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A CHRONIC MYELOGENOUS LEUKEMIA BCR-ABL POSITIVE PATIENT WITH


T3151 TYROSIN KINASE GENE MUTATION WHO FAILURE TO IMATINIB AND
PLEURAL EFFUSION

M. Hashemi Rafsanjani W

INTRODUCTION
Chronic myelogenous leukemia (CML) is a haematological malignancy that is
characterized by a reciprocal translocation between chromosomes 9 and 22, a reciprocal
translocation fuses the Abelson (Abl) tyrosine kinase (TK) gene on chromosome 9 with the
break-point cluster region (Bcr) gene on chromosome 22. This fusion forms the Philadelphia
chromosome, which is present in more than 90% of CML patients. (Deininger et al, 2000)
The annual incidence in US is 1.48 cases per 100,000 adults, with a male-to-female
ratio of 1.7/1.1. The median age at diagnosis is approximately 65 years, with less than 10% of
patients under the age of 20 years.(An et al, 2010). In China obtained a lower incidence is 0.4-
0.6 per 100,000 population. (Au et al., 2009). In Dr Soetomo Hospital is found an increased
incidence of CML in 2006 only 58 people, in 2014 160 people and in 2016 reached 297 people
consisting of people with 192 male and 105 female patients with an age range of 30-40 years is
24% and age over 50 years is 34%. (Bintoro, 2014)
Although most patients with CML showed hematological response but 3% of chronic
phase CML does not respond at all to the first-generation tyrosine kinase inhibitors (imatinib).
In fact, every year they were a response is still experiencing a recurrence of between 0.4%
-5.5%. From the results of the IRIS study reports about 10% of patients experienced a relapse
after 5 years of complete cytogenetic response.(Druker et al, 2006).
CML containing the T315I mutation remains a serious medical problem, particularly in
clinical practice. The Bcr-Abl T315I mutation, can be detected in 10-20% of patients with
CML after failure of imatinib therapy. The most prevalent and best-understood mechanism of
drug resistance in patients who relapse on imatinib therapy involves mutations within the
kinase domain of Bcr-Abl that impair drug binding (Lu et al, 2011)
Pleural effusion in patients with CML is a rare occurrence and poorly understood. The
possible mechanisms of exudative pleural effusion in CML patients include leukemic infiltration
into the pleura, extramedullary hematopoiesis, non malignant causes and drugs etc. Pleural
effusion in CML is generally considered as poor prognostic indicator.(Nuwal e tal, 2012)
The following will be reported to a case of a CML BCR-ABL positive patient with
T315I mutation who failure to imatinib and pleural effusion
Case Report Department of Internal Medicine Airlangga University School of Medicine Dr.Soetomo
Teaching Hospital Surabaya, January, 17, 2017
CASE
A man 26 years old, Javanese, married, traders work, admitted to hospital in the
emergency room Dr. Soetomo on October 2, 2016 with a chief complaint of shortness of
breath
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History of present illness: The patient complained of shortness of breath since 2 weeks
before admission, patient feels shortness more when he sleep than sit. Patient feels comfortable
when tilted to the right position. There is no cough or fever. Abdominal distended since one
year before entering the hospital and getting bigger in last a week, especially on the left.
Abdominal pain is felt left side of abdomen. Abdominal pain since 3 days before entering the
hospital. Urination and defecation within normal limits. There is no nausea or vomiting and
found a decrease of appetite and weight loss in patient.
Past medical history
History of hypertension or diabetes is denied. A family history of similar disease
symptoms are not obtained. Patient has already diagnosed CML since 1 year 8 months with
BCR-ABL positive results in May 2015 and routine control in poly hematology oncology
(POSA) and get hydroksiurea (Hydrea) and imatinib (Glivec) 400mg/ day. TB treatment
history is denied.
In physical examination found general weakness, composmentis, blood pressure 110/70
mmHg, pulse 110x / minute, respiratory 36x / minute, axillary temperature 36.7 ° C. From
head and neck examination obtained anemia of conjunctiva and dyspnoea. There were no
icterus and cyanosis. There is no lymph node enlargement around the neck and head. In thorax
examination symmetrical chest movement, vesicular lung sounds in the right side is decreased,
not obtained wheezing and ronkhi both sides. In heart examination ictus cordis in ICS V linea
midclavicularis, S1 and S2 single, no murmurs, gallops, and ektrasistole. In abdominal
examination be found abdominal distended, minimal ascites, liver not palpable and spleen
palpable at Schuffner 6 Hackett 3. In extremities examination akral warm, dry, red and there is
no edema.
