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A Concise History of Chronic Myeloid Leukemia Treatment
1. A Long Story with a Happy
End ?
Mustafa Selim
Chronic Myloid Leukemia
2. Give me one word about CML?
also known as
chronic myelocytic,
chronic myelogenous, or
chronic granulocytic leukemia
A myeloproliferative neoplasm
characterized by the dysregulated production&
uncontrolled proliferation of mature and maturing granulocytes
with fairly normal differentiation.
Philadelphia (Ph) chromosome BCR-ABL1 fusion proteinA reciprocal translocation
CML has
a triphasic or
biphasic clinical courses
splenomegaly
Absolute basophilia is
a universal finding in
the blood smears
Fluorescence in situ
hybridization analysis
(FISH)
Reverse transcription polymerase
chain reaction (RT-PCR)
Allogeneic stem
cell transplants
TKI
4. Hematopoiesis: Blood cell Lineages
Hematopoiesis: process by which blood-cell lineages are produced by
bone marrow
Granulocytes----expand to CML
Stem cells --- capable of
• Self-renewal
• Differentiation
Proliferation and differentiation
controlled by molecular signals
Biology
5. • Cancer of blood cells.
• Involves acquistion of growth
advantage by single cell.
•Uncontrolled growth results in
expansion of clonal population of cells.
•Neoplastic transformations initiated by
Point mutation
Chromosolmal loss, dupllication, or
inapproprite recombination.
Loss of expression of a gene that inhibits
cell proliferation or promotes apoptosis.
Biology
6. • Leukemia classified according to:
Cell linage (myloid or lymphoid)
Degree of terminal differentiation
• Acute (eg AML, ALL)
Primitive progenitor cell with limited capacity for further maturation.
Evolves rapidally, requires prompt intervention
• Chronic (eg, CML)
Primitive progenitor cell with capacity for further maturation
Generally progresses in indolent manner
Biology
7. A Long Story with a Happy End ?
John described Case of Hypertrophy of the Spleen and Liver
While Bennett thought that the disease represented an infection
Virchow recognized its cancerous nature and described it “leukemia.”
The next big step came, when Ernst Neumann recognized that
leukemia originated in the bone marrow.
1845
1872
Arsenicals had been in use for this cancer
In the Lancet 'a patient with the clinical presentation
of CML who achieved a partial response to arsenicals'
1882
8. A Long Story with a Happy End ?
The introduction of interferon-α. interferon-α led to complete
cytogenetic responses only in a subset of patients.
1982
1990
Revolution in therapy
“The magic bullet” to cure cancer by TIME magazine
TKI "Imatinib"
A second generation of Bcr-Abl TKI was subsequently
developed to combat the initial resistance that emerged
Nilotinib Dasatinib Bosutinib Ponatinib
TKIs have altered the landscape of therapy
2003-FDA approves Gleevec for children
2006
2001-FDA approves Gleevec for adults
9. A Long Story with a Happy End ?
The introduction of interferon-α. interferon-α led to complete
cytogenetic responses only in a subset of patients.
1982
Revolution in therapy1990
“The magic bullet” to cure cancer by TIME magazine
TKI "Imatinib"
A second generation of Bcr-Abl TKI was subsequently
developed to combat the initial resistance that emerged
Nilotinib Dasatinib Bosutinib Ponatinib
TKIs have altered the landscape of therapy
2003-FDA approves Gleevec for children2006
2001-FDA approves Gleevec for adults
Summary
10. CML accounts for 15-20% of all adult leukaemias
1-2 cases /100,000 population {adults}
1-2 cases /million population <19 years
Ocuurs slightly more in men than women {1.4-2.2:1}
The average age diagnosis “55-60 years".
Epidemiology
11. • Reciprocal Translocation between chromosome 9 and 22
• Detected in 95% of patients with CML
Fusion between the Abelson (Abl) tyrosine
kinase gene at chromosome 9 and the break
point cluster (Bcr) gene at chromosome 22,
resulting in a chimeric oncogene (Bcr-Abl)
Results in the formation of the BCR-ABL1 fusion
protein. This protein product includes an enzymatic
domain from the normal ABL1 with tyrosine kinase
catalytic activity.
