
 We can eliminate serious hematologic toxicity with
application of PBSC or BM graft.
 Engraftment after HCT and sequential recovery of
hematopoiesis – usually in interval 2-3 weeks after PBSC
graft. In HCT with BM graft is recovery interval longer.
HCT – introduction - II
 Autologous transplantation - hematopoietic stem cells of patient (donor
=recipient) are used.
 Allogeneic transplantation – hematopoietic stem cells of optimal health
donor are used from sibling donor or unrelated donor, donor and
recipient are different persons.
 Optimal allogeneic donor – HLA identical sibling or well-matched
unrelated donor from donor bone marrow registers (national or
international registers)
 A well-matched unrelated donor (MUD) is defined as a 10/10 or 8/8
identical donor based in HLA high-resolution typing for class I (HLA-A,-B,C)
and II (HLA-DRB1, DQ-B1).
 Alternative allogeneic donor: mis-matched unrelated donor (MMUD) -
9/10, 8/10), haploidentical donor (family donor with only one HLA
haplotype), blood core donor
HSCT – introduction - III
 Main post-transplant complications:
 toxicity of conditioning (preparative regimen)
 failure and rejection of graft
 infections
 graft-versus host disease (GvHD)
- in allogeneic transplantation
 relaps/progression of basic disease (acute leukemia)
 Allogeneic HCT and conditionings
for the first time only myeloablative regimens (MAC),
later (from 1990) non-myeloblative conditionings or reduced-intensity
conditionings (RIC)
 RIC regimens
immunossupresive effect, lower toxicity, lower anti-tumor effect
HCT – introduction - IV
Sources of hematopoietic cells – bone marrow –
region of aspiration of bone marrow from pelvis
(spina illiaca posterior superior)
19801970 1990 20191960
Progenitors in mouse
blood.
Goodman and Hodgson,
Blood 1962
Progenitors in human
blood. McCredie,
Science 1971
Using PBSC for autoTx.
Goldman, Lancet 1978
High levels of
progenitors in blood
after chemotherapy.
Richman, Blood 1976
Discovery of antigen
CD34. Civin, J Immunol
1984
Discovery of G-CSF.
Welte, Proc Natl Acad
Sci USA, 1985
The first using PBSC for
alloTx.
Abrams, Blood 1980
Mobilization PBSC by
GM-CSF. Socinski,
Lancet 1988
Mobilization PBSC by
G-CSF.
Duhrsen, Blood 1988
AlloTx - using PBSC
after mobilization with
G-CSF.
Weaver, Blood 1993
Approval of using
G-CSF in MUD. Lane,
Transfusion, 1996
Peripheral blood stem cells (PBSC)
- time evolution of knowledges PBSC
in 2019:
source of hematopoietic
cells in 90% of all transplants
Buffy coat (layer of white blood cells – leukocytes,
in this coat the PBSC are situated after PBSC
mobilization)
Principle –
centrifuge
loop
Harvest
of PBSC
Bag of PBSC – storing in liquid nitrogen
(temperature -196 °C) in tissue bank
Autologous
High anti-tumor intensity
Without immunosuppression
Short risk of infections
TRM < 5%
(mortality associated with transplantation)
Relapses of disease
Allogeneic
Predominantly
immunosuppressive efect
Long-term immunosuppressive
therapy
Higher risk of infections
TRM 20-30%
Graft-versus host disease (GvHD)
Autologous and allogeneic
transplantations - main differences
 Composition according to main diagnosis
 Aim – maximal anti-tumor effect
 Conditioning usually contains some alkylating drug
– busulfan, melphalan, carmustin (BCNU), cisplatin,
carboplatin, cyclophosphamide
– Why? Effect of alkylating drug is independent to phase
of cell cycle.
