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MYELOID LEUKEMIAS, MYELODYSPLASTIC AND MYELOPROLIFERATIVE SYNDROMES
ABSTRACT NO.: P-100
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Long-term follow-up of children with chronic myeloid leukemia after tyrosine kinase
therapy at the Republic of Bashkortostan
E.V. Yakupova, T.N. Krasavtceva, E.F. Amirova, A.I. Makhonina, V.B. Makhonin, R.N. Stepanova
Republican Children Clinical Hospital, Ufa, Republic of Bashkortostan
Key words: chronic myeloid leukemia, tyrosine kinase inhibitor, children
Introduction. Tyrosine kinase inhibitor (TKI) have become the standard first-line treatment for chronic phase of chronic myeloid leukemia (CP-CML) and transformed CML from fatal disease into a leukemia subtype with a favorable prognosis. ^
Aim. The purpose of this study is to report long-term outcomes of CP-CML patients at the Republic of Bashkortostan (RB).
Materials and methods. This is a retrospective analysis from the CML patients case records from RB. The method of limiting dilution was used to assay of BCR-ABL1 transcript level for the monitoring of the response to therapy (MRD). Q
A total of 8 CP-CML patients less than 14 years old at the time of diagnosis (with a median age of 10 years 1 month) registered in RB from a period of 2002 to 2015 year were enrolled in this study. >
Results. According to our research the annual incidence of CML in children at the RB is 0.08/100 000. Now we have 4 pediatric patients with CP-CML under the observation. Patient 1. Major molecular response (MMR) was received after 4 months treating with 400 mg imatinib mesylate (IM), after 14 months was diagnosed molecular response (MR) and it is saving ^
during 4 years. Patient 2. MMR (10-4) was received after 3 months treating with 400 mg IM, after 10 months'therapy BCR-ABL expression level 0.014 %. Patient 3. MR was received after 3 months treating with 400 mg IM and it saved during 3.5 years, but in the last test was determined slight increase BCR-ABL expression level (10-4). Patient 4. MR was received lu
after 12 months treating with 400 mg IM and it saved during 2 years, but late was determine increase BCR-ABL expression level (10-2) and IM dose was escalated to 600 mg, after 3
18 months' treatment there is decrease in the expression level for 3 log (10-5). ^
Two patients 24 and 26 years old are taking IM 400 mg during 10 and 12 years respectively, at this period of time they saved complete hematological response (CHR) and MMR. Patient q
R. MMR was received after 4 months treating with 400 mg IM and it saved during 4 years, but late was determine increase BCR-ABL expression level (10-4) and IM dose was escalated O
to 600 mg, after 12 months' treatment IM 600 mg loss of cytogenetic response was registered and IM dose was escalated to 800 mg, during 3 years' treatment IM 800 mg MR was not lu
still received and treatment was transitioned to the second-line ITK dasatinib 100 mg. At the dasatinib MR was received and it is saving during 4 years. Patient A. MMR was received Sg
after 16 months treating with 400 mg IM but due to irregular IM taking was diagnosed blast transformation and death from progression of disease. Conclusion. All the children were started on IM at a dose 400 mg. CHR was obtained within two months and confirmed thereafter monthly. 7 patients are alive. Hyperpigmentation, edema, growth retardation, nausea is the most common manifestations of adverse events (AE). AE were tolerable and did not require discontinuation of TKI therapy. IM dose escalation or switching to the second-line ITK dasatinib improve the results of therapy. Compliance between the patient, physician and close relatives increase the effectiveness of therapy. Acknowledgment. Authors thanks the laboratory of biological microchips for MRD testing.
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SOCIÉTÉ INTERNATIONALE D'ONCOLOGIE PÉHATRIQUE
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ABSTRACT TOPIC
ABSTRACT NO.: 0-108
Hematopoietic stem cell transplantation significantly improve outcome of infants with acute myeloid leukemia carrying translocation t(7;12)(q36;p13)
G.A. Tsaur1, E.A. Zerkalenkova2, O.M. Plekhanova1, E.V. Fleischman3, E.V. Volochnik4, I.I. Kalinina2, O.I. Sokova3, Yu.V. Olshanskaya2, A.M. Popov2, O.R. Arakaev1, L.I. Saveliev1, E.V. Shorikov1, L.G. Fechina1
'Children's Regional Clinical Hospital № 1/Research Institute for Medical Cell Technologies, Yekaterinburg, Russia; 2Federal Research Center of Pediatric Hematology, Oncology and Immunology named after Dmitriy Rogachev, Moscow, Russia;
3N.N. Blokhin Russian Cancer Research Center, Moscow, Russia; 4National Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Republic of Belarus
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Key words: acute myeloid leukemia, infants, treatment outcome, t(7;12)(q36;p13)
Introduction. Translocation t(7;12)(q36;p13) leading to MNX1 (HLXB9)-ETV6 fusion gene formation is recurrent chromosomal rearrangement, predominantly found in children under 24 months of age with AML and associated with dismal outcome. In the majority of cases t(7;12) is cryptic and can be detected by fluorescent in situ hybridization (FISH) only. Aim. To evaluate initial clinical parameters and input of hematopoietic stem cell transplantation in infants with AML carrying t(7;12) using novel 3-color FISH approach. Materials and methods. We retrospectively analyzed data of 81 infant AML cases, diagnosed between June 1999 and December 2014. Median age was 6.9 months (range 0.3-11.7). FAB variant was available in 72 patients. Chromosomal banding analysis (CBA) was performed in all cases, FISH for MLL rearrangements was done in 49 cases. All MLL-negative cases were screened for t(7;12) by novel 3-color FISH approach consisted of a break-apart probe composed of an orange labeled probe centromeric to the ETV6 gene in 12p13, a green labeled probe telomeric to ETV6 together with a probe combination made of two loci flanking the HLXB9 gene, both labeled in blue (MetaSystems, Germany). Results. Median age of t(7;12)-positive patients was similar to t(7;12)-negative ones (7.0 vs 6.9 mo, P = 0.241). All 6 patients with t(7;12) referred to AML high-risk group. Median WBC count was 29.7 x 109/L (range 15.7-210). Five of 6 patients had initial CNS disease, in all cases extramedullary organ involvement was observed. Three out of 6 t(7;12)-positive patients had immature FAB variants (one AML M0 and 2 AML M1), 2 patients had AML M5a and 1 biphenotypic acute leukaemia. Translocation t(7;12) was associated with immature immunophenotype: CD34-positive and CD117-positive cells were revealed in all 6 cases, that was significantly more common in comparison to t(7;12)-negative cases (P = 0.004 and P = 0.038, respectively). Interestingly, co-expression of CD7 antigen was detected in 5 out of 6 t(7;12)-positive cases and this phenomenon was observed in t(7;12)-positive group more frequent than in t(7;12)-negative ones (P = 0.001). In five out of 6 cases t(7;12) was cryptic and was not found by CBA. Hematopoietic stem cell transplantation (HSCT) was performed in the 1st remission in 4 cases (including 2 autologous HSCT) and in the 2nd remission in 1 case. EFS and OS were similar in t(7;12)-positive and t(7;12)-negative groups: EFS (0.33 ± 0.16 vs 0.39 ± 0.07, P = 0.573 and 0.60 ± 0.21 vs 0.45 ± 0.08, P = 0.571, respectively) with median of follow-up time 36 months.