Laboratory:
Hb 8,8 gr/dl , leukocytes 10.300/ul, platelet 218.000/ul , hematocrit 27,7 %, MCV 89,5 fl,
MCH 28,5 pg, MCHC 31,8 g/dl, basophil 4,15%
GDA 103,SGOT 8 ,SGPT 5 ,Albumin 3,5 ,BUN 16, SK 0,75 , Kalium 3,8 , Natrium. 136 , Cl
100 , Hbsag. non reactiv. BGA pH 7,523 pC02 31,2 pO2 98,5 HCO3 25,9 BE 2,9 SO2 98,4
Blood smear:
E:mostly normocromic, a fraction hypochromic, anisopoikilositosis (mikrosit, normosit,
ovalosit, target cell, fragmentosit), polikromasia cell+, normoblast-
L: normal count, a segment dominated by neutrophils, immature granulocyte + (promyelosite,
myelocyte, metamyelocyte, stab), blast -
T: normal count, giant platelets +
Conclusion: patients with a history of CML, currently not found blast
Results of pleural fluid analysis: pH 8 Wbc 1.426x103/ul, Rbc 0,011x106/ul, MN 1.421x103/ul,
PMN 0.005x103/ul, MN 99.6%, PMN 0.4%, The number of cells 1.498x103/ul, Glu 121, Prot
4,8 g/dl (6,4-8,2), LDH 97 u/l (100-190)
Urinalysis : glucose -, proteinuria -, nitrit -, erytrosit 0-1, leukocytes 0-1, bact -.
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Chest X-ray: Cor in normal limit, pulmo pleural effusion (D), costophrenicus angle blunt
ECG: sinus tachycardia rhythm 110 x / min, normal axis
Inter-disciplinary Consultation
Pulmonology: summary: patients with pleural effusion D pro evaluation can be related to fluid
retention ec TKI therapy (imatinib) dd pleural leukemic infiltration
Based on the data above of anamnesis, physical and laboratorium examination, then patient is
diagnosed CML chronic phase+pleural effusion (D)
Planning diagnosa: complete blood count post transfusion, pleural fluid cytology, smear gram
& BTA, aerobic culture & MTB pleural fluid, ADA test, serum LDH, serum total protein.
Therapy was given O2 nasal 3-4 lpm, high-protein, high-calorie diet in 2100 cal / day, PZ
infusion 7 dpm, transfusion PRC 1 kolf /d until Hb≥10 g / dl, hydroksiurea (Hydrea)
temporarily stopped, Glivec 0-0 -4 tab.
Progress of the disease
Day-2nd hospitalized
Composmentis, weakness. Blood pressure 120/70 mmHg, HR 84x/menit, RR 28x/menit, Temp
36,8 C. Patient still complained shortness of breath
Lab: Hb 9,8 gr/dl, leukocytes 10.500/ul, platelet 220.000/ul, hematocrit 27,7 %, MCV 89,5 fl,
MCH 28,5 pg, MCHC 31,8 g/dl, LDH serum 181, protein serum 6.1.
Assessment: chronic phase CML+ pleural effusion (D)
Planning chest x-ray post evacuation. Supportive therapy TKTP 2100 kcal / day, Imatinib
(Glivec) temporarily discontinued, patient has been evacuated ± 800 cc of pleural fluid was
reddish
Day-6th hospitalized
Composmentis, weakness. Blood pressure 120/70 mmHg, HR 84x/menit, RR 30 x/menit,
Temp 36,8 C. The patient still complained shortness of breath
Lab: Hb 11,2 gr/dl, leukocytes 21.150 /ul, platelet 217.000/ul, hematocrit 39,3 %.