 Combination with total body irradiation (TBI)
– usually in lymphoid malignancies
Conditioning – preparative regimen –
application before HCT
Intensity
Toxicity
Severe or irreversible nonhematological
toxicity
Severe or irreversible
hematological toxicityTherapeutic effect
Medium hematological
toxicity
Moderate hematological
toxicity
Intensity and toxicity of conditioning
 Total body irradiation+cyclophosphamide (TBI/CY) –
myeloablative
 Busulfan + cyclophosphamide (Bu/Cy) -myeloablative
 Reduced intensity conditionings (RIC)
– Non-myeablative regimens, high immunosupressive effect, lower
toxicity (mostly containing of fludarabine, anti-thymocyte
globulin). RIC examples: FLAMSA/RIC Cy+TBI, BuFlu+ATG
 BEAM - myeloablative
– Autologous transplantation in lymphomas
 High-dose melphalan 200mg/m2 - myeloablative
– Autologous transplantation in multiple myeloma
Various types of conditionings
-12 -11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0
Fludarabine 30 mg/m2
Cytarabine 2g/m2
Amsacrine 100 mg/m2
Cyclophosphamide (Cy)
40-60 mg/kg
ATG
10-20 mg/kg
TBI 4 Gy
Prophylactic application of DLI:
In patients with AML remission from day +120 after transplant
(Schmid et al., JCO 2005; 23:5675-5687) GvHD profylaxis:
CsA, mycophenolate
mofetil, ATG
Example of sequential administration of chemotherapy
and RIC regimen - FLAMSA/RIC protocol
GvHD (graft-versus host disease)
 one of main complications of allo-HCT
 Compatibility between donor and recipient – main role in
etiopathogenesis of GvHD
 Antigens of recipient are recognized with donor Tlymphocytes.
Donor T-lymphocytes are presented in PBSC graft. These
cells form GvHD reaction, but also graft versus tumor reaction (GvT
reaction), which is positive for recipient.
 GvHD – proliferation and differentiation of donor Tlymphocytes,
tissue damage of recipient, development of
GvHD symptomatology.
Complications of allo-HCT - GvHD
 Clinical symptoms are very variable, the first signs of acute
GvHD are usually appeared from day+30 after allo-HCT,
acute GvHD to day +100 after allo-HCT
 Usually involvement of skin, liver, or gastrointestinal
involvement (GIT symptomatology – nausea, loss of weight,
vomitus, diarrhorea, abdominal pains)
 GvHD- mostly combination of involvement more organs or
systems, but only one organ or system involvement (skin or
oral cavity mucosa) is possible too.
 GvHD intensity is also very variable.
Acute GvHD
Three phases: - afferent phase
- induction and expansion phase
- effector phase
Phase I – host tissue damage, induction of increasing of inflammatory
cytokines-IL2, TNF, IL6; increasing expression of HLA antigens on the surface
antigen-presented cells of recipient
Phase II – activation of donor
T-lymphocytes
Phase III – cytotoxic damage
recipient cells with clinical
manifestation of GvHD – skin,
GIT tract, liver, lung and others
Etiopathogenesis of acute GvHD
 Standard combination of cyclosporine A (CsA) and methotrexate
(MTX)
 Other possibilities – combination of CsA and mycophenolate
mofetil, combination tacrolimus+sirolimus
 Anti-thymocyte globulin – important part of conditioning, GvhD
prophylaxis in allogeneic HCT from unrelated donors
 CsA: calcineurin inhibitor with strong immunosuppressive effect blockade
of transcription IL-2 and other cytokines in activated T-
lymphocytes
 Adverse events of CsA: hypertension, nephrotoxicity, tremor,
hirsutism, hyperkalemia, hypomagnesemia
Prophylaxis of acute GvHD - possibilities
 Standard first-line treatment aGvHD: corticosteroids in dose
2mg/kg for 7-14 days, after this period decreasing of
corticosteroids, this therapy is effective in 50-60% of pts
 Categories of treatment responses: complete response (CR), partial
response (PR), stable disease (SD), progression (PD)
 Steroid-refractory GvHD - no response to cortisteroids, this is
very complicated treatment situation, treatment possibilities
for steroid-refractory GvHD are effective only partially
 Steroid-refractory GvHD - associated with high morbidity and
mortality
Therapy of acute GvHD
Acute GvHD after allo-HCT:
involvement of skin and oral mucosa
Shapira MY et al. BMT 2005; 36:1097–1101.
