Transcript Allogeneic Tx

Indications for allogeneic and
autologous HSCT
Prof. Ilona Hromadníková, Ph.D.
Department of Molecular Biology and Cell Pathology
Third Medical Faculty, Charles University in Prague
Risk factors for transplant outcome
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stage of the disease
age of the patient
time interval from diagnosis to transplant
for allogeneic HSCT:
– donor-recipient histocompatibility
– donor-recipient sex combination
• cumulative and can be modified with good/poor prognosis
• transplant related mortality↑and survival rates↓with:
– advanced disease stage
– ↑ age
– ↑ time from dg to Tx
– ↑ grade of histoincompatibility
– in grafts involving male recipients with a female donor
Most frequent indications
a) Malignant diseases
Hematologic diseases
leukemia (acute, chronic)
myelodysplastic syndrome (MDS)
lymphoma* (Hodgkin, non-Hodgkin)
multiple myeloma*
Solid tumors*:
breast and ovarian carcinoma, neuroblastoma, small cell lung carcinoma,
malignant melanoblastoma, colon cancer, Ewing sarcoma, brain tumors,
retinoblastoma, histiocytic tumors and others
* mostly autologous transplantation
Most frequent indications
b) Non-malignant diseases
• inborn failures of host defence
severe combined immunodeficiency (SCID), combined immunodeficiencies (T, Blymphocyte dysfunction), WAS, innate immunity defects,
X-linked lymphoproliferative syndrome, familiar hemophagocytic
lymphohistiocytosis (FHL)
• inborn and acquired failures of hematopoiesis
severe aplastic anemia, acquired and constitutive aplastic anemia in children,
hemoglobinopathies (thalassemia, sickle cell disease), primary polycytemia
• inherited metabolic disorders
mucopolysaccharidosis, leukodystrophy, lipidosis, Lesch-Nyhan syndrome,
adrenoleukodystrophy
• osteopetrosis
inherited disorder caused by osteoclast dysfunction (bone resorption deficiency)
Transplantation for leukemia
Leukemia
• clonal proliferation of hematopoetic cell stopped in some stage of its
development
• heterogenic group of disease – diverse epidemiologic, histologic, cytologic,
immunologic and genetic characterization
• differs in manifestation, malignity stage and treatment response
Acute leukemia
malignant transformation of myeloid lineage (AML) or lymphoid lineage (ALL)
classification: T-ALL, B-ALL, ALL with myeloid antigen expression
AML – 8 various types (AML M0-M7)
Chronic leukemia
CLL: most frequent B-CLL, T-, prolymphocytic leukemia B or T type (PLL)
CML
Transplantation for acute leukemia
Acute myeloid leukemia (AML)
most common adult leukemia (up to 85% over 20 years of age)
more rare in children (cca 15% of leukemias) – worse prognosis than in ALL
Adults
by chemotherapy 1st complete remission (CR) in 60 – 80% of adults, time duration
median 12-18 months, just 10-35% of patients survive 5 years
no prognostic criteria evaluating individually risk of relapse in time of remission (see
the table)
allogeneic Tx in 1st CR (within 2-3 months), if available HLA-compatible related
donor
urgently- high risk of relapse (prognostic factors), secondary AML, AML from
MDS, induction chemotherapy failure with residual or refractory disease, in 1st
relapse after achieving 2nd or next CR
contra-indications: infection, other disease, age over 60 years
Prognostic factors in AML
During the onset of the disease
favourable
unfavourable
FAB classification
M3, M4Eo (M2?)
(M5?)