Conclusion. Application of HSCT in both 1st and 2nd remission could overcome unfavorable influence of translocation t(7;12)(q36;p13) and led to OS equal to general cohort of infant AML. Among MLL-negative patients t(7;12) was the most common chromosomal aberration detected in 19.4 % of cases.
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ABSTRACT NO.: PP-113
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Outcome of the pediatric patients with normal karyotype acute myeloid leukemia in Yeungnam region, South Korea: multi-center retrospective analysis
Chueh Hee Won1, Lim Young Tak2, Kim Heung Sik3, Lee Jae Min4, Hah Jeong Ok5, Lee Kun Soo6, Park Jeong A7, Park Jikyoung7, Lim Jae Young8, Kim Ji Yoon6, Lee Mi Ji1
1Dong-A University Hospital; 2Busan National University; 3Keimyung University; 4Yeungnam University; 5Fatima Hospital; 6Kyungpook National University; 7Inje University Busan Paik Hospital; 8Gyeongsang National University
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Key words: normal karyotype AML, HSCT
Introduction. Recent progress on genetics, many karyotypes and genetic information which can refer prognosis, and furthermore, guiding the future treatment, have been found in
acute myeloid leukemia (AML). However, normal karyotype AML, which consist almost half of the AML, doesn't have any conclusions about its prognosis.
Aim. Therefore, in this study, outcome of the patients with normal karyotype AML in Yeungnam region of South Korea to make the guide for future treatment.
Materials and methods. Medical information of the patient who diagnosed and treated in Yeungnam region hospital between 1st Jan 2000 and 1st Aug 2015 were collected and
analyzed retrospectively.
Results. Total of 235 patients were diagnosed as AML in Yeungnam region, and the 197 patients received treatment at the hospital located in Yeungnam region. Among them, 36 patients were normal karyotype AML. 8 patients showed CR after 1st induction chemotherapy, but 26 patients achieved CR after all induction phase. Among the patient who achieved CR, 5 patients relapsed, and only 1 patient alieved. 14 patients received allogeneic hematopoietic stem cell transplantation (HSCT), and rest of them received only chemotherapy. 7 patients who received only chemotherapy were alive. The overall survival rate was 63.8 %, and the median survival time was 7.5 years. The overall survival of the patients who received allogeneic HSCT was 78.6 %, and the median survival time was 8.5 years. The survivals of the patients who received allogeneic HSCT superior significantly compared with that of the patients who did not received HSCT.
Conclusion. Patients with normal karyotype AML showed relatively good outcome. The survival rate of the patients who received allogeneic stem cell transplantation was significantly higher than that of the patients who did not. But due to the short-hand of this study, the roll of HSCT should be evaluated through further study.
ABSTRACT NO.: OP-121
The features of immunological and morphocytochemical diagnosis of acute
megakaryoblastic leukemia
O.I. Illarionova1, S.A. Plyasunova1, M.E. Dubrovina1, T.V. Konyukhova1, E.Y. Osipova1, E.B. Rusanova2, E.E. Zueva2
1Federal Research Center of Pediatric Hematology, Oncology and Immunology named after Dmitriy Rogachev, Moscow, Russia; 2First Pavlov State Medical University of St.Petersburg, Saint Petersburg, Russia
Key words: flow cytometry, immunophenotyping, acute leukemia, megakaryoblastic leukemia, megakaryoblasts, laboratory diagnosis
Introduction. Acute megakaryoblastic leukemia is a rare pathology that amounts up to 0.5 % of all acute nonlymphoblastic leukemias, including 1-10 % acute lymphoblastic leukemias (AML) in adults, 3-10 % childhood AML and 20 % AML in newborns. The incidence of AML-M7-variant in children with Down syndrome is 500 times higher than the incidence of children without this pathology.
Aim. To analyze the features of immunological and morphocytochemical diagnosis of acute megakaryoblastic leukemia.
Materials and methods. Over the period from 2012 to 2015 "acute megakaryoblastic leukemia" was diagnosed in 22 children (15 boys and 7 girls) based on the analysis of cytometry data of 2731 patients. The biological material for diagnostic investigation was presented as a bone marrow. Probe preparation was performed on a staining-lysis-washout technique. The flow cytometry was performed on BD FACSCanto II cytometer. The analysis of the flow cytometry data was carried out with BD FACSDiva Software. Results. The diagnosis was stated when detecting not less than 20 % of blasts in the bone marrow and at least the half of them had megakaryocyte differentiation indications. In a low level of differentiation megakaryoblasts are similar to myeloblasts and lymphoblasts, blasts with "lymphoid" morphology and cytoplasm budding; in a more differentiated forms megakaryoblasts are of medium (12-18 mem) and large size with less differentiated cells with high nuclear-cytoplasmatic relation. Nuclei of megakaryoblasts are round and slightly irregular-shaped or with impressions with a delicate chromatin network, with 1-3 nucleoli. A homogeneous distribution of chromatin and hyperchromia of nuclei are typical characteristics; cytoplasm of cells is basophil, frequently creates evagination or pseudopods; Auer bodies were not observed. oo
Cytochemical assessment of AML-M7 blasts: myeloperoxidase, chloroacetate esterase and lipids were absent. Immunophenotyping allows to state with accuracy the megakaryostic direction of blasts differentiation, to carry out the differential diagnosis with such pathologies as acute lymphoblastic leukemia, other forms of myeloblastic leukemias, metastases of malignant tumors O
to bone marrow. Immunologically in M7-variant expression of one or more platelet antigenes were detected: CD41a (glycoprotein IIb), CD61 (glycoprotein IIIa), as well as CD42b (glycoprotein Ib), q
that is common in more mature cells. CD36 antigene expression is a typical characteristic. In the majority of cases the expression of CD13 and CD33 myeloid antigenes, CD7, CD4 T-cell antigenes, ^
CD2 (rarely), NK-associated CD56 was detected on blastic cells. Also in the range of cases there were lineage-nonspecific CD34, CD38, CD117 antigenes on blastic cells. B-cell markers were negative. oo
Conclusion. The assessment of megakaryocyte markers requires caution as in many pathological states platelets stick to larger cells, monocytes and neutrophils, and as a result they >
create positivity effect on markers of megakaryocyte direction differentiation. Therefore when planning the assessment of megakaryocyte markers it is necessary to wash the sample h^
in advance in order to remove adherent platelets. Considering the possibility of platelet satellitesm and clinical significance of diagnosis it is not recommended to assess samples that oc
are not fresh; samples received with non-implementation of shipment regulations; samples received after the start of the treatment. ljl
The features of AML-M7 blasts allow to make an immunophenotupic diagnosis during 1 business day after the receipt of biological material.
