LAPORAN KASUS MEDICINA • VOLUME 46 NOMOR 3 • SEPTEMBER 2015

ACUTE PROMYELOCYTIC LEUKEMIA

Ni Wayan Kurnia Wati, Ketut Ariawati Department of Child Health, Udayana University Medical School / Sanglah Hospital Denpasar Bali

ABSTRACT

Acute promyelocytic leukemia (APL) is a subtype of (AML). The disease is very uncommon in children less than 10 years of age. Every sign and symptom that present on patient with APL are caused by the infiltration of the bone marrow with leukemic cells and resulting failure of normal hematopoiesis. Without the normal hematopoietic elements, the patient is at risk for developing life-threatening complications of anemia, infection due to neutropenia, and hemorrhage due to thrombocytopenia, disseminated intravascular coagulation, fibrinolysis, and proteolysis of mature cells. We reported one case of a nine-year-old girl with pale, limp, recurred fever, hematome, and petechiae. Physical examination revealed pale in conjunctiva, ginggival hypertrophy, and hepatomegaly. showed normochromic normocytic anemia, thrombocytopenia, and leukopenia, with neutropenia. Bone marrow aspiration revealed a bundle of auer rod, promyelocyte 60 %, 2 %, concluded AML(M3). We provided chemoterapy with vitamine A, daunorubicine, and cytarabine, but the condition was decreased and finally died after the first cycle of chemotherapy. [MEDICINA 2015;46:178-83].

Keywords: acute promyelocytic leukemia, children

LEUKEMIA PROMIELOSITIK AKUT

Ni Wayan Kurnia Wati, Ketut Ariawati Bagian/SMF Ilmu Kesehatan Anak Fakultas Kedokteran Universitas Udayana/ Rumah Sakit Umum Pusat Sanglah Denpasar Bali

ABSTRAK

Leukemia promielositik akut (LPA) merupakan salah satu subtipe dari leukemia mielositik akut (LMA). Penyakit ini sangat jarang pada anak-anak kurang dari 10 tahun. Semua tanda dan gejala klinis pada pasien dengan LPA disebabkan karena infiltrasi sumsum tulang oleh sel-sel leukemia dan mengakibatkan kegagalan hematopoiesis normal. Komplikasi LPA yang mengancam jiwa antara lain anemia, infeksi akibat netropenia, dan perdarahan akibat trombositopenia, disseminated intravascular coagulation, fibrinolisis, dan proteolisis. Kami melaporkan satu kasus anak sembilan tahun dengan keluhan pucat, lemas, demam berulang, hematoma, dan petekie. Pada pemeriksaan fisis didapatkan konjungtiva pucat, hipertrofi gingiva, dan hepatomegali. Pemeriksaan darah lengkap menunjukkan anemia normokronik normositik, trombositopenia, dan leukopenia, dengan neutropenia. Aspirasi sumsum tulang menunjukkan adanya bundle of auer rod, promyelocyte 60%, myeloblast 2%, disimpulkan sebagai AML (M3). Kami kemoterapi dengan vitamin A, daunorubisin, dan sitarabin, tapi kondisi anak kemudian menurun dan akhirnya meninggal setelah periode pertama kemoterapi. [MEDICINA 2015;46:178-83].

Kata kunci: leukemia promielositik akut, anak

INTRODUCTION the bloodstream, distance organs, is considered to be critical for the and induce loss of normal bone pathogenesis of the disease since cute promyelocytic leuke- marrow.1,2 it blocks differentiation during the Amia (APL) is a subtype Acute promyelocytic leukemia promyelocytic stage of myeloid of acute myeloid leukemia (AML) is characterized by the t(15;17) maturation. Promyelocytic with distinctive biologic and (q22;q11 sampai 21) translocation. leukemia has been shown to clinical features that is now highly This translocation reflects the function as a tumor suppressor and curable. Acute myeloid leukemia molecular rearrangement of the RARA has differentiation- is a type of cancer caused by the promyelocytic leukemia (PML) promoting and growth-suppressing malignant proliferation of bone gene, located at 15q22, with the activities, being essential for marrow-derived cells that invade RARA gene, located at 17q21, and normal hematopoiesis.3,4