ADA(Adenosine Deaminase) test 2,3 u/l (<24). Results of sputum smear ZN I, II, III was
not found acid-resistant bacteria. The results of pleural fluid culture: no growth of
aerobic bacteria and gram. Results of blood culture/ urine: steril
USG abdomen: splenomegaly size ±23,9 cm, bilateral pleural effusion
Assessment: chronic phase CML+ pleural effusion (D)
Planning chest x-ray post evacuation. Supportive therapy TKTP 2100 kcal / day, Imatinib
(Glivec) is temporarily stopped, patient had been evacuated ± 1000 cc of pleural fluid was
reddish.
Day-12th hospitalized
Composmentis, weakness. Blood pressure 120/70 mmHg, HR 90x/menit, RR 28x/menit, Temp
36,8 C. The patient still complained shortness of breath
Lab: Hb 10.9 gr/dl, leukocytes 19.750 /ul, platelet 177.000/ul , hematocrit 36,2 %, albumin
3,2
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MSCT Thorax results: bilateral pleural effusion with multiple loculated right, not found
mass in the right and left lungs/mediastinum
Pleural fluid cytology: atypical cytologic was not conclusive for malignancy
Assessment: chronic phase CML+ pleural effusion (D)
Planning chest x-ray evacuation. Supportive therapy TKTP 2100 kcal / day, Imatinib (Glivec)
temporarily discontinued, patients had been evacuated ± 610 cc of pleural fluid was reddish.
Patient was installated WSD.
Day-20th hospitalized
Composmentis, getting well, patient was attached WSD. Blood pressure 120/70 mmHg, HR
88x/menit, RR 22x/menit, Temp.36,8 C. Shortness of breath had already reduced.
Lab: Hb 10.6 gr/dl, leukocytes 20.770 /ul, platelet 116.000/ul , hematocrit 36,2 %.
Assessment: chronic phase CML+ pleural effusion (D) post WSD
Planning quantitative BCR-ABL, chest x-ray post WSD. Supportive therapy TKTP 2100
kcal/day, Imatinib (Glivec) is temporarily stopped. WSD patient had been released and
pleurodesis was performed.
Day-22th hospitalized
Composmentis, getting well. Blood pressure 120/70 mmHg, HR 90x/menit, RR 20x/menit,
Temp 36,8 C. Patient had no shortness of breath.
Lab. Hb 10.9 gr/dl , leukocytes 43.550/ul, platelet 108.000/ul , hematocrit 36,2 %.
The results of RT-PCR Quantitative: BCR-ABL was detected with international scale
ratio 57%
The results of blood smears
E: normocromic, anisopoikilositosis (normosit, mikrosit, ovalosit, sferosit), sel
polikromasia+, normoblast+
L: dominated by neutrophils increased number of segments, immature granulocyte (+)
(promyelocyte, myelocyte), blast-, atypical lymphocytes +, blast -
T: number decreased, giant platelets (-)
Conclusion: patients with a history of CML, currently not found blast
Assessment: chronic phase CML+ pleural effusion (D) post WSD
Planning T3151 mutation, consultation to cardiology, ecg and echocardiography, complete
blood count. Supportive therapy TKTP 2100 kcal / day. Patient was planned be given second-
line TKI is nilotib (Tasigna) 2x200 mg.
Day-24th hospitalized
Composmentis, getting well. Blood pressure 120/70 mmHg, HR 90x/menit, RR 18x/menit,
Temp 36,8 C. Patient had no shortness of breath.
Lab Hb 10.6 gr/dl , leukocytes 20.770 /ul, platelet 117.000/ul , hematocrit 36,2 %.
Echocardiography results: Valve within normal limit, chamber dimensions LA, LV, RA,
RV normally invisible thrombus / vegetation intracardiac, function of LV systolic normal
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(EF by Teich 77%, by biplanes 79%), the analysis of segmental LV normokinetic, there
was not LVH.
ECG results: normal sinus rhytm 90x/m, axis normal, no QT interval prolongation
Assessment: chronic phase CML+ pleural effusion (D) post WSD
Patient discharge from the hospital after 24 days hospitalization and was evaluated in poly
hematology oncology (POSA) and was treated with second-line tyrosine kinase inhibitor is nilotinib
2x200 mg.