A constitutively active Bcr-Abl tyrosine kinase that
has been implicated in the pathogenesis of CML
Pathohysiology
11 33X
11
33
22
11
12. Detected in 5-10% of patients with CML.
Due to additional translocation masking Ph chromosome or
Due to Break of 9q without reciprocal break 22q.
30 % has trisomy 8
Complex karytyping 3%
Translocation not involving 9q 3%
Additional karyotyping abnormalities 3
Pathohysiology
IS THERE CML without Ph chromosome ???
IS THERE other chromosomal translocations in CML???
2nd Ph chrom2nd Ph chromTrisomy 8Trisomy 8 Iso chro 17 qIso chro 17 q
3311 X
11
33
11
22
33
22
13. Detected in 3-10% of pediatric ALL.
Detected in 25-35% adult ALL.
Poor porgnosis.
Pathohysiology
IS THERE ALL with Ph chromosome ???
Favourable groupFavourable group Intermediate groupIntermediate group
3311 X
11
33
11
22
3322
Poor groupPoor group
< 10 Y,
<50.000
50%
1-Age
2-TLC
3-EFS
> 10 Y, or
50.000
-100.000
30%
Any age,
>100.000
20%
14. Pathohysiology
How to differentiat CML (blastic) from ALL (Ph +ve) ???
CML (blastic)CML (blastic) ALL (Ph +ve)ALL (Ph +ve)
>
>
additional
P 210
ph persist
1- basophiles
2- spleen
3- Cytogentic
4- Product protein
5- BM post TTT
<
<
no
p 190
ph revert to N
15. Pathohysiology
How to differentiat CML (chronic) from JMML ???
CML (chronic)CML (chronic) JMMLJMML
usually >2 Y
+ve
>
<
1-age
2- Ph chromosome
3-spleenomegally
4-monocytes
usually <2 Y
-ve
<
>
16. The normal Abl protein is involved in
The regulation of the cell cycle,
In the cellular response to genotoxic stress,
In the transmission of information about the cellular
environment through integrin signaling.
Carries the tyrosine kinase function
It is tightly regulated under
physiologic conditions.
For interaction
with other
proteins.
Pathohysiology
inhibitory process
17. The breakpoints within the ABL gene at 9q34 can occur
anywhere over a large area at its 5′ end, either
upstream of the first alternative exon Ib,
downstream of the second alternative exon Ia, or,
more frequently, between the two.
Breakpoints within BCR localize to breakpoint cluster regions (bcr).
Pathohysiology
3311 X
18. 1) The major breakpoint cluster region (M-bcr):
In most patients with CML and in approximately one third of patients with Ph-
positive acute lymphoblastic leukemia (ALL).
A 210-kilodalton weight (kd) chimeric protein (P210BCR-ABL) is derived from
this mRNA.
3) A third breakpoint cluster region (μ-bcr)
Associated with the rare Ph-positive chronic neutrophilic leukemia.
Giving rise to a 230-kilodalton weight (kd) fusion protein (P230BCR-ABL)
2) The minor breakpoint cluster region (m-bcr):
In the remaining patients with ALL and rarely in patients with CML.
The resultant mRNA is translated into a 190-kd protein (P190BCR-ABL).
5 folds higher in tyrosine kinase activity than P210
Pathohysiology
3311 X
19. Abl tyrosine kinase activity is tightly regulated under physiologic conditions.
inhibitory process
The SH3 domain play a critical role in this inhibitory process.
carries the tyrosine
kinase function
Pathohysiology
20. inhibitory process
Abi-1
Abi-2
Several proteins {Abi-1 and Abi-2} have been identified that bind to the
SH3 domain & activate the inhibitory function of the SH3 domain.
On exposure of cells to oxidative stress such as ionizing radiation, this small
protein is oxidized and dissociates from Abl, whose kinase is in turn
activated.
carries the tyrosine
kinase functionX
• So deletion or positional alteration SH3 domain activates the kinase.
Pathohysiology
21. • Most important, autophosphorylation,
• There is a marked increase of phosphotyrosine on Bcr-Abl itself,
• which creates binding sites for the SH2 domains of other proteins.
Pathohysiology
22. Pathohysiology
Tyrosine kinases are enzymes responsible for the activation of many proteins
by signal transduction cascades.
The proteins are activated by adding a phosphate group to the protein
(phosphorylation).
24. • Adhesion to stroma negatively regulates cell proliferation.