Steroid-refractory skin GvHD
after allogeneic HCT
 Very different and various clinical course, from mild
involvement of one organ to multiorgan involvement with
high morbidity and mortality; mostly from day +100
 Symptoms cGvHD – can be similar as symptoms of
autoimmune diseases – such as systemic lupus
erythematosus, Sjögren syndrome, skleroderma or
rheumatoid arthritis
 Serious cGvHD – treatment by systemic immunosupressionincidence
at 30-70% of pts after allo-HCT, mostly long-time
GvHD treatment
Chronic GvHD
 1-2 mismatches in I or II class of HLA system
 Previous aGvHD grade II and higher
 Peripheral blood stem cells versus bone marrow
 Higher age of recipient
 Female donor for male recipient
 Female donor after more pregnancies
 Unrelated donor versus sibling donor
Risk factors for development of cGvHD
1. The presence of at least 1 diagnostic clinical sign of chronic
GvHD (e.g. poikiloderma, oral lichen planus=oral mucosal
specificic lesions and many others)
2. The presence of at least 1 distinctive manifestation
(e.g. keratoconjuctivis sicca and others) confirmed by
pertinent biopsy or other relevant tests (e.g. Schirmer test)
in the same or another organ
Filipovich AH et al., BBMT, 2005
Diagnosis of chronic GvHD
– NIH consensus (Filipovich 2005)
 Course of cGvHD - typically long-term process, with
repeating exacerbations of GvHD. It takes for several months
or years.
 Aim of treatment - to interrupt of destructive immunologic
process, to reduce of clinical symptoms and to stop
progression cGCHD to stage of irreversible damage of
organs.
 Systemic immunosupressive (IS) treatment - in medium or
severe forms of cGvHD (extensive previously)
 In mild form cGvHD (limited previously) - mostly sufficient
local IS therapy
Therapy of cGvHD
Economic point of view – cost of autologous HCT aproximatelly
105 Czech crowns or 3333 Euro;
cost of allogeneic HCT- approximatelly 106 Czech crowns
or 33 333 Euro.
(example from real life: patient after allo-HCT: sum for one year financial
cost according to health insurance company: 4.5 million of Czech crowns =
150 000 Euro)
Medical point of view – achievement of cure or
prolongation of remission of disease
Ethical point - emphasis on quality of life, return to
common life, return to job and family life
Why we can still try to improve
the results of HCT?
Success versus failure of HCT
 Correct indication of HCT – using of prognostic factors for
various diseases and transplant risk score
 Optimal timing of HCT
 Optimal choice of conditioting
– decreasing of post-transplant toxicity  RIC regimens
(reduced-intensity conditionings)
 Influencing of GvHD (graft-versus host disease) in allo-HCT
– accent to GvHD prophylaxis - using of anti-thymocyte
globulin (ATG); effort to improving of steroid-refractory
GvHD therapy
 Modification of GvL effect (graft-versus leukemia effect)
– prophylactic application of donor lymphocyte infusions (DLI)
in high-risk patients with aim to prevent relaps of disease
How to improve of HCT results?
Positive factors:
Lower toxicity, it is possible to transplant older patients with
presence of comorbidities
Negative factors:
Higher risk of relapses, low effectivity for patients with acute leukemia
How to improve results of HCT after RIC regimen?
 Sequential application of chemotherapy and RIC regimen
–higher anti-tumor effectivity
 Prophylactic application of ATG – with aim to impact GvHD
 Prophylactic application of DLI (infusion of donor lymphocytes)
with aim to induce GvL effect
Reduced intensity regimens in allo-HCT
A record number of 40 829 HCT in 36 469 patients were reported
by 656 centers in 47 countries to the 2014 survey of the European Society of
Blood and Marrow Transplantation (EBMT).
 40 829 HCT in 36 469 patients were performed per year in Europe,
 15 765 allogeneic HCT (43%)
 20 704 autologous HCT (57%)
 HCT in children – 4400 procedures, 11% of all HCT,
3279 allogeneic and 1121 autologous
Hematopoietic stem cell transplantation
(HCT) in Europe
HCT is an established procedure for many acquired and
congenital disorders of the hematopoietic system,
including some disorders of the immune system
Passweg JR et al., BMT 2016
 International recommendations – are updated
repeatedly
 EBMT recommendations: the last 6th special report:
Sureda A et al. Indications for allo- and auto-SCT for
haematological diseases, solid tumours and immune
disorders: current practice in Europe 2015. Bone
Marrow Transpl 2015: 1037-1056
 National Czech recommendations – according to the
EBMT guidelines
 Transplant section of Czech Haematology Association
(the last version of recommendations from year 2016)
Indications for allo- and auto-HCT
1. Standard of care (S): results compare favourably to those
of non-transplant treatment approaches.