Seven days later, patient go to poly hematology oncology (POSA) and has no complaints, no
shortness of breath. Lab : Hb 10,1 gr/dl , leukocytes. 11.200 /mm3, platelet. 117.000. Results
T3151 mutation on PCR-ASO (Allele Specific oligonucleotides): was found the mutation
T3151 which is indicated at 158bp band. Treatment: Supportive, nilotinib 2x200 mg
continued.
DISCUSSION
Two pathologists, Drs. Rudolf Virchow and John Hughes Bennett, first described CML
in 1845. In 1960, Drs. Peter Nowell and David Hungerford, who worked in Philadelphia,
described a consistent chromosomal abnormality in patients with CML. The chromosome was
subsequently called the Philadelphia (Ph) chromosome. (Nowell PC, 2007).
Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized
by increased myeloid cell numbers with intact maturation. CML is caused by Bcr-Abl, a
constitutively active fusion tyrosine kinase, that is the result of the translocation t(9;22)
(q34;q11) which generates the Philadelphia chromosome (Ph). (Cardama&Cortes, 2008). This
translocation results in the head to tail fusion of the breakpoint cluster region (BCR) gene on
chromosome 22 at band q11 and the Abelson murine leukemia (ABL) gene located on
chromosome 9 at band q34. The fusion gene, BCR-ABL, encodes a protein (p210BCR-ABL).
(O’Brien et al, 2011)
Patient had been diagnosed CML clinically from enlarged left abdomen with
splenomegaly S6H3, weight, from abdominal ultrasound: splenomegaly size ± 23.9 cm, and
the cytogenetic examination result of BCR-ABL was positive since May 2015 and routine
control of poly hematology oncology (POSA) and be given imatinib (Glivec) 400mg / day.
There are any different types of responses in CML: a hematological response (HR), a
cytogenetic response (CR) and a molecular responses (MR). Criteria for hematological,
cytogenic and molecular response: (An et al, 2010)
Response Criteria Monitoring
Hematological
Complete (CHR) Complete normalization of peripheral blood count: white blood cell count < 10×109 L , -1
Check every 2 weeks until CHR achieved,
platelet count < 450×109 L-1; no immature cells; no splenomegaly then monitor every 3 months
Partial Same as complete hematological except for: persistent of immature cells; platelet count <
50% of pretreatment count, but >450×109 L -1; splenomegaly <50% of pretreatment extent
but persistent
Cytogenic
Complete (CCR) No Ph+ metaphases Check every 6 months until CCR achieved
then every 12–18 months
Major (MCR) 0–35% Ph+ metaphases (complete + partial)
Partial 1–34% Ph+ metaphases
Minor 36–90% Ph+ metaphases
Molecular
Complete (CMR) BCR-ABL mRNA undetectable by RT-PCR; Check every 3 months
Major (MMR) ≥3-log reduction of BCR-ABL mRNA
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The European LeukemiaNet (ELN) guidelines, published in 2006, define a suboptimal


response as less than a complete hematologic response (CHR) at 3 months, less than a major
cytogenetic response (MCyR) at 6 months, less than a CCyR at 12 months, or less than a
major molecular response (MMR) at 18 months. Imatinib therapy failure is defined as the
absence of any hematologic response at 3 months, less than a CHR or absence of any
cytogenetic response at 6 months, less than an MCyR at 12 months, less than a CCyR at 18
months, or loss of CHR or CCyR at any time.(Jabbour et al, 2009)
Recommended Frequencies of Response Assessment in Patients With Chronic Myeloid
Leukemia and Definitions of Resistance (Suboptimal Response or Failure) During Initial
Imatinib Therapy(Jabbour et al, 2009)
Recommended frequencies of assessment Definitions of resistance
Assessment method Initial monitoring Subsequent monitoring Suboptimal response Failure
(for suboptimal response) (for loss of response)
Hematologic Every 2 wk Every 3 mo once CHR is No CHR within 3 mo No hematologic response achieved
achieved within 3 mo
Loss of CHR at any time
Cytogenetic Every 6 mo Every 12 mo once CCyR is No MCyR within 6 mo No cytogenetic response within 6 mo
achieved No CCyR within 18 mo No MCyR within 12 mo
No CCyR within 18 mo
Loss of CCyR at any time
Molecular Every 3 mo Every 3 mo, increasing to No MMR within 18 mo Not applicable
monthly if an increasing BCR- Loss of MMR at any time
ABL1 transcript level is detectedb
Mutational Immediately after detection of a Immediately after imatinib failure Any BCR-ABL1 mutation BCR-ABL1 mutation with high level
suboptimal response or an increasing BCR-ABL1 detected at any time of imatinib resistance detected at any
transcript level is detectedb time
a CCyR = complete cytogenetic response; CHR = complete hematologic response; MCyR = major cytogenetic response; MMR = major molecular response.
b Two-fold increase in BCR-ABL1 transcript level and loss of MMR if achieved.