ABSTRACT NO.: OP-197
Morphological characterization of the leukocytes bound to an anti-CD antibody microarray allows suggesting preliminary diagnosis in acute myeloid leukemia
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S.A. Kuznetsova1, A.N. Khvastunova1, A.O. Zakirova1, O.S. Fedyanina2, A.A. Maschan1, F.I. Ataullakhanov1 q
1Federal Research Center of Pediatric Hematology, Oncology and Immunology named after Dmitriy Rogachev, Moscow, Russia; u!
2Center for Theoretical Problems of Physicochemical Pharmacology, Moscow, Russia
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Key words: morphology, cluster of differentiation, cytochemistry, microarray <
Introduction. The diagnosis of acute leukemia and related conditions starts from the analysis of morphology, cytochemistry and immunophenotyping of the bone marrow aspirate. S
In case of acute myeloid leukemia (AML) morphology and cytochemistry are crucial for the diagnosis while the immunophenotyping confirms the myeloid origin of the blasts but is ^
not sufficient to distinguish between the AML subvariants. A technique permitting to determine the immunophenotype of a leukocyte with certain morphology would facilitate the 2
comparison of the two diagnostic methods and would increase the reliability of the diagnosis. ^
Aim. We have earlier suggested an anti-cluster-of-differentiation (anti-CD) antibody microarray on a transparent support for leukocyte sorting and a method for preparation of the microarray-bound cells for high-resolution morphology analysis. This work aimed to develop a microarray-based method for preliminary diagnosis of AML. ^
Materials and methods. The suspension of mononuclear cells separated by density gradient from bone marrow aspirate is incubated with the microarray in non-mixing conditions. After the unbound cells are washed away the leukocytes on the microarray are grouped according to their surface CD antigens. The microarray-bound cells are then dried and flattened using a home-developed cytocentrifuge resulting in a"cell-sorted"smear.We have studied the bone marrow aspirates of 40 pediatric patients with AML (M5 - 10 patients, M4 - 11 patients, M7 - 6 patients, M3 - 5 patients, M2 - 5 patients, M1 - 3 patients) and 20 patients with acute B-lymphoblastic leukemia (B-ALL). Results. We have shown that morphological and cytochemical characteristics of the microarray-bound cells are close to their characteristics in smears. We suggest a diagnostic strategy for differentiation between AML and ALL based on morphological blast detection and determination of blast immunophenotype by analyzing their relative amount among the cells captured by the antibodies against all the CD antigens. We also show that the further differentiation between the AML subtypes can be done using the leukocyte cytochemistry (myeloperoxidase and nonspecific esterase).
Conclusion. Combined analysis of the pathologic cells' immunophenotype, morphology and cytochemistry on the microarray permits to arrive at preliminary diagnosis and can be used in cases of any controversies between morphology, cytochemistry and immunophenotyping. This work is partially supported by RFBR grants 16-34-01030 and 16-04-00282.
SOCI&Tt INTERNATIONALE D'ONCOLOGIE PEHATRIQUE
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ABSTRACT TOPIC
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ABSTRACT NO.: P-215
Case of successful treatment of acute myeloid leukaemia with extramedular affection
at child in Tyumen region
A.Yu. Chernova, T.I. Ksenzova, L.A. Ilarionova, E.V. Anikina, O.V. Ananieva, O.V. Sofeicova
Regional Clinical Hospital № 1, Tyumen, Russia
Key words: myeloid leukaemia, clinical case, extramedullar affection
Introduction. Literature data shows that acute lymphoblastic leukaemias (ALL) occupies about 80 % of cases among oncological disease at children and acute myeloid leukaemias (AML) - 15-17 %. Extramedular affections (EA) in case of AML diagnosed in 3 % of cases. Ten - twenty cases of acute leukaemias diagnosed every year in Tyumen region at children, AML occupies 10-45 % among them. Twenty six cases of AML at children were revealed in Tyumen region, in 4 (15 %) cases EA was diagnosed. Aim. To show the features of diagnosing and treatment of AML with EA on the clinical case demonstration.
Materials and methods. Boy M., 14 years old, during one month suffered from pain in chest, cough, dyspnea. Entered the department of haematology and chemotherapy of Regional clinical hospital No. 1 (Tyumen) in the very severe condition. Defense attitude, fever to 38.0 °C. Skin surface pale-grey, weeping, lymph nodes conglomerates with diameter to 2 sm. All abdominal cavity was occupied by palpated volume mass. CT scan of mediastinum showed: nodular lesions located paratracheally up to 6.0 sm. in diameter with confluent characteristics. These lesions sharply attached inner vessels, hydrothorax at right with prolongation to interlobar pleura and compression of lung parenchyma on 1/3, hydropericardium. Lesion of soft tissue density cavity was registered in parapancreatical area with expansion to the area of portal fissure and in para-aortal area, to the small pelvis with compression of pancreas, all vessels of this area, bile ducts, nodules lesions under the diaphragm, on peritoneum longitude, in small pelvis to 5.3 sm., perineal lymph nodes up to 2.0 sm. in diameter, hepatosplenomegaly, ascite. Toracocentesis were done multiple times, 450 ml to 1500 ml of fluid were evacuated. Bone marrow aspiration - blast cells - 71.8 %, myeloperoxidase activity - 2 %, glycogen in cells - 80 % in diffuse and diffuse-granular form, lipids in cells - 100 % negative, activity of non-specific esterase - 90 %, full blocked by sodium fluoride. Cells of bone marrow region (CD45+) 38 % with the following phenotype: HLA-DR+ CD34- CD38+/- CD58+ CD117- CD33+ CD4+ CD64+ CD36+ CD11b-/+ CD11c-/+ CD15+ CD65+ CD56+ MPO+ Ki67+ med BCL2+ CD19- CD10- CD22- CD79a- CD13- TdT- CD20- s cyt K/L/IgM- NG2-/+s cytCD3-, what is characterize AML, M5 is possible. Myelosarcoma with EA verified: volume lesion in abdominal cavity, retroperitoneal cavity, small pelvis, lesion in chest, specific pleurisy, ascite, pericarditis, bone marrow involvement. Histological verification of EA, cytogenetic study was not done due to bad status of patient. Two courses of induction 7+3 were done (rubomycin 60 mg/sq.m.), 3 courses of HD Ara-C 1 gr/sq.m., IdaAC-Ida, IdaAC-Mito. Specific therapy was complicated by myelotoxic agranulocytosis, double-sided pneumonia, mucosytis, gastroenterpathy, invasive hepatolyenal mycosis after third course of consolidation. Multiple hypodensive lesions in liver sized 5-10 mm with fuzzy contour were revealed. Successfully treated with voriconazole.