leukocyte number
CNS or other extramedullar
involvement
cytogenetics
< 25 x 109/l
> 25 x 109/l
-
unfavourable
t(8;21) (q22;q22)
t(15;17) (q21;21)
inv(16) (p13;q22)
del5,5qdel7,7qt(9;22) (q34;q11)
inv3
complex anomaly
mdr-1 gene expression in blasts
(multiple drug resistance)
not proved
proved
dysplastic changes
LDH in serum
not found
< 16,5 mkat/l
present
> 16,5 mkat/l
During the treatment
favourable
unfavourable
response to induction chemotherapy
complete remission after no CR after 2 induction
1-2 induction phases
phases
MRD in remission
not found
proved
Transplantation for acute leukemia
Acute myeloid leukemia (AML)
Allogeneic Tx in adults
• Remission achieved by Tx in 90% of adults who did not achieve remission by
induction chemotherapy, 20% of adults survive 3-5 years in complete remission
after Tx
• Patients – for whom HLA-compatible related donor is not available
Tx using the graft from unrelated donor mostly after the relapse, 30-40%
survive 2 years
Chemotherapy treatment types:
induction– initial treatment phase, eradicates maximum of leukemic cells
consolidation – further induction cycles of same doses (after remission)
intensification – other cytostatic combination and doses (after remission)
reinduction (late intensification) – with the time interval after remission achievement
maintenance – long-term administration of low dose cytostatics to hold remission
Transplantation for acute leukemia
Acute myeloid leukemia (AML)
Autologous Tx in adults
• usage as a very intensive consolidation therapy after CR achievement, if stem cells
taken in time of CR (molecular-biological) are available
• usage as an intensive reinduction therapy in relapse (lower chance for permanent
curative outcome)
Children
worse outcome than in children‘s ALL
25% of children not reaching the remission due to toxic death or therapy resistance
50-70% relapse
FAB subtypes – different reaction on treatment
indication to Tx in 1st CR – if HLA-compatible family donor and in high-risk leukemias
Transplantation for acute leukemia
Acute lymphoblastic leukemia (ALL)
most common children‘s leukemia (80% of all leukemias), in adults cca 20% of all acute leukemias – rather
older patients, in children more favourable prognosis than in adults
Adults
1st remission reached in 65-85%, from them cca 35% after consolidation,
reinduction and maintenance therapy stay symptomless in the long term, worse
in patients older than 60 years
unfavourable prognostic factors:
- remission in > 4-5 weeks after therapy start
- leukocytes > 30 x 109/l at therapy start
- higher age (> 50-60 years)
- chromosomal aberation t(9;22) (q34;q11) or bcr-abl positivity (in 25-30%) or
t(4;11)(q21;23)
- B-ALL (50% bcr-abl positive)
- presence of Ph1-chromosome (so called Philadelphia chromosome) – rare longer
remission (< 10 months), positivity increases with patient‘s age
Transplantation for acute leukemia
Acute lymphoblastic leukemia (ALL)
Allogeneic Tx in adults
Tx outcome in 1st CR unsatisfactory – 20-60% survive 5 years (not better than in case of
consolidation and maintenance therapy of 1st remission)
better outcome in Ph1-positive ALL (with regard to high risk of relapse)
indication to consideration according to unfavourable prognostic factors
indication in B-ALL:
if CR after 3 therapy phases is not achieved
in all patients below 50 years of age after relapse, if matched donor (related or
unrelated) is available
Transplantation for acute leukemia
Acute lymphoblastic leukemia (ALL)
Autologous Tx in adults
relevance and indication are not clearly defined
outcome depands on the amount of residual leukemic cells and autotransplant contamination
Indication: complete assessment of leukocyte count during the disease onset
(> 50 x 109/l higher risk of relapse)
cytologic subtype of ALL
chemoterapy intensity for reaching 1st CR
time duration of remission
age
quality of purified bone marrow (better than in AML)
to improve Tx outcome - the effort to reduce risk of relapse (conditioning regimen modification)
Transplantation for acute leukemia
Acute lymphoblastic leukemia (ALL)
Children
in 70% of children is possible to reach long-term CR by chemotherapy
supportive treatment (plasma, thrombocytes, ATB administration) – lowering of mortality below