• An important role for β-integrins in the interaction between stroma
and progenitor cells.
Progenitor
CML
CML
CML
β-integrins
-ve
Progenitor
β1-integrins
CML
CML
• CML progenitor cells exhibit decreased adhesion to bone marrow stroma cells
and extracellular matrix.
• CML cells express an adhesion-inhibitory variant of β1 integrin that is not found in
normal progenitors.
Altered Adhesion
25. 20 to 50 % of patients are asymptomatic
When u suspect in CML?
• The disease suspected from examination (-_-_-_-_-_-_-_-).
• The disease suspected from routine blood tests.
26. The symptoms of chronic myeloid leukemia (CML) are often
vague and are more often caused by other things.
• Asymptomatic
• Abdominal enlargment
• Acute gouty arthritis
• Weakness
• Weight loss
• Fatigue
• Fever
• Feeling full after eating even a small amount of food
• Bone pain
• Night sweats
• Involvement of extramedullary tissues such as the lymph nodes, skin,
and soft tissues is generally limited to patients with blast crisis.
30. COMPLICATIONS
TLS
Hyperleukocytosis
Thrombocytosis
Priapism
Why it happend?
Mechanical obstruction by leukemic cells.
Thrombocytosis (coagulation in corpara).
Pressure of spleen on abdominal veins and nerves.
How to treat ?
Analgesics, hydration, hydroxyurea, warm compression
+/- Radiotherapy (penis & spleen)
31. • A leukocytosis with a median white count of 250,000/microL.
• Anemia {normochromic, normocytic} is seen in 45 to 60 %.
• Thrombocytosis {it can be normal}.
• The disease suspected from examination (spleenomegally).
• The disease suspected from routine blood tests
• Absolute basophilia is a universal finding.
• Absolute eosinophilia is seen in about 90 % of cases.
• Absolute monocytosis (>1000/microL) is not uncommon.
Prominent monocytosis and a low neutrophil/monocyte ratio in the
peripheral blood of patients with CML who have an alternate breakpoint
in chromosome 22, producing a p190 BCR-ABL1 fusion protein.
32. Courtesy of John K. Choi, MD, PhD, University of Pennsylvania.
Normal Chronic phase CML
CML: Peripheral Blood Smear
34. Routine tests
Bone marrow aspiration demonstrates granulocytic
hyperplasia.
BMA
CBC
•A leukocytosis with a median white count of 100,000/microL.
•A normochromic, normocytic anemia is seen in 45 to 60 %.
•The platelet count can be normal or elevated.
•Platelet >600,000/microL are seen in 15 to 30 % of patients.
•Absolute basophilia is a universal finding.
•Absolute eosinophilia is seen in about 90 % of cases.
•Absolute monocytosis (>1000/microL) is not uncommon.
Chemistry
Risk for tumor lysis syndrome
P/A U/S Organomegally mainly spleenomegally
35. Diagnostic criteria BMA
CXR
Genetic testing for the Philadelphia chromosome, the BCR-ABL1 fusion gene
or the fusion mRNA gene product is done by
conventional cytogenetic analysis (karyotyping),
fluorescence in situ hybridization (FISH) analysis,or by
reverse transcription polymerase chain reaction (RT-PCR).
• The majority of patients (90 to 95 %) demonstrate the t(9;22)
(q34;q11.2) reciprocal translocation.
• The remaining minority have variant translocations such as complex
translocations involving other chromosome (eg, t(9;14;22)).
• The rest have cryptic translocations of 9q34 and 22q11.2 that
cannot be identified by routine cytogenetics. These are referred to
as "Ph-negative".
When u suspect CML
"the typical findings in the blood and bone marrow"
U should confirm by molecular dettection of T (9:22)
The "gold
standard" for
the diagnosis
36.
37. Chronic phase: Hyper prolipheration ↑ production of nature
of hematopoeitic cells.
Chronic phase: Hyper prolipheration ↑ production of nature
of hematopoeitic cells.
3311 XPh chromsomePh chromsome
• Progression to accelerated phase or blast crisis requires the acquisition
of other chromosomal or molecular changes.
• Additional cytogenetic abnormalities develop in over 80 % of patients, most
commonly:
trisomy 8,
trisomy 19,
duplication of the Ph chromosome, and
isochromosome 17q (leading to the loss of the P53 gene on 17p).