Results. Complete bone marrow remission and reduction of EA was reached based on the therapy. Match related bone marrow transplantation in Saint-Petersburg Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation was done. Follow-up continuing.
Conclusion. EA at AML at children is predictors of severe clinical condition and unfavorable prognosis. Remission can be reached on background of program high-dose chemotherapy and bone marrow transplantation.
ABSTRACT NO.: P-231
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Myasthenia gravis and chronic myeloid leukemia in a child
N. Tursunova, I. Erimbetova, Kh. Khazakbaeva, G. Ismatova
Scientific-Research Institute of Hematology and Blood Transfusion, Tashkent, Republic of Uzbekistan
Key words: myasthenia gravis, chronic myeloid leukemia, child, therapy
Introduction. Myasthenia gravis is an autoimmune disease, with transient muscle weakness and abnormal fatigue. The prevalence of myasthenia gravis is from 1 to 5 per 100 000 population. Children and adolescents up to 17 years make up 9-15 % of patients with myasthenia gravis. Usually disease begins from 7.2 years (in average). The annual frequency of CML is 1-1.5 per 100 000 population. Chronic myeloid leukemia is very rare among children, no more than 1-2 % of childhood leukemia. Nowadays 80 children with CML receive therapy with tyrosine kinase inhibitors of the 1st generation in Uzbekistan. Aim. To study the characteristics of chronic myeloid leukemia and myasthenia gravis in children.
Materials and methods. Boy (11 years old) was ill from the spring of 2014, weakness, lethargy, decreased motor activity, and ptosis were observed. CBC: Hb 101g/L, white blood cells 83.3 thousand, a shift to the left to metamyelocytes 10 %. RT-PCR BCR-ABL p210-200, 89 %. Chronic myeloid leukemia was diagnosed, with following prescription of gidroksikarbomid 2000-1000 mg, and further imatinib 340 mg/m2. The dynamics of the RT PCR M-BCR-ABL p210 -61.42 %. In a year after diagnosing CML problems with chewing and swallowing food, active and passive movements were limited, nasal voice, then joined paresthesia, orthostatic overload intolerance were periodically detected. Muscle tone was lowered. Abdominal reflexes were weak. Neurologists examined the patient, after electromyographic study was provided they diagnosed myasthenia gravis. Symptomatic treatment with anticholinesterase drugs, small doses of corticosteroids and therapeutic plasmapheresis were prescribed and executed.
Results. During imatinib monotherapy, clinical-hematological improvement and absence of cytogenetic and molecular responses were noted. The myasthenia gravis aggravated the patient's condition. Combined therapy of both diseases did not lead to a positive result. The patient died in six months after diagnosis of myasthenia gravis. Conclusion. Chronic myelogenous leukemia is rare among children and teenagers. A myasthenia often appears among children. The combined therapy of two competing diseases failed to stabilize the situation and led to patient's death. It is necessary to develop the principle of CML therapy in combination with autoimmune diseases, such as myasthenia gravis.
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OF PEDIATRIC HEMATOLOGY and ONCOLOGY
ABSTRACT NO.: P-232
Myeloproliferative disorders and leukemia in newborns with Down syndrome
T.V. Stepanova1, G.V. Trubnikova2, M.V. Budanova1, A.F. Karelin2
1Voronezh State Medical University named after N.N. Burdenko, Russia; 2Voronezh Regional Children's Clinical Hospital № 1, Russia
Key words: Down syndrome, newborn, leukemia
Introduction. The type of congenital leukemia must be distinguished from leukemic reactions and Down transient myeloproliferative disorder. Children with Down Syndrome (DS) have a markedly enhanced incidence of myeloid (ML-DS) and lymphoid (DS-ALL) leukemias. The risk of DS-ALL has been estimated to be 10-20 times higher than sporadic ALL1-2. In most published multi-institutional ALL protocols DS-ALL comprises about 1-3 % of total patients. This suggests a leukemogenic role of constitutional trisomy 21. The role of the trisomy 21 has remained a mystery.
Aim. We present two cases of Down transient myeloproliferative disorder and congenital leukemia in newborns.
Materials and methods. Transient myeloproliferative disorder is a rare condition in the neonatal period, connected with trisomy, or other abnormalities of chromosome 21. It is characterized by high blastosis in peripheral blood and bone marrow and it usually resolves without specific therapy in 1 to 3 months.
The first patient was a boy with Down syndrome, karyotype - 47XY+21 and a cardiac defect (common atrioventricular channel anomaly). His mother was 39 years old, had professional diseases. The second patient was a neonate female with Down syndrome. Her mother was a healthy woman 21 years old,
Results. This male neonate manifested with hyperleukocytosis (85.0 x 109/l), blastosis (79 %) in peripheral blood and bone marrow (59 %) detected at 6 days of age. His liver and spleen were enlarged. No specific antileukemic therapy was given. After 3 weeks leukocytosis and blastosis were decreased, and we observed normalization of peripheral blood. At 3 months of age the bone marrow smear was normal.
The girl showed leukocytosis (57 x 109/l) and blastosis (46 %) in peripheral blood and bone marrow (69 %) at age of 12 days. In the second case congenital myelomonoblastic
leukaemia (M4 in FAB classification) was diagnosed. She was treated according to BFM for acute myeloblastic leukemia protocol and maintained a complete remission. Recurrence
of leukemia occurred after 11 months. The second remission was remained during of 6 months. Finally the girl died of progressive congenital leukemia after 18 months. oo
Conclusion. Despite of the great progress in the treatment of childhood leukemia, prognosis of congenital leukemia is sad. These cases confirm the difficulties in differentiation
between congenital Down leukemia and transient myeloproliferative disorder. О
ABSTRACT NO.: OP-239
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in childhood acute myeloid leukemia o
A.V. Popa, V.S. Nemirovchenko, G.L. Mentkevich 2
Pediatric Oncology and Hematology Research Institute of N.N. Blokhin Russian Cancer Research Centre, Moscow, Russia ^
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Key words: acute myeloid leukemia, epigenetic therapy y
Introduction. The results of treatment children with acute myeloid leukemia (AML) are not satisfied yet. The standard chemotherapy allows achieve complete remission in 92-96 % ¡^
of patients, but disease free survival (DFS) and event free survival (EFS) are not good yet. Many AML study groups could decrease count of some complications which developed during ^
chemotherapy, but not avoided of relapses which developed from residual leukemia stem cell. ^
Certain cytogenetic abnormalities and gene mutations are well-known and have been recognized in the World Health Organization classification. AML results from collaborating genetic aberrations in at least 2 different classes. Type I aberrations induce uncontrolled proliferation and/or survival of the leukemic cell and are often represented by activating o
mutations in genes involved in signal transduction pathways, such as FLT3, KIT, NRAS, KRAS and PTPN11. Type II aberrations inhibit cell differentiation and mainly result from u!