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Acute promyelocytic leukemia The purpose of this case report to L). There was also leukopenia is relatively uncommon, the determine APL in children. (WBC=0.85x109/L) with frequency being estimated as 10% neutrophenia (Ne=0.46x103/µL). of acute leukemias. The mean CASE ILLUSTRATION Her first C-reactive protein (CRP) incidence in Europe is about 2-3 SP, a nine-year-old girl was was elevated (3.605 mg/L) and first cases per million inhabitants per referred to Sanglah Hospital with urine culture and blood culture year.3 In the United States is diagnosis of aplastic anemia and revealed no growth. The estimated 600 to 800 new cases differential diagnosis myelo- hemostatic function was within every year.3,5 The frequency seems displasia syndrome. She normal limits with bleeding time to be higher in Southern Europe complained pale since two weeks, was 1’30", clotting time 7’00", (Italy and Spain: 15% of AML). limp from 6 months, and recurred prothrombin time was 13.30 Both sexes are equally vulnerable fever since 6 months before. seconds (control 12.00 seconds), to APL, and there is a wide range Hematoma and petechie often activated prothrombin time 35.10 in age at first presentation.3 One appeared in her body since 6 seconds (control 39.40 seconds), of the most striking features of months. She was in a generally and international normalized ratio APL is its age-asssociated satisfactory condition. Her was 1.15. The liver function test incidence rate. The disease is very respiratory rate was 22 times/ and kidneys function test were uncommon in children less than minute, her heart rate was 94 within normal limits. Abdominal 10 years of age. Its incidence beats/minute, her blood pressure ultrasonography showed mild increases steadly during the teen was 100/70 mmHg, and O2 hepatomegaly. years, reaches a plateau during saturation 98%. Blood smear revealed normo- early adulthood, and remains Head examination revealed chromic erythrocytes, anisopoi- constant until it decreases after pale in conjunctiva and ginggiva kilocytosis (burr cell, tear drop age 60 years.5 hypertrophy on the gums (Figure cell), polichromasia, leukocytes The diagnosis of APL is made 1). Chest examination was within leukopenia, differentiated neutro- morphologically on bone marrow normal limit. Abdomen exa- penia, toxic-granule, no blast, smears. The malignant cells bear mination revealed no hepatosple- decreased platelet with no giant numerous large granules and nomegaly nor lymphadenopathy. platelets, and pancytopenia. Bone several Auer rods. Bone marrow Extremities examination revealed marrow aspiration revealed aspirates (BMA) also taken at petechiae and hematoma. The hypercellularity, erythroid system persentation for cytogenetic complete blood count showed activities decline, myeloid system evaluation and for reverse normochromic normocytic anemia activity was increased, a bundle of transcriptase polymerase chain (Hb=8.3g/L; Ht=20.50%; auer rod, promyelocyte 60 %, reaction (RT-PCR) assays in order MCHC=40.30g/L, MCV=92.8fL) myeloblast 2 %, megakaryocyte to detect the t(15;17) translocation with elevated reticulocyte (4%) and system activities were declined, and the PML-RARá mRNA thrombocytopenia (PLT=48x109/ with conclusion AML(M3). respectively. Immunophenotyping confirms the myeloid lineage (CD13-CD33) with association in some cases with CD19 and/or CD2 antigens usually found in lymphoid lineages.3 Although 65 to 80 percent of patients with APL have a complete remission with standard chemo- therapy, approximately 10 to 20 percent die either before or during chemotherapy of bleeding attri- butable to disseminated intra- vascular coagulation, fibrinolysis, and proteolysis into mature cells.1 Standard chemoterapy and all- trans-retinoic acid (ATRA) as induction or maintenance treat- ment improves disease free and overall survival as compared with chemoterapy alone and should be included in the treatment of APL.1,6 Figure 1. Gingival hypertrophy.