5% due to toxic treatment
risk factors of unfavourable course of ALL:
high leukocytosis during the onset, bad response to prednison pre-phase, age < 1 yr
with t(4;11) translocation and the presence of Ph1 chromosome (in 3-5% of ALL), age >
10 yrs during the onset, later remission
Allogeneic Tx in children
rarely in 1st remission, indication in 5-10% of patients with unfavourable prognosis:
children with Ph1 positive ALL, infants with t(4;11) translocation, children not achieving
remission after induction therapy – bad response to prednison , dg. T-ALL
presumption of Tx - the availability of HLA-identical sibling
Transplantation for acute leukemia
Acute lymphoblastic leukemia (ALL)
Allogeneic Tx in children
other indications:
• early relapse – within 3 yrs from diagnosis
• extramedullary relapse (CNS, testes) – chemotherapy has the same outcome
as Tx but is less risky
• late isolated bone marrow relapse – higher chance for recovery when
transplanted
• T-ALL diagnosis
Autologous Tx in children (rather experimental method)
• BM taken in 1st or 2nd remission, purification and cryopreservation
• PB progenitor cells from separator after growth factor stimulation, may
contain also tumor cells
• major limit is no GvL-effect
• indication: 2nd remission of T-ALL and early relapse within 3yrs from dg., if
donor for allogeneic Tx is missing
Transplantation for chronic leukemia
Chronic myeloid leukemia (CML)
clonal myeloproliferative disease of pluripotent progenitor cell, specific Ph1 chromosome
positivity (marker for the presence of bcr-abl fusion gene)
mainly in patients of 40-65 yrs, can occur in children, bad prognosis – survival 3-5 yrs after
conventional chemotherapy (a-interferon, imatinib), complete remission in 20-80%
(mostly transient)
Allogeneic Tx
the only treatment leading to long-term remission – up to 15 yrs survival
the best choice for younger patients with HLA-identical sibling transplants
best outcome for chronic phase untill 1 yr after dg., 5 yr survival cca in 50% after Tx from
HLA-identical sibling
worse outcome for accelerated phase and blast crisis (later, terminal phase of CML)
Autologous Tx
rare, rather experimental
for consideration: if suitable donor for allogeneic Tx is not available
The effort to collect Ph1-negative stem cell in early phase after intensive chemotherapy
Transplantation for chronic leukemia
Chronic lymphoid leukemia (CLL)
clonal lymphoproliferation at certain level of maturation process
mostly in patients over 50 yrs, most common type of leukemia in Europe and
North America
early stages – long symptomless period, not necessary to treat
chemotherapy is the first line treatment
Tx is not standard treatment – in more advanced stages for consideration, under
research
Tx for myelodysplastic syndrome (MDS)
MDS in adults
• bone marrow stem cell failure resulting in disorderly and ineffective
hematopoiesis manifested by irreversible quantitative and qualitative defects
• characterized by anemia, leukopenia and thrombocytopenia, classified into
several categories
• mostly in patients older than 40 yrs
• 10-40% of patients transformation into acute leukemia
Indication for allogeneic Tx
morphologic type of MDS
age of patient
prognostic factors of individual MDS subtypes (blastic infiltration of bone marrow,
level of thromcytopenia)
MDS with clonal malignant transformation
for consideration in secondary MDS (unfavourable prognosis) – development after
treatment for another malignity
best outcome in younger patients without malignant transformation
Tx for myelodysplastic syndrome (MDS)
MDS in children
Allogeneic Tx
• the only curative treatment prior to transformation into AML
• often failure in children with chromosome 7 monosomy and in children
with high-risk chronic myelomonocytary leukemia (CMML) older than 2 yrs
• indication in patients with CMML, RAEB and RAEBt if suitable donor
available, without previous chemotherapy
RAEB – refractory anemia with blast excess
RAEBt - refractory anemia with transformed blast excess
Tx for lymphoma
Hogdkin‘s lymphoma (malignant lymphogranuloma)
malignity of lymphatic tissue treated with radio/chemotherapy