• These can be seen singly in addition to the Ph chromosome or in any
combination.
38. Chronic phase: Hyper prolipheration ↑ production of nature
of hematopoeitic cells.
Chronic phase: Hyper prolipheration ↑ production of nature
of hematopoeitic cells.
Accelerated phase: Progressive maturation defect→AL-like.Accelerated phase: Progressive maturation defect→AL-like.
3311 XPh chromsomePh chromsome
• It ocures in 50% of patients.
• Uncommen in 1st 3 years.
• Usually lymphoblastic morphology.
39. Chronic phase: Hyper prolipheration ↑ production of nature
of hematopoeitic cells.
Chronic phase: Hyper prolipheration ↑ production of nature
of hematopoeitic cells.
Accelerated phase: Progressive maturation defect→AL-like.Accelerated phase: Progressive maturation defect→AL-like.
Blastic phase: Leukemic clone loses its capacity to differentiate.Blastic phase: Leukemic clone loses its capacity to differentiate.
3311 XPh chromsomePh chromsome
• Myeloblastic 60-70% of patients.
• Lymphoid morphology 35-40% (usually B).
• If lymphoid T-cell
usually no chronic phase,
marked lymph node enlargment.
40. These additional cytogenetic aberrations may also be
found at the time of diagnosis in approximately 7 % of
patients and are associated with"
A lower response rate to tyrosine kinase inhibitors.
Inferior survival.
42. WHO criteria Chronic Accelerated Blast crisis
Blast < 10%
10-19%
blood or marrow
≥ 20%
blood or marrow
Large foci or
clusters of blasts
in BMB biopsy
Basophiles ↑ ≥20% blood
Platletes Normal or ↑
Persistent ↓
(<100 X 109
/L)
unrelated to therapy
WBCS ↑ ↑
Extramedullary
blast proliferation
apart from spleen
Spleen size ↑
↑
unresponsive to TTT
Ph CCA/Ph1 on treatment
43. ELN criteria Chronic Accelerated Blast crisis
Blast < 10%
15-29%
blood or marrow
≥ 20%
blood or marrow
Large foci or
clusters of blasts
in BMB biopsy
Basophiles ↑ ≥20% blood
Platletes Normal or ↑
Persistent ↓
(<100 X 109
/L)
unrelated to therapy
WBCS ↑ ↑
Extramedullary
blast proliferation
apart from spleen
Spleen size ↑
↑
unresponsive to TTT
Ph CCA/Ph1 on treatment
45. 1845 1974
1975
Potential cure with
allogeneic hematopoietic
cell transplantation (HCT)
1990
Disease control without
cure using (TKIs)
1
3
2
Palliative therapy with cytotoxic agents
46. The only option for cure is allogeneic hematopoietic stem cell
transplantation (HCT)
The response to TKI is the most important
prognostic factor.
Disease phase at the time of HCT is the most
important prognostic factor for survival following
allogeneic HCT for CML.
47. Factors influencing the choice of therapy ?
IS THERE A ROLE FOR TKI before-
HCT ?
IS THERE A ROLE FOR TKI post-HCT ?
Can we discontinue TKI therapy ?
48. A number of issues must be addressed when transplantation is considered:
Patient eligibility
Choice of donor
Closeness of match
Method of hematopoietic cell collection
Preparative regimen
Disease phase
Age Medical comorbidities
HaploidenticalMatched
Unrelated
Mismatched
PB
Myeloablative Non myeloablative
Identical twin Relative (eg, sibling, parent)
BM Blood
Disease phase at the time of HCT is the
most important prognostic factor for
survival following allogeneic HCT for CML.
The ability of allogeneic HCT to cure CML is
related to th the conditioning regimen and the
GVL effect of the donor lymphocytes.
Myeloablative conditioning are preferred
whenever possible. Intravenous busulfan and
cyclophosphamide (BU/CY)
1)An HLA-matched sibling donor
2)Matched unrelated donor
3)Haploidentical donors &umbilical cord blood
Treatment
options
Treatment
options
49. Patients who received imatinib before transplantation had
significantly lower risk of death compared with patients who did not
receive imatinib.
TKI leads to lower disease burden at time of transplantation,
decrease the likelihood of relapse after transplantation.