genetic aberrations in hematopoietic transcription factors, due to, for instance, AML-characteristic translocations t(8;21)(q22;q22)/AML1-ETO and 11q23/MLL rearrangements, or from mutations in NPM1 and CEBPA genes. However, certain aberrations found in AML, including those related to epigenetic deregulation, do not completely fit into the current type ,
I and type II classification. Research into the epigenetic control of gene expression in AML, including histone modifications, DNA methylation and aberrant expression of microRNAs, <
promises better understanding of the biological nature of the disease. 2
Aim. To issue effectiveness and toxicity demetilating medicine (Decitobine) and to find it's place in standard chemotherapy. ^
Materials and methods. From 01.2013 to 12.2015 21 patients were enrolled into NII DOG AML 2012 study. The average was 6.5 ± 1.24 years (6 month - 16 years); 12 males and ^
9 females, standard (SR) - 1 (4.8 %), intermediate (IR) - 6 (28.6 %) and high (HR) - 14 (66.7 %) risk groups. Chemotherapy consisted on 5 curses for HR and IR (AIE, HAM, AI, hAM, HAE) and 4 curses for SR (AIE, HAM, hAM, HAE). Epigenetic therapy consisted on Valproic acid (VA) days1-78, All Trans Retinoic Acid (ARA) 1-43 days and from the day one to day ^
14 of the every course chemotherapy and Decitobine in "window" regime before induction (5 patients) and on day 16 after beginning of induction . _i
Results. Decitobine was used as a demetilating medicine 20 mg/m2 for 5 days in "window" regime before induction (AIE) in five patients. There were no any toxicity and we did not check decrease of blasts in BM and peripheral blood after Decitobine, one of them developed relapse and one died from severe infection, three pts are alive, and two - underwent by haploidentical HSCT. Three years DFS was 75 ± 21.7 %, median follow up 30.4 ± 4.8 mo, and EFS - 60 ± 21.9 %, median follow up 24.6 ± 6.4 mo. Thus, Decitobine was moved on the day 16. Now, 16 pts got this therapy, all of them achieved CR after AIE with VA, ATRA and Decytobine. Two years DFS and EFS were the same - 76.9 % median follow up 24.6 ± 24 mo, OS - 89.9 ± 10.5 % median follow up 27.1 ± 2.1 mo. None of the patients underwent by allo-HSCT.
Conclusion. The epigenetic therapy increased CR count and survival of children with AML. The place of demetilating agent in AML therapy has to be used in aplasia period after the first course of induction when patients had got minimum counts of blasts.
SOCI&Tt INTERNATIONALE D'ONCOLOGIE PEHATRIQUE
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ABSTRACT NO.: OP-248
The impact of conditioning intensity on allogeneic stem cell transplantation outcome of children and adolescents with acute myeloid leukemia
S.N. Bondarenko1, S.V. Razumova1, O.A. Slesarchuk1, A.L. Alyanskiy1, O.V. Paina1, A.S. Borovkova1, P.V. Kozhokar1, K.A. Ekushov1, Yu.G. Fedukova1, B.I. Smirnov2, E.V. Semenova1, L.S. Zubarovskaya1, B.V. Afanasyev1
'First Pavlov State Medical University of St. Petersburg, Russia; 2Saint Petersburg Electrotechnical University "LETI", Russia
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Key words: pediatric and adolescent patients, acute leukemia, allogeneic hemopoietic stem cell transplantation, related and unrelated donors, conditioning regimens, donor lymphocyte infusion
Introduction. Allo-HSCT is the main curative option for the patients with acute myeloid leukemia (AML). The choice of the conditioning regimen intensity may impact on the allo-HSCT outcome, and still remains the controversial issue.
Aim. The aim was to compare the efficacy of allo-HSCT in children and adolescents with AML in dependence on conditioning regimen intensity.
Materials and methods. We retrospectively analyzed the data of 118 pediatric and adolescent patients (pts) with AML who underwent allo-HSCT. The median pts age was 12.5 (range 1-21) years. The median follow-up period was 27 (range 2-120) months. At the moment of allo-HSCT 42 (36 %) pts were in the 1st CR, 30 (25 %) in the 2nd CR, 46 (39 %) had active disease. Thirty one pts (26 %) received allo-HSCT from HLA-matched related, 87 (74 %) - from unrelated donor. The stem cell source was bone marrow in 59 (50 %) and PBSC in 59 (50 %) allo-HSCT. The myeloablative (MAC, busulfan or treosulfan based) and reduced-intensity (RIC, fludarabine based) conditioning regimen were used in 66 (56 %) and 52 (44 %) pts respectively. Acute GVHD prophylaxis consisted of cyclosporine A (n = 79, 67 %) or tacrolimus (n = 39, 33 %).
Thirty pts received donor lymphocyte infusion (DLI) after allo-HSCT. The indications for DLI (n = 35) were disease relapse/progression after allo-HSCT in 26 pts (therapeutic DLI), minimal residual disease in 4 pts (preventive DLI), and disease relapse prophylaxis in 5 pts (prophylactic DLI). After RIC allo-HSCT more therapeutic (15 vs 11) and less preventive/ prophylaxis (3 vs 6) DLI were used in comparison with MAC allo-HSCT. DLI were combined with additional therapy (chemotherapy (n = 18), hypomethylating agents (n = 9), interleukin-2 or interferon-a (n = 12)) in 28 pts, or as a monotherapy in 7 pts.