Data from Blood15 and the National Comprehensive Cancer Network.

There are two categories of resistance: primary and secondary. Primary resistance is the
failure to achieve any of the landmark responses established by the European LeukemiaNet
(ELN) or National Comprehensive Cancer Network (NCCN) guidelines. Primary resistance
can be further divided into primary hematologic resistance, which occurs in 2–4% of cases who
fail to normalize peripheral counts within 3–6 months of initiation of treatment; or primary
cytogenetic resistance, which is more common, and occurs in approximately 15–25% of
patients who fail to achieve any level of cytogenetic response (CyR) at 6 months, a major CyR
(MCyR) at 12 months or a CCyR at 18 months. Secondary resistance occurs in those who
have previously achieved and subsequently lost their response in accordance with those
guidelines. (Assouline&Lipton, 2011)
The mechanisms of resistance to imatinib can be either BCR-ABL dependent (gene
amplification or point mutations) or BCR-ABL independent. BCR-ABL-dependent mechanism
includes point mutations within the BCR-ABL kinase domain that interfere with imatinib
binding and the over-expression or amplification of the BCR-ABL gene. BCR-ABL-
independent mechanisms include factors influencing the intracellular concentration of imatinib,
and activation of BCR-ABL independent pathways. (Nardi et al, 2004)
Patient was included in failure category because absence of hematological response
within three months, the loss of CHR which was found Wbc 21.150, splenomegaly S6H3.
There is no cytogenetic response within 6 months, no MCyR in 12 months, no CCyR within
18 months (57%), loss of CCyR at any time (Ph +) and was found T3151 mutations in BCR-
ABL which is detected on PCR-ASO (Allele Specific oligonucleotides) test.
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The gatekeeper residue threonine, located near the kinase catalytic domain controlling
the access to a hydrophobic pocket that helps inhibitors to the active site, is found in many
tyrosine kinase. In Bcr-Abl, the threonine residue at position 315 is substituted by the bulky
isoleucine, namely T315I mutation. Early studies postulated that threonine altered the 3D
structure of ATP pocket by featuring a missing fundamental hydrogen bond and a steric clash
with imatinib. However, recent studies suggested that the missing critical hydrogen bond is not
the main cause of imatinib resistance of T315I, instead, it resulted from a domino effect
induced by the conformational readjustment necessary to accommodate the mutant residue and
involved several other important drug contact point. Furthermore, suggested that T315I
resistance to imatinib resulted mainly from the breakdown of interactions between imatinib and
both Glu286 and Met290, leading to significant conformational changes(Lu et al, 2011)
Based on the understanding of the mechanism of imatinib T315I resistance, compounds
that inhibit Bcr-Abl avoiding or minimizing the interactions with Ile315 would be promising
candidates for combating T315I resistance. Some class of Bcr-Abl third generation inhibitors,
divided into ATP-competitive and non-ATP competitive inhibitors, have been developed as
effective therapies for overriding the gatekeeper T315I mutation. .( Schenone et al, 2010).
On PCR-ASO (Allele Specific oligonucleotides) in this patient was found mutations
T3151 which is be shown at 158bp band
Imatinib, originally designated CGP57148 and later signal transduction inhibitor 571
(STI-571), is marketed in the United States as Gleevec and in Europe as Glivec.Increasing the
dose of imatinib (dose escalation) has been shown to overcome some cases of primary imatinib
resistance, but the response is usually short acting. In the United States, imatinib dose
escalation from 400 to 600 mg/d is approved for patients with CP-CML (escalation of 600 to
800 mg/d is approved for advanced disease). In the European Union, escalation to 800 mg/d is
approved for patients with CP-CML.(Jabbour et al, 2009)
The treatment options for imatinib-resistant or intolerant CML patients may include
strategies such as increasing the dose of imatinib, the use of second-generation TKIs such as
dasatinib and nilotinib and HCT or other investigational compounds. Theurapeutic options
after suboptimal response to and failure of imatinib therapy after initial treatment with imatinib
at 400 mg/d, subsequent therapeutic options include imatinib dose escalation (to 600 or 800
mg/d), dasatinib, nilotinib, allogenic SCT, or clinical trial with an investigational agent.