in case of progression Tx is possible – often in later stages of the disease – usually
autologous
Indication for autologous Tx in adults in earlier stages:
in patients failed to respond to first line chemo/radiotherapy
first relapse within 12 months
first relapse later, after chemotherapy
in III. and IV. stage after reaching 2nd CR: progenitor cell collection, Tx in 3rd CR
Allogeneic Tx
eliminates the risk of malignant cell reinfusion
if the bone marrow is infiltrated and in case of low quality autologous BM (infiltration
with lymphoma, chemotherapy involvement)
lower number of relapses, but higher mortality due to GvHD
Tx for lymphoma
Non-Hodgkin‘s lymphoma (NHL)
diverse group of hematologic cancers derived from lymphocytes in any stage of
development (B and T), originated in any organ – most often in lymphatic nodes
prognosis depands on localization, origin, differentiation stage, maturity grade and
others
Autologous Tx in adults
Lymphomas with low malignity grade – good response to chemo/radiotherapy
Tx rarely due to slow progression, higher age
Lymphomas with intermediate malignity grade – indication: not reached CR or relapse,
and 1st CR with unfavourable prognosis
Lymphomas with high malignity grade – conventional treatment fails in 50% of patients
indication usually: partial remission, relapse, negative prognosis in remission,
histologic type of lymphoblastic or Burkitt‘s lymphoma
Allogeneic Tx
uncertain better outcome comparing to autologous Tx, indication can be BM
involvement and patients with slow progressed lymphomas (graft vs. tumor effect)
Tx for solid tumors
• the aim of Tx is to enable intensive tumorablative treatment
• combination of high-dose chemotherapy and autologous Tx represents the
possibility to further increase the cytostatic dose in some types of tumors
• supralethal dose administration (i.e. the dose higher than minimal
absolutely lethal)
• positive outcome
in children especially: neuroblastoma, Ewing‘s sarcoma, rabdomyosarcoma
and Wilms‘ tumor (nephroblastoma)
in adults: chemotherapy good-responded tumors: testicular tumors,
breast, ovarian and small cell lung carcinoma
• worse outcome
cerebral glioma, melanoma, sarcoma, colon and gastric cancer and others
Tx for non-malignant diseases
Inborn failures of host defence
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standard indication for Tx
Severe combined immunodeficiency (SCID)
heterogenic group of diseases with T, B lymphocyte‘s dysfunction
in the absence of treatment leads to early death caused by opportunistic infection within
the first year of life
Allogeneic Tx
• Tx from HLA-identical sibling – without conditioning regimen, 80% of patients live
symptomless, low risk of GvHD
• successful Tx from HLA-non-identical relatives (mostly parents), T-cell depletion, 50%
survival
• better outcome in Tx from matched unrelated donor
• non-engraftment risk in Tx w/o conditioning, however, conditioning increases the risk
of early death caused by infectious complications
• higher chance for complete cure if transplanted within first 6 months of life (early
diagnostics!)
Tx for non-malignant diseases
Inborn failures of host defence
Combined immunodeficiency
T, B lymphocyte‘s dysfunction – defective expression of HLA antigens, Omenn syndrome, activation T
lympho disorder and others, severe infections, 60% of patients have autoimmune diseases
Tx the only effective treatment, worse outcome than in SCID, necessary to make within 2
yrs of age – chronic infectious disease not yet developed
60% chance for complete cure, worse with increasing age, most frequent cause of death:
infection
conditioning regimen necessary, higher risk of GvHD in HLA-identical sibling Tx than in SCID
Wiskott-Aldrich syndrome (WAS)
X-linked disease, immunodeficiency concerns both humoral and cellular immunity
eczema, thrombocytopenia, higher appearence of infection and lymphoreticular malignant diseases
Tx from HLA-identical sibling – necessary intensive conditioning regimen
Tx from HLA-non-identical relatives and matched unrelated donor are risky
Tx for non-malignant diseases
Inborn failures of host defence
Innate immunity defects
• LAD syndrome – deficiency of membrane adhesive glycoproteins