Results. The 5-year OS in MAC and RIC allo-HSCT recipients in the 1st CR was 65 % (95 % CI: 45-85) and 80 % (95 % CI: 59-99) (P = 0.4) respectively. In patients with 2nd CR it was 65 % (95 % CI: 35-95) and 17 % (95 % CI: 1-37) (P = 0.003), in patients with active disease 17 % (95 % CI: 1-43) and 19 % (95 % CI: 1-37) (P = 0.4) respectively. MAC and RIC allo-HSCT recipients had relapses in 24 % (95 % CI: 10-41) and 29 % (95 % CI: 12-48) (P=0.7) of cases, respectively. The relapse rate was significantly lower in MAC allo-HSCT recipients with aGVHD Gr 1-3 compared to RIC allo-HSCT recipients (P = 0.05), although no correlation was observed in patients with cGVHD (P = 0.2). RIC allo-HSCT was associated with significantly lower toxicity rate, while the infectious complications and GVHD (acute and chronic) rate was comparable for both MAC and RIC allo-HSCT recipients groups. The CR after DLI was achieved in 12 pts (40 %): in 6 (50 %) pts after RIC and 6 (50 %) pts after MAC allo-HSCT. The median duration of CR after DLI was 5.5 (range 1-38) months. The relapse occurred in 8 (47 %) out of 17 pts who had CR after DLI.
The mortality rate did not correlate to age or conditioning regimen type. The most common death causes in RIC allo-HSCT recipients were disease progression (36 %), infectious complications (21 %) and aGVHD (43 %), in MAC - disease progression (37 %), infectious complications (30 %), aGVHD (22 %) and treatment-related toxicity (11 %). Conclusion. Our results demonstrated the comparable efficacy of RIC and MAC in children and adolescences with AML in 1 CR and relapse at the moment of allo-HSCT. Efficacy of DLI was revealed after both RIC and MAC allo-HSCT.
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ABSTRACT NO.: OP-262
High Level of miR-196b at newly diagnosed pediatric acute myeloid leukemia predicts a poor outcome
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Li-hua Xu, Qing Yan, Shaoyan Hu
Children's Hospital of Soochow University
Key words: miR-196b, AML, pediatric/child, biomarker
Introduction. MicroRNAs (miRNAs) are small non-coding RNAs consisting of ~22 nucleotides, with highly conserved sequence. They widely participate in cellular processes such as proliferation, differentiation, and apoptosis at the post-transcription level. Also, as described having oncogenic or anti-oncogenic properties, miRNAsare implicated in leukemogenesis and the prognosis, due to some microRNA genes locating in regions of translocations and deletions frequently occurring in leukemia (e.g. miR-15a-miR-16-1 cluster and chronic lymphocytic leukemia). Moreover, miRNA expression profiles could classify specific cancers such as discriminating acute lymphoblastic leukemia (ALL) from AML. Overexpression of miR-196b has been reported in71 European pediatric AMLwith MLL gene rearrangements, NPM1mutations, as well as FLT3-ITD in cytogenetically normal background. Aim. To further explore and confirm the potential function of miR-196b, we investigated the expression of miR-196b and its possible relevant genes SMC1A/MLH1 in 83 Chinese pediatric AML. Materials and methods. Using quantitative real-time PCR (qRT-PCR), we detected the expression of miR-196b and its correlative genes (SMC1A/MLH1) in initial 83 Chinese pediatric AML. Results. A significant association was observed between overexpression of miR-196b compared to controls and inferior overall survival of pediatric AML (Log Rank Pission group after the first induction chemotherapy possessed higher miR-196b expression. Furthermore, a positive relationship was found between the expression of miR-196b and SMC1A/MLH1 (Spearman's r = 0.37 and 0.44, P = 0.001).
Conclusion. These findings suggest that differentially high expression of miR-196b in diagnostic marrow samples of pediatric AML is associated with unfavorable outcome, and miR-196b potentially can be a novel biomarker for the diagnosis, prognosis and treatment in pediatric AML.
ABSTRACT NO.: OP-263
The suppression of CCL2 expression decrease the proliferation of HL-60 cells through downregulation of cyclin D1 via arresting cells at the G1 phase
Jin Yang, Dan Hong, Qi Zhou, Qing Yan, Shaoyan Hu
Children's Hospital of Soochow University
Key words: chemokine (C-C motif) ligand 2 (CCL2), HL-60 cell line, RNA interference, proliferation, cell cycle, cyclin D1
Introduction. Chemokine (C-C motif) ligand 2 (CCL2) has been demonstrated to be induced and involved in various diseases. In many solid tumors, CCL2 signaling has been shown to correlate with tumor growth, invasion and metastasis. In hematologic neoplasms, the role of CCL2 has not yet been explicit. There is evidence suggesting that the level of CCL2 has increased in the bone marrow environment of acute lymphoblastic leukemia (ALL) patients and in the serum of untreated patients with acute myeloid leukemia (AML). Aim. To explore the mechanism of CCL2 gene on leukemogenesis.
Materials and methods. Lentivirus with CCL2-knockdown was successfully constructed after screening effective shRNA sequence and tranfected into HL-60 cells which was validated on the level of mRNA and protein by qRT-PCR and Western blot, respectively. The cells coming from parental, sh-Vectors and shCCL2 were detected for cell growth viability by CCK-8 assay, cell cycles and apoptosis by Flow cytometry. We applied exon sequencing technology to identify the gene profiling between the CCL2 knockdown and the control, of which, Cyclin D1 was selected for further experiments as it was significantly downregulated. We successfully downregulated Cyclin D1 in HL-60 by means of RNA interference to detect. Meanwhile, the cell proliferation, cell cycle and apoptosis were detected by CCK-8 assay, Flow cytometry, respectively.
Results. After suppressing CCL2 in HL-60 transfected cells, the cell proliferation rate decreased at the most of 44.44 % compared to control cells. Cell cycle analysis demonstrated that 12 % more cells arrested at G1 phase. Gene expression profiling data revealed there are total 159 differentially expressed genes related to cell cycle, NOD-like receptor signaling pathway, TNF signaling pathway and NF-kappa B signaling pathway including Cyclin D1 which was downregulated by 60 %, meanwhile, Cyclin D1 was decreased on the level of mRNA and protein. Moreover, the shRNA-mediated inhibition of Cyclin D1 suppressed cell growth and blocked more cells at G1 phase, which was consistent to that of CCL2 silencing. Conclusion. Downregulation of CCL2 inhibits the cell proliferation which was mediated by suppressing cyclin D1 via blocking more cells at G1 phase.
ABSTRACT NO.: OP-265
High expression of S100A8 gene is associated with drug resistance to etoposide via influencing apoptic genes expression and poor prognosis in acute myeloid leukemia
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Xiaoyan Yang, Mingying Zhang, Qi Zhou, Shaoyan Hu >!