(Bhamidipati et al, 2013)
The second-generation TKIs nilotinib (AMN107; Tasigna ™ ) and the dual Abl/Src
inhibitor dasatinib (BMS-354825; Sprycel ™ ) offer improved potency and a greater likelihood
of success in imatinib resistant patients. Nilotinib, a second-generation tyrosine kinase inhibitor
(TKI) formerly known as AMNI07, was approved by the US Food and Drug Administration
(FDA) on October 29, 2007. Nilotinib is available as 200-mg orally administered capsules and
is dosed at 400 mg twice/day, with doses given approximately 12 hours apart. Doses of up to
600 mg twice/day were used in clinical trials, but the response rates were similar to those of
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400 mg twice/day, with a slightly worse safety profile.(Jarkowski&Sweeney, 2008). Food


increases absorption of the drug; therefore, it should be taken on an empty stomach, at least 1
hour before or 2 hours after a meal. The most serious side effects of nilotinib is rarely is
tachyarrhythmias, QT interval prolongation and sudden death. (DeRemer et al, 2008)

Algorithm for chronic myeloid leukemia (CML) treatment (adapted from Baccarani) cp = chronic
phase; tki = tyrosine kinase inhibitor; Allo-sct = allogeneic stem cell transplantation
Allogeneic HCT (AlloHCT) is another potential therapeutic modality for CML patients,
particularly in those who are intolerant to TKIs or have mutations such as the T315I mutation,
which can produce significant resistance to all of the clinically available TKIs. The updated
ELN guidelines recommends AlloHCT for patients in CML-AP or BP or with the T315I
mutation and also for the patients who fail or have suboptimal response to second-line TKIs
such as nilotinib or dasatinib.(An et al, 2010)
This patient experienced a failure of the imatinib therapy and based on algorithm, 3rd
generation TKI or aloSCT should be given but in this patient can only be provided a higher
generation was 2nd generation TKI. Echo results: Valve Valve invisible disorder, chamber
dimensions LA, LV, RA, RV normally invisible thrombus / vegetation intracardiac, function of
LV systolic normal (EF by Teich 77%, by biplanes 79%), the analysis of segmental LV
normokinetik, not there LVH. ECG result was no QT interval prolongation. QTc interval is 0.3
(<0,45s) so this patient can be given a 2nd generation TKI is nilotinib 2x200 mg
Imatinib is generally very well tolerated. Although side effects are quite common, they
are usually mild and only rarely lead to discontinuation of therapy. Toxicity can be broadly
divided in hematological and nonhematological adverse events. Nonhematological toxicity are
edema and fluid retention, gastrointestinal side effects, skin reactions, arthralgia, myalgia, and
bone pain and liver toxicity. Hematological toxicity is myelosuppression Generally, severe
neutropenia and thrombocytopenia are more common in advanced disease.(Deinenger&
Druker, 2003)
In some cases, more severe forms of fluid retention occurred, such as pleural and
pericardial effusions, pulmonary edema, ascites, anasarca, and cerebral edema. The more
serious adverse reactions necessitate interruption of therapy, while in the milder forms,
diuretics may be used.(Deininger&Druker, 2003). There is no effective standard treatment of
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pleural effusion in CML patients and these patients are managed with thoracocentesis,
treatment of underlying CML by chemotherapeutic agents and pleurodesis. (Nuwal et al, 2012)
Several possible mechanisms of pleural effusion in patients with CML have been considered
includes Leukemic infiltration into the pleura that usually occurs at the time of or just prior to bone
marrow evolution to blast crisis phase, Second possible cause of pleural effusion in CML is
extramedullary hemopoiesis, although the pleura are rarely a site in these patients. Third mechanism of
development of pleural effusions in CML is the possible obstruction of pleural capillaries or infiltration