treated with Tx, necessery immediately prior to chronic infection development
• chronic granulomatous disease – involvement of enzyme of granulocyte‘s oxygen
metabolism (defect NADPH oxidase) , Tx is treatment of choice, in some forms INF-g
therapy successful
• Chediak-Higashi syndrome – defect in bactericidal activity and chemotaxis of
leukocytes, Tx can cure manifestation of the disease except of albinism
• Kostmann agranulocytosis – stopped maturation of granulocyte precursors in BM
successful treatment with growth factors G-CSF, GM-CSF, Tx is treatment of choice
X-linked lymphoproliferative syndrome
inability to make antibodies against EBV, Tx is the only treatment
Familiar hemophagocytic lymphohistiocytosis (FHL)
decreased activity of NK cells, non-controlled histiocyte proliferation and clonal expansion
of T lympho, remission by immunosuppression - however, complete cure after Tx
Tx for non-malignant diseases
Osteopetrosis
dysfunction of osteoclasts → enclosure of bone marrow cavity with newly
created bone followed by hematopoiesis failure and periphery pancytopenia
partial provision of hematopoiesis in liver and spleen
treatment with Tx – BM supplies functional osteoclasts, risk is frequent nonengraftment
Tx for non-malignant diseases
Severe aplastic anemia in adults (SAA)
• dysfunction of stem cell, attenuation of hematopoiesis
• usually treated with immunosuppression
• Tx in patients with the level of neutrophiles below 0.2x109/l and in age below 20
yrs
Tx first choice if HLA-identical related donor is available, previous transfusion
increases the risk of GvHD
Aquired and constitutive aplastic anemia in children
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immunosuppression less successful – gives worse results than Tx
80% chance for complete cure if Tx from HLA-identical sibling
Tx from unrelated donor usually indicated after unsuccessful immunosuppression
SAA in children with age below 5 yrs chance for survival only 10% without Tx
Fanconi anemia – inborn, BM failure in school age, indication for k Tx if HLAidentical sibling available, otherwise treated with androgens
Tx for non-malignant diseases
Hemoglobinopathy - defects in structure or synthesis of hemoglobin
Thalassemia – inborn defect in synthesis of b- or a-globin chain of hemoglobin
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•
treated with erythrocyte transfusion
Tx cures 67-90% cases according to various studies – frequent liver involvement is the
risk of veno-occlusive disease development after Tx
children: more probable survival after conventional therapy
Sickle cell disease – hemoglobin S presence (Glu substituted by Val in b-chain), inclination
to polymer creation followed by forming sickle shape of erythrocytes
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most frequent hemoglobinopathy in central Africa, appears in India, the Middle East,
Mediterranean states
symptomatic treatment: blood transfusion, chelator administration, infection treatment,
analgetics
very few patients treated with Tx (tens), difficult choice of patients – variable course
successful Tx = complete cure
Tx for non-malignant diseases
Primary polycytemia
- abnormal precursors for ery, granulo, thrombo form cell clone with
increased proliferation, only 5% of patients < 40 yrs
long-term good control by conservative treatment
Tx only in youth with progressive character of the disease not responding to
usual treatment, the risk is transformation to MDS or acute leukemia
Tx in isolated cases, complete cure
Tx for non-malignant diseases
Inherited metabolic disorders
relatively new indication for Tx, increases in last years
group of rare, in final prognosis lethal diseases
Tx successfully made in:
Lysosomal storage diseases – progression of neurological symptoms
mucopolysaccharidosis I.-IV.type
leukodystrophy
lipidosis
Other metabolic diseases
Lesch-Nyhan syndrome
adrenoleukodystrophy – X-linked, demyelinisation and adrenal insufficiency
Principle: supply of hematopoietic cells able to produce missing enzyme
(not possible in cystic fibrosis, hemophilia, phenylketonuria)
Inherited metabolic disorders
Mucopolysaccharidosis – lysosome overload with mucopolysaccharides,