2. Clinical option (CO): HCT as a valuable option for
individual patients after carefull discussion of risks and
benefits with the patient
3. Developmental (D): limited experience with this
indication, additional research is needed to define role of
HCT
4. Generally not recommended (GNR): disease in a phase or
status in which pts are conventionally not treated by HCT
Evidence grading: evidence from randomized trial (I), evidence from welldesigned
clinical trial (II), other possibilities (III)
Sureda A et al., BMT 2015
Categorization of transplant procedures
1. Performance of HCT – this procedure has got a lot of risk
for pts, the major problems – infections, toxicity, GvHD.
Transplants may be performed in a specialized centre with experience
with HCT procedures and an appropriate infrastructure – in Czech
Republic 10 hemato-oncology transplant centres – in University Hospital Brno, Prague,
Pilsen, Hradec Kralove, Olomouc, Ostrava
2. Indications for HCT- influence of many factors – whole
clinical status, presence of comorbidities, age, status of main disease,
prognostic factors, availibility of donor and others
3. Allogeneic HCT - EBMT risk score (Gratwohl et al., Cancer,
2009) and comorbidity index (HCT-CI skore, Sorror et al., Blood
2005) – carefull balancing of the risk of allo-HCT against the risk
factors and course of disease in each individual patient
HCT – complications
Survival and TRM of 56,605
patients with an allogeneic
hematopoietic stem cell
transplantation for an acquired
hematological disorder is
shown by risk score.
Graphs reflect probability of
survival (Top) and transplantrelated
mortality (Bottom) over
the first 5 years after HCT.
Gratwohl A et al, Cancer, 2009
EBMT transplant risk score
Passweg JR et al., BMT 2016
Transplant rates in Europe (= total number of auto- and allo-HCT
per 10 million inhabitants): comparison of 1998 and 2013
Allogeneic HCT – rates in Europe 2014
Passweg JR et al., BMT 2016
Autologous HCT – rates in Europe 2014
Passweg JR et al., BMT 2016
Allogeneic
1st HCT
Autologous
1st HCT Total
Leukemia
Lymphoma
Plasma Cell disorder
Solid tumor
Non-malignant disorders
Bone marrow failure
Other
Total 1st Transplants
11348
1712
580
44
1942
833
139
15765
505
8089
10421
1414
261
4
14
20704
11853
9801
11001
1458
2203
837
153
36469
Indication
EBMT Activity Survey in 2014:
Main indications
Passweg JR et al., BMT 2016
Baldomero: Transplant Activity
Survey Dec 2015
Allogeneic HCT in Europe 2014
- indications and diagnoses
Passweg JR et al., BMT 2016
Baldomero: Transplant Activity
Survey Dec 2015
Autologous HCT in Europe 2014
- indications and diagnoses
Passweg JR et al., BMT 2016
Baldomero: Transplant Activity
Survey Dec 2015
HCT activity in Europe 1990 - 2014:
Transplant type 1st HCT
Passweg JR et al., BMT 2016
Baldomero: Transplant Activity
Survey Dec 2015
HCT activity in Europe 1990 - 2014:
Donor origin: 1st HCT
Passweg JR et al., BMT 2016
Baldomero: Transplant Activity
Survey Dec 2015
HCT activity in Europe 1990 - 2014:
Main indications: allogeneic
Baldomero: Transplant Activity
Survey Dec 2015
HCT activity in Europe 1990 - 2014:
Main indications: autologous
 Leukemia: 11 853 (33% of all HCT; 96% allogeneic), mostly
AML+ALL (acute leukemia)
 Lymphoid neoplasias: 20 802 (57% of all HCT; 89%
autologous), mostly PCD (multiple myeloma) and NHL
(lymphomas)
 Solid tumors: 1458 (4%; 3% allogeneic)
mostly children neuroblastoma, germ cell tumours, Ewing´s sarcoma
 Non-malignant disorders: 2203 (6%, 88% allogeneic)
mostly BMF- SAA and other types, hemoglobinopathies, primary
immune deficiences, inherited diseases –metabolic diseases,
autoimmune diseases
Main indications of HCT in Europe
- year 2014 Passweg
JR et al., BMT 2016
 Increasing numbers of both auto- and allo-HCTs
 Increasing numbers of sibling and unrelated donors
 In patients without a matched sibling or unrelated donor,
alternative donors are used, the number of transplants
performed from haploidentical relatives is increased
(802 in 2010, 1571 in 2013)
 The number of unrelated cord blood transplants has
sligthly decreased (789 procedures in 2010, 666 in 2013,
632 in 2014).