Children's Hospital of Soochow University 2
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Key words: S100A8, HL-60 cell, drug resistance, acute myeloid leukemia (AML), prognostic factor, anti-apoptosis <
Introduction. S100A8 have been increasingly recognized as biomarkers in multiple solid tumors and played pivotal roles in hematological malignancies. S100A8 is potentially y
an indicator for poor survival in acute myeloid leukemia (AML) in retrospective studies. However, the mechanisms of S100A8 are diverse in cancers. ¡^
Aim. In this study we investigated the correlation of S100A8 at the transcription level with clinical parameters in AML patients and explored its chemoresistance mechanism in vitro. ^
Materials and methods. A total of 189 AML patient specimens from different treatment stages of AML underwent induction chemotherapy between 2010 to 2014 was included. ^ Among them, 91 were de novo AML patients (excluded secondary AML, therapy related AML or AML evolved from antecedent haematological disorders), 64 patients in complete
remission (CR) and 34 patients in relapse, in addition to 20 controls without leukemia. S100A8 transcription level was detected by real-time RT-PCR and normalized to p-actin o
transcription level. Lentivirus vector with S100A8 overexpressed was constructed and transfected into HL-60 cell line. Biological characters and resistance to chemotherapy drugs u! were compared between transfected cells.
Results. The transcription levels of S100A8 was significantly associated with cytomorphological classification, the results showed that S100A8 transcription levels were higher in ,
FAB M4 and M5 than in the M0 and M1 subtypes (P = 0.042). Patients with high and low S100A8 transcription levels had median OS times of 15 (IC: 12.8, 20) and 23 (IC: 18.5, 23.5) <
months, respectively (P = 0.024). The estimated 3-year OS rates of high expression S100A8 group was 32 % (IC: 16 %, 52 %) versus 59 % (IC: 41 %, 76 %) for the low expression 2
group (P=0.042). Based on multivariate model for OS, high S100A8 transcription was a significant prognostic factor (P=0.003) after adjustment for age (P=0.025), bone marrow ^
blast percentage (P = 0.016) and cytogenetic classification (P = 0.039) at diagnosis. Overexpression of S100A8 caused etoposide resistance in a dose and time dependent manner. ^ Using real-time apoptosis PCR arrays, we analyzed and clustered the expression of 370 genes associated with apoptosis pathway in control and S100A8 overexpression cells treated
by etoposide. Thirty six genes were significantly downregulated and 12 genes were significantly upregulated in S100A8 overexpression group compared with control group, of which ^
the caspase-3, Bcl-2 and Bax was verified by western blot analysis. _i Conclusion. Critical S100A8 provided useful clinical information in predicting the outcome of AML. One of the mechanisms was that S100A8 involved in chemoresistance via anti-
apoptosis way. 2
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SOCI&Tt INTERNATIONALE D'ONCOLOGIE PEHATRIQUE
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ABSTRACT TOPIC
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ABSTRACT NO.: OP-272
Abandonment and outcome of childhood acute myeloid leukaemia in a tertiary level hospital
Momena Begum, Chowdhury Yakub Jamal, Afiqul Islam, ATM Atikur Rahman, Mehnaz Akter, Chowdhury Shamsul Hoque Kibria, Rasel Siddique, Lutfor Rahman Molla, Zannat Ara
Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh Key words: abandonment, outcome, childhood acute myeloid leukemia
Introduction. Acute leukemias are the most common child hood malignancy, of which acute myeloid leukemia (AML) are 15 % to 20 %. Abandonment is one of the most important causes of treatment failure in AML in developing countries. Lost to follow-up is also a big problem in low income countries . Many patients stop therapy soon after diagnosis due to cost, distance and ignorance.
Aim. To determine the abandonment, outcome and treatment related mortality (TRM) and morbidity among children with AML.
Materials and methods. This prospective observational study was conducted in the Department of Pediatric hematology and Oncology, BSMMU, Dhaka for duration of one year. Fifty (50) patients of AML visited to out patient department (OPD) of Pediatric hematology and Oncology. Among them 11 (22 %) patients refuse treatment from outdoor. Thirtynine 39 (78 %) patients of AML were selected as per inclusion and exclusion criteria. After proper evaluation and clinical examination of these patient, CBC and Bone marrow examination was done for confirmation of diagnosis.
Results. A total of 39 patients were recruited in this study. 17 (43.6 %) patients were male and 22 (56.4 %) were female. Mean ± SD of age was 7.80 ± 4.42 and range was 6 months to 15 years. Out of 39 patients, 18 (46.1 %) patients were abandoned, 15 (38.4 %) expire, relapse 2 (5.2 %) & alive 4 (10.3 %).
Conclusion. High abandonment (46.1 %) and treatment related toxic death (38.4 %) has compromised the outcome of Acute myeloid leukemia. However AML can be treated with better outcome if improved the supportive care, reduce toxic death, refusal or abandonment.
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ABSTRACT NO.: PP-289
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Crosstalk between THP-1 and MSC changes adipocyte and osteoblast differentiation
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Moon Kyu Kim1, Kyoung-Mi Lee2, Kiwon Park2, Seung Min Hahn1, Jung Woo Han1, Chuhl Joo Lyu1
'Yonsei University College of Medicine; 2Yonsei University BK21 plus
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Key words: human bone marrow derived, mesenchymal stromal cells, adipogenesis, osteogenesis, acute myeloid leukemia
Introduction. Leukemic cells can acquire chemo-resistance during therapy and human Bone marrow derived mesenchymal stromal cells (hBMSCs) are one of the key players in this process. The crosstalk between leukemic cells and BMSCs results in changes of characteristics in both cells. Aim. We investigated the effects of THP-1 on differentiation potency of MSCs when co-cultured.
Materials and methods. Bone marrow aspirates were obtained from the posterior iliac crest of 10 healthy adult donors ranging from 20-69 years of age under the approval of the Institutional Review Board (IRB). The BMSCs from healthy donor's BM was co-cultured with THP-1 in DMEM. To identify the effects of THP-1 cells dosage on BMSC differentiation potency, the 3X10e4, 6X10e4, and 1X10e5 of THP-1 cells were added in 1X10e5 of BMSCs cells. To confirm the osteogenic and adipogenic differentiation ability of hBMSC by THP-1, we co-cultured BMSCs and THP-1 cells in osteogenic and adipogenic medium. Osteogenic medium consisted of complete growth medium plus osteogenic growth supplements comprised of 50 pM ascorbic acid, 0.1 pM dexamethasone, and 10 mM p-glycerophosphate and adipogenic medium consisted of DMEM-low glucose supplemented with 1 % antibiotic-antimycotic solution plus MDI (0.5 mM isobutylmethylxanthine, 1 mM dexamethasone, and 200 mM indomethacin, and 5 mM insulin. After 14 days, osteogenic and adipogenic differentiation were determined by Alizarin red S and Oil-Red-O staining respectively.
Results. At differentiation condition, the THP-1 cells were attached to hBMSCs during osteogenesis, but less in adipogenesis. The co-culture of THP-1 cells and BMSCs had enhanced differentiation ability when compared to differentiation of BMSCs alone. The osteogenic and adipogenic differentiation potency of BMSCs were increased when the number of THP-1 cells were increased in dose dependent manner.