Lee SJ., et al 2008
IS THERE A ROLE FOR TKI before-HCT ?
Treatment
options
50. Initial studies suggest that there may be a role for imatinib maintenance therapy
after allogeneic HCT. Olavarria et al., Blood 2007
IS THERE A ROLE FOR TKI POST-HCT ?
Chronic phase CML no benefit if a molecular remission has been achieved.
Myeloid or lymphoid blast crisis, they suggest the use of a TKI for two years
after allogeneic HCT {if tolerable}, rather than postponing its use until the
emergence of MRD positivity, especially if nonmyeloablative conditioning is
used.
Treatment
options
53. Administration: Imatinib is associated with a moderate emetic potential
antiemetics may be recommended to prevent nausea and vomiting.
(Dupuis, 2011; Roila, 2010)
Should be administered with a meal and a large glass of water.
It is not recommended to crush or chew tablets due to bitter taste.
Tablets may be dispersed in water or apple juice (using ~50 mL for
100 mg tablet,~200 mL for 400 mg tablet); stir until dissolved and
administer immediately.
Treatment
optionsImatinib
Dosing: Pediatric Oral: 340 mg/m2/day;maximum: 600 mg daily.
Drug information
Dosing in children may be once or twice daily for (CML) and once daily for
Philadelphia chromosome–positive (Ph+) ( ALL).
54. Absorption: Rapid
Protein binding: ~95% to albumin and alpha1-acid glycoprotein.
Metabolism: Hepatic via CYP3A4.
Bioavailability: 98%; may be decreased in patients who have had
gastric surgery (eg, bypass, total or partial resection).
Half-life elimination: Adults: ~18 hours; Children: ~15 hours.
Time to peak: 2 to 4 hours
Excretion: Feces (68% primarily as metabolites, 20% as
unchanged drug); urine (13% primarily as metabolites, 5% as
unchanged drug).
Imatinib
Treatment
options
Pharmacodynamics and Pharmacokinetics
55. Inhibits Bcr-Abl tyrosine kinase, the
constitutive abnormal gene product of
the Philadelphia chromosome in
chronic myeloid leukemia (CML).
Also inhibits tyrosine kinase for
platelet-derived growth factor (PDGF),
stem cell factor (SCF), c-Kit, and
cellular events mediated by PDGF and
SCF.
Imatinib
Treatment
optionsMechanism of Action
57. Treatment
optionsImatinib
Avoid concomitant use of strong CYP3A4 inducers (eg, dexamethasone,
carbamazepine, phenobarbital, phenytoin, rifampin).
Drug interactions
If concomitant use cannot be avoided, increase imatinib dose by at least 50%
with careful monitoring.
Ibuprofen may decrease intracellular concentrations of imatinib, leading to
decreased clinical response.
58. Treatment
optionsImatinib
Dosing: Renal Impairment
• Mild impairment (CrCl 40-59 mL/minute): Maximum recommended
dose: 600 mg.
• Moderate impairment (CrCl 20-39 mL/minute): Decrease dose by
50%.
• Severe impairment (CrCl <20 mL/minute): Decrease dose by 75%.
(Gibbons, 2008)
Dose adjustment
Dosing: Hepatic Impairment
• If elevations of bilirubin >3 times ULN or transaminases >5 times ULN
occur:
Withhold treatment until bilirubin <1.5 times ULN and
transaminases <2.5 times ULN.
Resume treatment at a reduced dose (25% reduction)
60. Administration:
Administer once daily (morning or evening).
Swallow whole; do not break, crush, or chew tablets.
May be taken without regard to food.
If GI upset occur take with a meal or with a large glass of
water.
Treatment
optionsDasatinib
Dosing: Pediatric Oral: 100 mg once daily.
Drug information
Dosing :Sprycel: 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, 140 mg.
Spectrum :binds active & inactive conformation of ABL-kinase, SRC family
kinase, C-KIT & PDGFR.
61. Side effects:
Fluid retension & edema
Treatment
optionsNilotinib
Dosing (Tasigma): Pediatric Oral: 400 mg /12 h.
Drug information
Spectrum : highly selective binding of ABL-kinase, C-KIT & PDGFR.
62.
63. Discontinuing CML treatment is not recommended unless
part of a clinical trial (Baccarani, 2009).