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During hospitalization, the ages, reaches a plateau during presenting complication of AML patient was sufferred febrile early adulthood, and remains particulary in acute promyelocytic neutropenia, anemia, and constant until it decreases after leukemia but also in acute thrombocytopenia. Antibiotics and age of 60.5 In this case the myelomonocytic leukemia and blood transfusion were given. One symptoms of leukemia occured at acute monocytic leukemia months later, general condition the age of nine years and eight subtypes. The coagulopathy may was improved, without fever, and months old. result from thrombocytopenia as she was planned to receive There is large range of well as from disseminated chemotherapy. On January 8th presenting signs and symptoms for intravascular coagulation (DIC) 2013 chemoterapy was started pediatric AML. Life threatening due either to infection or to the with high dose vitamin A 200.000 complications occur due to release of coagulant activity IU/day as a substitute of ATRA, decreased normal hematopoiesis associated with the cytoplasmic followed by daunorubycine 60mg/ secondary to leukemic infiltration activity of some AML blasts. m2/day for 3 days and cytarabine of the bone marrow as well as to Disseminated intravascular 200 mg/m2/day for 7 days that was organ dysfunction and failure as a coagulation may worsen as given 3 days after free of vitamin result of leukemic infiltration. The therapy is initiated due to A consumption. After first cycle of complete blood count and increased release of these period of chemotherapy, the examination on peripheral blood coagulant proteins associated with patient was clinically unstable. smear are the first step in the tumor lysis and leading to factor She was sufferred from recurred laboratory diagnosis of leukemia. depletion and bleeding.8 In our febrile neutropenia, anemia, and Blood cell counts are variable in case, physical examination trombocytopenia and got blood patients with AML. White blood revealed bleeding manifestation, transfusion. Physical examination cell (WBC) count may be normal, such as petechiae and hematome revealed gingival hypertrophy and increased, or decreased. It is on skin. Thrombocytopenia was hepatomegaly. The complete blood markedly elevated over 100 x 109/ noted in our cases. count on January 15th 2013 showed mL cells in less than 20% of cases. Organomegaly is seen in normochromic normocytic anemia Conversely, the WBC is less than approximately half of patient of (Hb=6.8g/L; Ht=19.3%; MCHC= 5.0 x 109mL in about half of the AML due to hepatic and splenic 34.9g/L, MCV=79fL), thrombocy- patients at the time of diagnosis. infiltration with leukemic blasts. topenia (PLT=5x109/L). There Blasts are usually seen on the Extramedullary leukemia is was also leukopenia (WBC= peripheral smear examination, but observed in 10-20% of patient with 0.36x109/L) with neutrophenia in leukopenic patients, the gingival hyperthrophy, lympha- (Ne=0.1x103/µL). On Pebruary 16th numbers maybe few and require a denopathy, and leukemic cutis 2013, the patient suddenly suffered diligent search to uncover. (palpable non tender nodules in the hematemesis and melena. The Cytoplasmic inclusion known as skin) being the most common.8 In hemostatic functions were auer Rods often present in a small our case, physical examination prolonged, prothrombin time 32.10 percentage of the , revealed ginggival hiperthrophy, seconds (control 12.4 seconds), , or promyelocytes in without hepatomegaly and nor activated partial thromboplastin the various subtype of AML.7 In splenomegaly. Abdomen ultrasono- time 96.8 seconds (control 36.8 our case the WBC was decreased graphy showed mild hepatomegaly. seconds), and international (WBC = 0.85 x109/L). On In 1976, the French- normalized ratio 2.57. The liver peripheral blood smear exami- American-British (FAB) group function test, kidneys function test nation revealed leukopenia, proposed a system of classification and electrolytes were within differentiated neutropenia, no toxic of AML based on morphologic and normal limits. She got blood granule, and no blast. cytochemical features (Table 1). transfusion such as packed red Anemia is a very common The system divides AML into cell, platelet concentrate, fresh feature due to inadequate pro- seven subtypes, M1 through M7. frozen plasma, and cryoprecipitate. duction of normal red cells. The An M0 subtype was later added to However her condition was reticulocyte count is usually describe undifferentiated leukemia deteriorated and finally died on normal or decreased. Red cell and since 1976 immunophenotypic Pebruary 17th 2013. anisopoikilocytosis is mildly data have also been included.9 abnormal, with few The presumptive diagnosis of DISCUSSION presents.7 In our case the complete APL can usually be made by review Acute promyelocytic leukemia blood count showed anemia, with of the peripheral blood smear alone in children is rare. The disease is increased reticulocyte count and or with the bone marrow aspirate very uncommon in children less anisopoikilocytosis on peripheral and core biopsy by an experienced than 10 years of age. Its incidence blood smear. hematologist and hematopa- increases steadily during teen Coagulopathy is a common thologist in the presence of the