Conclusion. Our results suggest that the THP-1 cells effects on adipogenic and osteogenic differentiation potency of hBMSCs, and these changed potency might augment chemo-resistant characteristics of THP-1 cells. To identify our expectation, the further study is required such as the effect of leukemic cells from different lineage and hBMSCs from various origin.
ABSTRACT NO.: PP-301
Prognostic significance of molecular genetic changes in childhood acute myeloid leukemia
Yu. Barouskaya, M. Stsiohantsava, A.M. Kustanovich, O.I. Bydanov, O.V. Aleinikova
National Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Republic of Belarus
Key words: acute myeloid leukemia, molecular genetic changes, prognosis
Introduction. The most important prognostic factors in acute myeloid leukemia (AML) are molecular genetic changes in blast cells and response to treatment. Aim. An analysis of prognostic significance of molecular genetic changes in AML in children, that received treatment in the Republic of Belarus.
Materials and methods. 151 patients aged 0.02 to 25.8 years are included in the study (median age - 10.75 years) with de novo AML, that received programmed treatment in Republican research and practice centre of pediatric oncology, hematology and immunology (Minsk) from May 1999 to December 2013 according to original protocols AML-MM-2000 (n = 81) and AML-MM-2006 (n = 70). Patients treatment results are defined on 01.02.2016. Follow-up median was 1.75 years. A cytogenetic analysis was performed in a common method of short-term bone marrow cell cultivation with further differentiated G-staining of metaphase chromosome, as well as by method of fluorescence in situ hybridization (FISH). A method of reverse transcription polymerase chain reaction was used to detect chimeric oncogenes. Prescrining by method of SSCP (Single Strand Conformational Polymorphism) was performed to detect mutations in CEBPA and NPM1 genes. The results were confirmed by method of direct Sanger sequencing.
Results. A cumulative incidence of relapse (CIR) in patients with CBF-leukemia (inv(16) and t(8;21)) was 8.9 ± 4.9 % in comparison with the ratio 35.8 ± 4.5 % in the remaining/ rest cohort of patients, P = 0.0030. In 11q23-anomalies group t(1;11)(q21;q23) was detected only in 2 patients. Both of the children are in the first long-term remission without performing of hematopoietic stem cell transplantation. CIR in the group wfth t(9;11)(p22;q23) appeared to be lower than in patients with t(10;11)(p12;q23) (18.8 ± 10.2 % u 58.3 ± 19.3 %, respectively, P = 0.0384) and in patients with t(6;11)(q27;q23) (33.0 ± 25.6 %, P = 0.7026). In the investigated/studied cohort t(2;11)(p21;q23) was reported only in 1 patient with congenital AML that died in induction. In the group of patients with normal karyotype (NK) where no additional genetic event was reported by accessible methods, CIR was oo
44.4 ± 12.4 %. However CIR in the group of patients with NK and CEBPA and NPM1 gene mutations appeared to be significantly lower compared to a similar ratio in patients with NK ig
and FLT3 mutation (16.7 ± 16.7 % and 100 %, respectively, P=0.0254). O
Conclusion. The presence of inv(16) u t(8;21) in AML was associated with a favorable outcome. CIR ratios in patients with t(1;11) are comparable to CBF group, that also assigns q
this anomaly to prognostically favorable. Relapse development risk in patients with t(10;11) is higher than in the remaining cohort with 11q23. Prognostic influence on a disease Z
outcome in patients with NK is made by the absence or presence of additional genetic events. The presence of CEBPA or NPM1 mutations determines a favorable prognosis, whereas oo
FLT3 mutation - adverse prognostic factor. >
For improvement of stratification of this cohort of patients with AML a detection of additional genetic prognostic factors is required. ¡^
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ABSTRACT NO.: O-315 §
Acute myeloid leukemia as a second disease. Belorussian experience a
Yu. Barouskaya, O.V. Aleinikova
National Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Republic of Belarus
Key words: acute myeloid leukemia, second disease, children oo
Introduction. A definition «acute myeloid leukemia (AML) as a second disease» is not clear. According to World Health Organization AML, appeared in patients, that received cytotoxic q
chemotherapy and/or radiation therapy for malignant or non-malignant disease is qualified as AML, associated with previous treatment (tAML). AML development in patients with O
non-malignant hematopoietic diseases (ex., aplastic anemia (AA)) is rarely reported. Secondary AML (sAML) is defined as AML associated with previous myelodysplastic syndrome ^
(MDS) or myeloproliferative disease. Generally development of AML as a second disease is significant adverse prognostic factor. ^
Aim. To evaluate molecular genetic specifics and treatment results of patients with AML, developed after myeloid neoplasm (MNO) and AA therapy. uo
Materials and methods. Fourteen patients received treatment in our clinic for first and second disease from 1999 to 2015. Girls were predominant (boys/girls - 0.27). Median age at AML was 13.8 years (range - 6.3-20.8). In 8 (57 %) patients AML developed after MNO (3 cases of osteosarcoma, 2 - acute lymphoblastic leukemia, 1 - rhabdomyoblastoma, ^
1 - non-Hodgkin lymphoma, 1 - Hodgkin lymphoma); in 5 (36 %) - after acquired AA treatment; in 1 case - transformation from Fanconi anaemia. Median time from the moment of the first disease to AML development was 2.12 years (range - 0.8-8.8). AML treatment was performed according to protocols for de novo AML. Medan follow-up was 1.34 (0.002-10.9) years. lli
Results. In all patients (5/5) from the group with acquired AA anomalies of chromosome 7 were detected. In the development of AML a complex karyotype was found in patient with Q
Fanconi anemia. In 5 of 8 patients from the group of MNO 11q23 anomalies were shown. q
The probability of 15-years overall and event-free survival for the whole cohort of patients was 47 ± 14 % and 43 ± 13 %, respectively. In groups with first MNO and AA there were ¡jj
no significant differences. Induction failures were admitted in 4 (28.6 %) patients, death in remission - in 2 (14.3 %), relapse - in 1 (7 %) patient. In 1 patient first tumor progression ^
(rhabdiosacioma) was reported after AML remission. Hematopoietic stem cell transplantation was performed in 7 patients (3 patients from the group with acquired AA, 4 - from the group of MNA). EFS after HSCT was 71 ± 17 %. 3 (100 %) patients from the group with acquired AA are alive after HSCT, 2 (50 %) patients from the group of MNA died from the posttransplantational complications.
Conclusion. With tAML development in the structure of first disease MNO are dominant (osteosarcoma is in the lead). Effective tAML treatment method (especially after AA) is HSCT. In first AA diagnostics it is necessary to undertake a cytogenetic study for monosomy 7, thereby performing a differentiated diagnostics with MDS and selecting potential
candidates for HSCT.
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