Passweg JR et al., BMT 2015 and 2016
HCT - trends in Europe
- year 2014 -
 Hematopoietic stem cell transplantation (HCT) is used
with increasing frequency in Europe with 40 000
transplants reported in 2014.
 Transplant-related mortality remains high in allogeneic
HCT (10–20%); high-dose chemotherapy is toxic and
demanding for patients.
 Drug development is accelerating and with limited
toxicity of some targeted drugs may replace HCT, whereas
others may function as a ‘bridge to transplant’.
Passweg JR et al., BMT 2017
Impact of new drug development on the
use of HCT: a report by the EBMT – I
 We analyzed HCT reported to the activity survey for
selected diseases in which major advances in drug
development have been made.
 Tyrosine kinase inhibitors markedly changed the number
of allogeneic HCT in early CML.
 In myelodysplastic syndromes, hypomethylating agents
show no effect on HCT activity and Janus kinase inhibitors
for myeloproliferative neoplasm appear to have only a
temporary effect.
Passweg JR et al., BMT 2017
Impact of new drug development on the
use of HCT: a report by the EBMT – II
 For CLL autologous HCT decreased after publication of trials
showing improved PFS but no overall survival advantage and
allogeneic rates are dropping after the introduction of Bruton
kinase and PI3K Inhibitors. Whether these are ‘game changers’
as was imatinib for CML requires additional follow-up.
 For myeloma, proteasome inhibitors and new
immunomodulatory drugs do not appear to impact transplant
rates for autologous HCT.
 Drug development data show different effects on HCT use;
highly effective drugs may replace HCT, whereas other drugs
may improve the patient’s condition to allow for HCT.
Impact of new drug development on the
use of HSCT: a report by the EBMT – III
Passweg JR et al., BMT 2017
Multiple myeloma (MM)
1% of all cancer disorders, 10% of all hematological
malignancies
Median age at diagnosis: 65-70 years; only 2% of pts are
younger than 40 years
MM - uncurable chronic cancer disease
Median of overall survival from MM diagnosis: 3-4 years
with standard treatment, 5-7 years with treatment
including autologous transplantation
MM still remains the main indication for autologous
transplantation (over 50% of all autologous
transplantations).
Moreau P et al. Annals of Oncol, 2017; 28:52-61.
Clinical symptoms of MMClinical symptoms of MM
Osteolysis induced
by tumor cytokines
 Osteolytic lesions
 Diffuse osteoporosis
(or combination of boths)
Bone pains
Monoclonal immunoglobulin:
complete molecule of MIG
or free light chains
 Nephropathy
 Neuropathy
 Coagulation disorders
Cytopenie
Defect of functional B
and T lymphocytes,
often infections
Number of clonal plasma cells
in bone marrow over 10% or biopsy-proven bone or extramedullary
plasmacytoma
Evidence of serum M protein (IgG or IgA) over 30g/l or urinary M
protein over 500 mg per 24 h
Evidence of end stage organ damage that can be attributed to the
MM, specifically:
C - calcium over 2.8 mmol/l (hypercalcemia)
R - renal insufficiency – serum creatitine over 177 umol/l
A – anemia (hemoglobin value under 100 g/l)
B – bone osteolytic lesions on skeletal radiography, CT or PET-CT
or multiple focal lesions on MRI studies
Diagnostic criteria for multiple myeloma
- IMWG (2014)
Myeloma osteolytic lesions
(radiography of skull)
Extramedullary myeloma lesions of skin and
soft tissues (biopsy-proven)
Bone lesions on skeletal radiography of femoral
bones and MRI of spine
Female, 62 years
 Diagnosis of carcinoma ovarii pT2a pN0 M0, treatment with surgery and
chemotherapy from 10/2014, status of disease after treatment – remission of
disease
 PET/CT from 9/2015: new osteolytic lesions - in os sacrum 20 mm and spine
corpus of L4 - 21x14x19 mm, unknown etiology, bone pains
 In 10/2015 – biopsy from osteolytic lesion in L4 was performed, diagnosis of
plasmocellular myeloma was established
 Complete examination was done in our department in 12/2015, diagnosis MM,
IIA according to DS criteria, ISS1, type IgG lambda, with CRAB criteria
 Treatment: 4 cycles of bortezomib-based regimen (VTD), autologous PBSC
mobilisation and harvest in 5/2016, autologous HCT in 6/2016, conditioning
MEL200, hospitalization after autologous HCT: 16 days
 Treatment response: remission of MM, PET/CT from 10/2017 and 1/2019 –
without abnormal metabolic active skeletal lesions. In 2/2019: remission of MM.