dysfunction in process of „recyclation“ of some enzymes followed by their
insufficiency
• the highest number of Tx
• presumption of successful Tx: low age, IQ over 70, HLA-identical donor
Gaucher disease – deficiency of glucocerebrosidase decomposing lipids followed
by accumulation of lipid particles in organs and bones
• best Tx outcome in infantile form
Adrenoleukodystrophy – failure in oxidation of saturated fatty acids with long
chains followed by their accumulation in tissues and liquids
• early Tx prior to development of neurological changes – complete cure
decision to Tx generally: not only patient‘s survival, but also life quality and
future independance
A case report 1 - patient indicated to HSCT
• male, 7 years
• HLA non-identical sister
• c-ALL diagnosed after anamnesis of febrile infection with hemorrhagic
diathesis, hepatosplenomegalia, hyperleukocytosis
BM: uniform infiltration with lymphoblasts of type L1, FACS: euploid cALL
with aberant expression of CD15
• chemotherapy 3/2006 (ALL-IC 2002-IR)
good response, no bigger complications, remission achievement D+33
maitenance chemotherapy from 11/2006, no complications
1/2008 early isolated bone marrow relapse with characteristics of primary
diagnosis (21.5 months from diagnosis)
→ combined chemotherapy (ALL-REZ BFM 2002)
after F1 block achievement of hematological remission, infectious complications,
ARDS, chronic pancreatitis without cholelithiasis, neutropenia, pancytopenia
5/2008 end of chemotherapy followed by aplasia, hyperbilirubinemia
5/2008 MUD HSCT
Pre-Tx examination
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•
•
•
•
physical examination
blood counts
bone marrow examination
biochemic examination
infectious disease markers -------→
Donor: US 035477694
Blood group
HLA
match 10/10
CMV status-patient
EBV
HSV
VZV
hepatitis panel
HIV
CMV status-donor
IgG[+] IgM[-]
IgG[+] IgM[-]
IgG[+] IgM[-]
IgG[+] IgM[-]
negative
negative
IgG[-] IgM[-]
weight: 97 kg
Recipient
A Rh
age: 28 years
Donor
+
A *2402 *3001
B *1801 *3503/70/74
Cw *0401/20 *0701
DRB1 *1101/33
*1104/35/60
DQB1 *0301
DPB1
sex: male
O Rh +
A
*2402 *3001
B
*1801/18 *3503/70/74
Cw *0401 *0701
DRB1 *1101/27/33
*1104/35/60
DQB1 *0301
DPB1
Conditioning regimen
fractionated TBI 12 Gy D-4..D-2
etoposide 60mg/kg D-1
GvHD prophylaxis
cyclosporine A targeted from D-1
ATG Fresenius 3 x 20 mg/kg D-3..D-1
methotrexate 10-10-10 mg/m2
Transplantation
Graft: bone marrow
adjustment:concentration, centrifugation
nucleated cells
:
6.49
x 108/kg of patient
CFU-GM
:
68.1
x 104/kg of patient
BFU-E
:
76.2
x 104/kg of patient
CD 34+
:
6.49
x 106/kg of patient
CD 3+
:
60.04 x 106/kg of patient
volume
:
396 ml viability 95.3%
whole blood
:
614.4 ml
frozen 2x DLI (1 x 10/6/kg, cca 1,5 x 10/6/kg)
A case report 2 - patient indicated to HSCT
• male, 8 years
• inborn sceletal anomalia (doubled distal phalange of right thumb)
• Fanconi anemia diagnosed after anamnesis of thrombocytopenia,
macrocytosis, anemia
BM: normocellular, few megacaryocytes, cellularity < 20% →BM failure
pathologic cultivation of fibroblasts
• HLA non-identical brother
Pre-Tx examination
•
•
•
•
•
physical examination
blood counts
bone marrow examination
biochemic examination
infectious disease markers -------→
donor: DKM 2521428
age:
Donor
Recipient
blood group
B
HLA
Match
10/10
A
CMV status-patient
EBV
HSV
VZV
hepatitis panel
HIV
CMV status-donor
weight:
kg
26 years
sex: M
Rh +
*0201
IgG[+] IgM[-]
IgG[+] IgM[-]
IgG[-] IgM[-]
IgG[-] IgM[-]
negative
negative
IgG[-] IgM[-]
A Rh
+
*0301
A
*0201
*0301
*5601
B
*0702
*5601
*0102/15-19 *0702
B
*0702
Cw
*0102/15-19 *0702
Cw
DRB1
*0101
*0404
DRB1 *0101
*0404
DQB1
*0501
*0302
DQB1 *0501
*0302
DPB1
DPB1
Conditioning regimen
Fludara 30 mg/m2 x 6 D-8,D-7,D-6,D-5,D-4,D-3
Cyclophosphamide 300 mg/m2 x 4 D-6,D-5,D-4,D-3
GvHD prophylaxis
Cyclosporine A 5 mg/kg/d targeted from D-1
Thymoglobuline 2.5 mg/kg/d…D-1, D0, D+1
Mycophenolate mofetil (MMF) 1500 mg/m2/d from D0
Transplantation
Graft:
bone marrow
nucleated cells
CFU-GM
BFU-E
CD 34+
CD 3+
volume
whole blood
adjustment :concentration, sedimentation 2x
:
3.8 x 108/kg of patient
:
64.7 x 104/kg of patient
:
63.5 x 104/kg of patient
:
4.9 x 106/kg of patient
:
23.8 x 106/kg of patient
:
138 ml
:
96 ml