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Table 1. FAB classification9 Table 3. In our case, including low M0 AML with minimal differentiation risk using European regimen. M1 Myeloblastic leukemia without maturation However because they have not M2 Myeloblastic leukemia with maturation availability of ATRA in Indonesia M3 Acute promyelocytic leukemia we used high doses of vitamin A M4 Acute myelomonocytic leukemia derivates 200,000 IU as a M5 Acute monoblastic leukemia substitute for ATRA. It was M6 Acute erythroblastic leukemia expected by administering M7 Acute megakaryoblastic leukemia combination of vitamin A and chemotherapy would give equal prognosis with ATRA and chemotherapy. Acute promyelocytic leukemia therapy is intensive and nearly myeloblative, supportive care measures have a large impact on overall survival mortality and morbidity. Current standards of care include mandatory hospitalization for the duration of pancytopenia, with prompt initiation of an empiric antibiotics regiment for fever. Antifungal prophylaxis is standard, as is prompt initiation of empiric antifungal treatment for prolonged fever without a source. Nutritional support is important, in addition to routine transfusion support with both platelets and packed red blood cells.12 In our case we treated her with empiric antibiotic followed Figure 2. Bone marrow aspiration showed bundle of auer rod, with definitive antibiotic according promyelosit was 60 %, myeloblast 2 %. to blood culture. We gave nutritional support, oxygen characteristic clinical findings. bundle of auer rod, promyelosit therapy when needed, and The peripheral blood smear often was 60 %, myeloblast was 2 %, transfusion of packed red cells and shows leukopenia with circulating decline megakaryocyte system platelets. promyelocytes, which usually have activities (Figure 2). The Coagulopathies can also abundant, often irregular- conclusion was AML(M3). complicate the hemostatic defects appearing primary azurophilic Stratified APL based on the associated with thrombocytopenia. granules. Leukemic promyelocytes WBC count and platelet count, as Disseminated intravascular with multiple auer rods may be shown in Table 2. Chemotherapy coagulation is most often seen in found and are identified only in in patients with APL depending on APL due to release of APL. The bone marrow aspirate stratified of the disease based on procoagulants from the abnormal shows morphologically classic APL the WBC count and platelet count. primary granules, which activate which is characterized by the Chemotherapy regimen are widely cascade, leading to decreased presence of blasts promyelocytes used European APL regimen or factors II, V, VIII, and X, and hypergranulate > 20% with PETHEMA regimen as shown in fibrinogen, as well as rapid platelet intracytoplasmatic auer rods that in several cases, for their high Table 2. Stratified APL 10,11 number, form the so-called “faggot cells”. 3,6 In our case bone marrow Low risk Intermediete risk High risk aspiration shows the description of hiperselularity, eritroid system WBC < 10,000/µL < 10,000/µL > 10,000/µL activities was increased, myeloid Platelet > 40,000/µL < 40,000/µL system activity increase, showed

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Table 3 . Protocol therapy APL10-13

consumption.13 Disseminated 32.10 seconds (control 12.4 intravascular coagulation may seconds), activated partial SUMMARY worsen as therapy is initiated due thromboplastin time was 96.8 We reported a case of a 9 year to increased release of these seconds (control 36.8 seconds), and old girl with APL, with chief coagulant proteins associated with international normalized ratio was complain were pale, limp, recurred tumor lysis and leading to factor 2.57. She got blood transfusion fever, often appearing petechiae depletion and bleeding.8 In our case such as packed red cell, platelet and hematoma in the skin. On the patient suddenly was suffered concentrate, fresh frozen plasma, physical examination we found from hematemesis and melena. and cryoprecipitate, However the gingiva hypertrophy. Complete The hemostatic function were condition was deteriorated and blood count showed normochromic prolonged, prothrombin time was finally died. normocytic anemia, throm-

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