of interstitial tissue by leukemic cells during uncontrolled leucocytosis and increased capillary
permeability due to cytokine production. Non malignant causes like infection and hypoproteinemia have
also been postulated as the cause of effusion. The last possible cause of pleural effusion in CML is drug
induced. Dasatinib and imatinib are tyrosine kinase inhibitor with significant anti-leukemic activity in
CML patients. Their use has been associated with pleural effusion in 15% cases in one study.(Nuwal et
al, 2012)
Analysis of the pleural fluid showed glucose 121 mg/dL, protein 4.8 g/dL (serum protein 6.1
g/dL), LDH 97 U/L (serum LDH 181 IU/L, reference range 100-190 IU/L), pH 8,, WBC count 1426/
L, MN 99.6%, PMN 0.4%, Rbc 11000/Ul, the number of cells 1498. Protein pleural fluid/plasma
=0,78(>0,5), LDH pleural fluid/plasma=0,53(<0,6), pleural fluid LDH <2/3 of the highest value of
serum LDH=97(<120) so pleural effusion in patient, including transudate type. Cause of pleural
effusion fluid in this patient should be excluded fromTb and malignancy. Tb was ruled out because
value of ADA test is 2,3u / l (<24) and sputum smear negative. For tumor suspected can be ruled out
because of pleural fluid sitology was found atypical cells and MSCT thorax is not found mass
formations so pleural effusion in patient might be due leukemic infiltration pleura or can be related
to fluid retention ec TKI therapy (imatinib). Therefore we regarded the pleural effusion of the patient
as related to CML.
There are three prognostic staging scores for CML in common practice – the Sokal score15, the
Euro or Hasford score and EUTOS.The scores are used to determine if a patient is at low, intermediate
or high risk of death and may also predict response to treatment. It must be applied at diagnosis, prior to
any treatment. The Sokal score is based on age, spleen size and platelet and peripheral blood blast
count. The Hasford score also includes data on eosinophil and basophil counts.(Baccarani et al, 2013)
Calculation of relative risk
Study Calculation Risk definition by calculation
Sokal et al.1984 Exp 0.0116x(age-43,4)+0.0345x(spleen-7.51)+0.188x[(platelet Low risk<0.8
count:700)2-0.563]:0.0887x(blast cells-2.10) Intermediate risk:0.8-1.2
High risk>1.2
Euro 0.666 when age≥50 y+(0.042xspleen)+1.0956 when platelet Low risk:≤780
Hasford et al.1998 count>1500x10 L+(0.0584xblast cells)+0.20399 when basophils>3%
9
Intermediate risk:781-1480
+(0.0413xeosinophils)x100 High risk:>1480

EUTOS Spleenx4+basophilsx7 Low risk≤87


Hasford et al.2011 High risk:>87

According to Sokal core, this patient was obtained a value of 1.10 (intermediate risk)
According to the Euro hasford score, values obtained in 1,216 (intermediate risk) while according to
the Eutos Hasford score be obtained value of 125.05 (high risk) so that the relative risk for the
occurrence of progressivity and risk of death in these patients is high.
SUMMARY
It has been reported a case, a man aged 26 years was diagnosed CML BCR-ABL positive and pleural
effusion D . Patient had been diagnosed CML from clinically, laboratorium and the cytogenetic
examination and be given imatinib (Glivec) since May 2015. Patient was included in failure category
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and was found T3151 mutations in BCR-ABL which is detected on PCR-ASO (Allele Specific
oligonucleotides) test. Patient be given a 2nd generation TKI is nilotinib 2x200 mg. Analysis of the
pleural fluid showed transudate type. We regarded the pleural effusion of the patient as related to CML.
According to Eutos Hasford score, relative risk for the occurrence of progressivity and risk of death in
this patients is high.

DAFTAR PUSTAKA
An X, Tiwari AK, Sun Y, Ding PR, Ashby CR, Chen ZS, 2010. BCR-ABL tyrosine kinase inhibitors in
the treatment of Philadelphia chromosome positive chronic myeloid leukemia: A review.
Leukemia Research 34:1255–1268.