Autologous transplantation in MM:
case report 1
 First symptoms of disease – 8/2016: fatigue, weakness,
bleeding, fever, infection of upper respiratory tract; acute
disease – symptoms appeared in several days
 Hyperleukocytosis 437x109/l (normal value 4-10x109/l);
anemia Hb 47,9 g/l (normal value of Hb: 135-175g/l);
trombocytopenia 42x109/l (normal value: 150-350)
 In peripheral blood: presence of blasts (95%), normal
value: 0% of blasts
 Diagnosis of acute lymphoblastic leukemia was established
 Diagnosis of acute leukemia: over 20% of blasts in
peripheral blood or bone marrow
Allogeneic transplantation in ALL:
case report 2 – ZR, male born on 1991 - I
 Therapy: several courses of chemotherapy – combination of
cytostatic drugs + corticosteroids: 2 courses of induction and 1
course of consolidation (8-10/2016), response - complete
response of ALL
 HLA typing was done in patient and his 3 siblings, only 1 sister
is completely HLA identical (10/10)
 In 1/2017 allogeneic transplantation of PBSC from HLA
identical sibling was performed after myeloablative
conditining Cy/TBI, day 0 (application of PBSC) was 31.1.2017
 Hospitalization after allo-HCT : 24.1.-7.3.2017, infectious
complications, febrile neutropenia, GIT mucositis, upper GIT
acute GvHD, pneumonia
 2/2019: patient alive, in good clinical condition, in remission of
ALL, without immunosupressive therapy, he is observed in outpatient
department, now he is preparing to study in university
Allogeneic transplantation in ALL:
case report 2 – ZR, male born on 1991 - II
 First symptoms of disease – 10/1996: fatigue, weakness,
bleeding, fever; acute disease – symptoms appeared in
several days
 Age at diagnosis of AML: 44 years
 In peripheral blood count: leukocytosis, anaemia,
thrombocytopenia
 Diagnosis of AML: from bone marrow examination
(sternal puncture - BM aspiration from sternum) – 77% of
blasts in bone marrow
 Therapy: chemotherapy – induction, 2 courses of
consolidation, effect of CR, HLA typing of 2 siblings, 1 HLA
identical brother
 In 4/1997 allogeneic HCT was performed, after MAC BuCy,
hospitalization for allo-HCT: 2 months
Allogeneic transplantation in AML: case report 3
- PM, born on 1952, female - I
 Complications in the first year after allogeneic HCT:
reccurent infections (CMV, EBV), acute GvHD, hemorhagic
cystitis by viral BKV etiology and others
 Status to 2/2019: 22 years after allo-HCT, patient alive,
remission of AML, in good clinical condition, without
specific therapy
 Patient returned to her job 2 years after allogeneic
transplant – she is teacher on the university. She worked
on the university to her 62 years. Now (2/2019) she is
retired, but she is living very active life.