Can we discontinue TKI therapy ?
Treatment
options
64. The phase of CML.
Vailability of a donor for HCT.
Patient age.
The presence of medical co-morbidities affecting patient suitability for
HCT.
The response to treatment with TKIs.
Factors influencing the choice of therapy
ALLO BMT vs TKIs ?
65. Initial treatment
TKIs are the initial treatment of choice for the majority of patients with
CML.
Second generation TKIs (eg, dasatinib or nilotinib) produce faster and deeper
responses than imatinib.
Careful follow-up of response is critically important to predict when other
therapies,
such as alternative TKIs or transplantation, should be considered.
Data at eight years of follow-up show that the response to imatinib have been
very durable, with very few relapses after three to four years of follow-up.
66. Definition of response to treatment
Time landmarks and response criteria to TKI
1>23
Monitionring response
3 M 18 M6 M 12 M
67. Complete:
WBC < 10 X103
/L,
Platelets < 450 X 109
/L,
Differential no immature granulocytes and
Basophils <5%
Effectiveness of TKI therapy is determined by the achievement of landmark
responses {hematologic, cytogenetic, and molecular} at specific time.
Monitoring response
69. ÷ 10
Molecular response is best assessed according to the International Scale (IS)
– As the ratio of BCR-ABL1 transcripts to ABL1 transcripts, or
– Other internationally recognized control transcripts and
– It is expressed and reported as BCR-ABL1 % on a log scale.
10%,
1%,
0.1%,
1 log,
2 log,
3 log,
4 log,
4.5 log,
correspond to a decrease
100% N LOG reduction
= Major molecular response (MMR)
= Deep molecular response (MR)
The term complete molecular response
should be avoided and substituted with the
term molecularly undetectable leukemia.
Monitoring response
72. The responses are defined as
Optimal
Warning Zone
Faiure
Primary Faiure
Secondary Faiure
Optimal response is associated with the best long-term outcom
The patient should receive a different treatment to limit
the risk of progression and death.
Failure to achieve a given response at a given time
Loss of response
Warning implies that the characteristics of the disease and the
response to treatment require more frequent monitoring to
permit timely changes in therapy in case of treatment failure.
Monitoring response
74. At any time
Loss of CHR
Loss of CCyR
Confirmed loss of MMR
Mutations
CCA/Ph1
Monitoring response
75. 0 M 3 M 6 M 12 M
≥1 log reduction
and/or Ph1 ≤35%
Non-CHR
and/or
Ph1 >95%
<1 log reduction
and/or Ph1 36-95%
>2 log reduction
and/or
Ph1 0 %
<1 log reduction
and/or
Ph1 .35%
1-2 log reduction
and/or
Ph1 1-35%
≥ 3log reduction
and/or
Ph1 0 %
<2 log reduction
and/or
Ph1 >0
<3---≥2 log reductionAt any
time
≥ 3log reduction
Loss of CHR
Loss of CCyR
Confirmed loss of
MMR*
Mutations
CCA/Ph1
Start with
imatinib or
nilotinib or
dasatinib
Monitoring response
76.
77. They recommend as initial treatment --- imatinib or nilotinib,or dasatinib.
• Jeffrey R., et al Blood. 2012; recommend that front line therapy for
pediatric CML in chronic phase is TKI therapy without transplantation.
R
R
The response to TKI is the most important prognostic factor.F
In the previous versions of the ELN recommendations to the response to first line
treatment was limited to imatinib. Now they do not recommend which TKI should be
used but which response should be achieved, irrespective of the TKI that is used.
78. Response is assessed with :
Quantitative PCR and/or cytogenetics
At 3, 6, and 12 M.
R
In case of warning, it is recommended to repeat all tests,
cytogeneticand & molecular, more frequently, even monthly.
R
In case of treatment failure or of progression to AP or BP,
cytogenetics of marrow cell metaphases, PCR and mutational analysis
should be performed.
R
79. • Only in case of baseline warnings (high risk, major route CCA/Ph1)
HLA type patients and siblings should be done.
• Patients should pursue stem cell transplantation in:
Accelerated or blast crisis or
Who fail to reach landmarks on TKIs either because of intolerance
or resistance. {Jeffrey R., et al Blood. 2012}
R
R
Patients should be monitored after transplant by RQ-PCR.
R