Assouline S, Lipton JH, 2011. Monitoring response and resistance to treatment in chronic myeloid
leukemia. Current Oncology. 18: 71-81
Au WY, Priscillia B., Caguioa PB, Chuah C, Hsu SC, Jootar S, Kim DW, Kweon I-Y, O’Neil WM,
Saikia TK, Waang J, 2009. Chronic myeloid leukemia in Asia. Int J Hematol 89:14-23
Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, Cervantes F, Clark RE,
Cortes JE, Guilhot F, Hansen H, Hughes TP, Kantarjian HM, Kim DW, Larson RA, Lipton JH,
Mahon FX, Martinelli G, Mayer J, Muller MC, Niederwieser D, Pane F, Radich JP, Rousselot
P, Saglio G, Saußele S, Schiffer C, Silver R, Simonsson B, Steegmann JL, Goldman JM,
Hehlmann R, 2013. European LeukemiaNet recommendations for the management of chronic
myeloid leukemia: 2013.Blood 122:872-884
Bhamidipati PK, Kantarjian H, Cortes J, Cornelison AM, Jabbour E, 2013 Management of imatinib-
resistant patients with chronic myeloid leukemia. Ther Adv Hematol 4(2) 103–117
Bintoro UY, 2014. Chronic Myelogenous Leukemia Patogenesis, diagnosis dan terapi. 1st edition.
Surabaya: Global Persada Press, 7-26.
Cardama QA, Cortes J, 2008. Molecular biology of BCR-ABL1-postive chronic myeloid leukemia.
Blood; 113(8):1619-30
Deininger MW, Goldman JM, Melo JV, 2000. The molecular biology of chronic myeloid leukemia.
Blood: 96(10):3343-56
Deininger MW, Druker BJ, 2003. Specific Targeted Therapy of CML with Imatinib. Pharmacological
Reviews 55(3): 402-23
DeRemer DL, Ustun C, Natarajan, K, 2008. Nilotinib: A Second-Generation Tyrosine Kinase Inhibitor
for the Treatment of Chronic Myelogenous Leukemia. J Clinical Therapeutics 30: 1956-71
Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver
RT, Goldman JM, Stone RM, Cervantes F, 2006. Five-year follow up of patients receiving
Inhibitor Tirosin Kinase for chronic myeloid leukemia, 2006. N Engl J Med 355: 2408-17.
Jabbour E, Cortes JE, Kantarjian HM, 2009. Sub Optimal Response to or Failure of Imatinib
Treatment for Chronic Myeloid Leukemia: What Is the Optimal Strategy? . Mayo Clin Proc.
84(2):161-169.
Jarkowski A, Sweeney RP, 2008. Nilotinib: A New Tyrosine Kinase Inhibitor for the Treatment of
Chronic Myelogenous Leukemia. Pharmacotherapy 11:1374–1382.
11

Lu XY, Cai Q, Ding K, 2011. Recent Developments in the Third Generation Inhibitors of Bcr-Abl for
Overriding T315I Mutation. Current Medicinal Chemistry 18: 2146-2157.
Nardi V, Azam M, Daley GQ, 2004. Mechanisms and implications of imatinib resistance mutations in
BCR-ABL. Curr Opin Hematol; 11:35-43
Nowell PC, 2007. Discovery of the Philadelphia chromosome: a personal perspective. The Journal of
Clinical Investigation 117(8): 2033-35
Nuwal P, Dixit R, Dargar P, George J, 2012. Pleural effusion as the initial manifestation of chronic
myeloid leukemia: Report of a case with clinical and cytologic correlation. J Cytol 29:152-4.
O’brien S, Berman E, Moore JO, Ibarz JP, Radich JP, Shami PJ, Smith BD, Snyder DS, Sundar HM,
Talpaz M, Wetzler M, 2011. NCCN Task Force Report:Tyrosine Kinase Inhibitor Therapy
Selection in the Management of Patients With Chronic Myelogenous Leukemia. Journal of the
National Comprehensive Cancer Network. 9:1-12.
Schenone S, Brullo C, Botta M, 2010. New Opportunities to Treat the T315I-Bcr-Abl Mutant in
Chronic Myeloid Leukaemia: Tyrosine Kinase Inhibitors and Molecules that Act by Alternative
Mechanisms. Current Medicinal Chemistry 17: 1220-1245.

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