Allogeneic transplantation in AML: case report 3
- PM, born on 1952, female - II
Allogeneic transplantation in CLL: case report 4
- RK, female, born in 1968, high-risk CLL – part I
 Diagnosis of CLL: 6/2000, Rai stage IA, progression
to stage IIB in 11/2012, p53 mutation from 6/2016
 Treatment before HCT - 4 lines: 4x FCR, alemtuzumab,
bendamustin+R, ibrutinib
 Status of disease at transplant: stable disease
 Age at transplant: 48
 Conditioning: FC-RIC protocol, day 0: 31.8.2016
 Donor: unrelated donor 9/10
 Regular monitoring after HCT: examinations of blood count,
biochemistry and bone marrow; CsA levels; chimerism; PCR-CMV;
MRD – flow, PCR; PET/CT scans
 Complications after allo-HCT: febrile neutropenia, infections
 Treatment response: hematological remission
 MRD-flow negativity from peripheral blood and bone marrow,
complete chimerism was achieved
 Follow-up from HCT to February 2019: 30 months, patient is
alive and disease free, she returned to her job after 9 months
from alo-HCT
Allogeneic transplantation in CLL: case report 4
- RK, female, born in 1968, high-risk CLL – part II
Transplant rates - total number of HCT per
10 million inhabitants in Czech Republic
(period 1993 - 2015)
59
136
202
282
409
437
487
461
562
531
618
590
564
518 530 542 537
578
554
589
675
696
718
0
100
200
300
400
500
600
700
800
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
počty(n)
Survey on Transplant Activity, EBMT
Proportion of the first and additional HCT
in Czech Republic (time period 1997-2015)
0
100
200
300
400
500
600
700
800
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
další SCT 1.SCT
počty(n)
Survey on Transplant Activity, EBMT
 718 HCTs were performed in 2015 in Czech
Republic in 10 transplant centres
264 allogeneic HCT
454 autologous HCT
 The first HCTs: 591 (83%)
348 autologous HCT
243 allogeneic HCT
Number of non-myeloablative HCT: 143
Number of DLI applications (donor lymphocyte
infusions): 92
HCT activities in Czech Republic in 2015
Grafts from sibling and unrelated donors in the first
allogeneic HCT in Czech Republic
0
25
50
75
100
125
150
175
200
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
počty(n)
family unrelated
Survey on Transplant Activity, EBMT
Numbers of allogeneic and autologous HCTs
in Czech Republic (time period 1993 - 2015)
0
50
100
150
200
250
300
350
400
450
500
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
počty(n)
allo ČR auto ČR
Survey on Transplant Activity, EBMT
Main diagnoses for allo-HCT in Czech Republic
and time evolution (1993 - 2015)
0
25
50
75
100
125
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
počty(n)
AML ALL MDS/MPN CML CLL lymfomy nemaligní on. PCD solidní tu jiné
Survey on Transplant Activity, EBMT
Main indications for allogeneic HCT in Czech
Republic in 2015: AML, ALL, MDS/MPD
121; 50%
29; 12%
36; 15%
10; 4%
5; 2%
19; 8%
16; 7% 6; 2% 1; 0%
AML
ALL
MDS/MPN
CML
CLL
lymfomy
nemaligní on.
PCD
solidní tu
Survey on Transplant Activity, EBMT
0
25
50
75
100
125
150
175
200
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
počty(n)
NHL HL CLL MDS/MPN PCD ca prsu jiné tu AML, ALL NMD CML jiné
Main diagnoses for auto-HCT in Czech Republic
and time evolution (1993 - 2015)
Survey on Transplant Activity, EBMT
109; 31%
23; 7%
193; 55%
20; 6%
2; 1% 1; 0%
NHL
HL
PCD
jiné tu
AML, ALL
NMD
Survey on Transplant Activity, EBMT
Main indications for autologous HCT in Czech Republic
in 2015: PCD, NHL, HL – myeloma and lymphomas
The first HCT was performed in 1993
25 years of IHOK hematopoietic stem cell transplant program in 2018
In summary, 2418 hematopoietic stem cell transplantations were
performed in period 1993- 10/2018
Overall number of autologous transplantations: 1795
Overall number of allogeneic transplantations: 623 (relative donor in
295 patients, unrelated donor in 328 patients)
Numbers of HCTs per year at IHOK:
(median for last 5 years)
85 autologous transplantations, 35 allogeneic transplantations
Hematopoietic stem cell transplantations at our
department (IHOK) – summary of activities
Main indications for HCTs in Czech Republic are in
concordance with EBMT guidelines.
Hematological malignancies – 93% of all HCT indications in
Czech Republic; rest (7%): non-malignant diseases and
solid tumors.
In Czech Republic 591 first HCTs were performed in 10
transplant centres (Brno, Prague, Ostrava, Hradec Kralove,
Pilsen, Olomouc) in 2015; 243 (41%) allogeneic and 348
(59%) autologous HCT.
Conclusions - I
Main indications for autologous HCT: multiple myeloma
and lymphomas, 86% of all indications.
Main indications for allogeneic HCT: acute leukemias
(AML+ALL) and myelodysplastic syndrome +
myeloprolipherative disease (MDS+MPD) -77% of all
indications.
The decision to transplant involves careful balancing of
the risks of allo-HCT against the risk factors and course of
disease in each individual patient.
HCT still remain in present time (year 2019) treatment
method of choice in many hematological and nonhematological
disorders at suitable patients.
Conclusions - II