A need for cautious interpretation of elevated serum germ cell tumor markers in children. Review and own experiences.

Protocols for pediatric germ cell tumors (GCT) allow for chemotherapy (CHT) initiation without histological diagnosis, based on typical clinical and radiological picture and increased alphafetoprotein (AFP) or beta-human chorionic gonadotropin serum levels. Such strategy may result in misdiagnoses in rare cases. We present two patients with abdominal tumors and high serum AFP levels, diagnosed as GCT. In both, no tumor shrinkage and increasing AFP was observed after first cycles of multidrug CHT for pediatric GCT. Histological examination of biopsied tumor tissues revealed metastatic cholangiocarcinoma in patient 1 and pancreatoblastoma in patient 2, which implicated immediate change of therapy. Presented cases support the necessity to consider the tumor biopsy when patients diagnosed with GCT based on typical clinical presentation and elevated AFP do not respond to CHT with AFP decrease and tumor size reduction.

Increased µ-Calpain Activity in Blasts of Common B-Precursor Childhood Acute Lymphoblastic Leukemia Correlates with Their Lower Susceptibility to Apoptosis.

Childhood acute lymphoblastic leukemia (ALL) blasts are characterized by inhibited apoptosis promoting fast disease progress. It is known that in chronic lymphocytic and acute myeloid leukemias the reduced apoptosis is strongly related with the activity of calpain-calpastatin system (CCS) composed of cytoplasmic proteases--calpains--performing the modulatory proteolysis of key proteins involved in cell proliferation and apoptosis, and of their endogenous inhibitor--calpastatin. Here, the CCS protein abundance and activity was for the first time studied in childhood ALL blasts and in control bone marrow CD19+ B cells by semi-quantitative flow cytometry and western blotting of calpastatin fragments resulting from endogenous calpain activity. Significantly higher µ-calpain (CAPN1) gene transcription, protein amounts and activity (but not those of m-calpain), with calpastatin amount and transcription of its gene (CAST) greatly varying were observed in CD19(+) ALL blasts compared to control cells. Significant inverse relation between the amount/activity of calpain and spontaneous apoptosis was noted. Patients older than 10 years (considered at higher risk) displayed increased amounts and activities of blast calpain. Finally, treatment of blasts with the tripeptide calpain inhibitors II and IV significantly and in dose-dependent fashion increased the percentage of blasts entering apoptosis. Together, these findings make the CCS a potential new predictive tool and therapeutic target in childhood ALL.

On the significance of germline cytogenetic rearrangements at MYCN locus in neuroblastoma.

BACKGROUND: MYCN oncogene amplification is the most important prognostic factor in neuroblastoma. 25% neuroblastoma tumors have somatic amplifications at this locus but little is known about its constitutional aberrations and their potential role in carcinogenesis. Here, we have performed an array-CGH and qPCR characterization of two patients with constitutional partial 2p trisomy including MYCN genomic region. RESULTS: One of the patients had congenital neuroblastoma and showed presence of minute areas of gains and losses within the common fragile site FRA2C at 2p24 encompassing MYCN. The link between 2p24 germline rearrangements and neuroblastoma development was reassessed by reviewing similar cases in the literature. CONCLUSIONS: It appears that constitutional rearrangements involving chromosome 2p24 may play role in NB development.

Cytometric evaluation of transferrin receptor 1 (CD71) in childhood acute lymphoblastic leukemia.

Transferrin receptor 1 (CD71) is a transmembrane glycoprotein responsible for cellular iron uptake. Higher expression of CD71 has been identified as a negative prognostic marker for numerous solid tumor types and for some lymphomas. The aim of this study was to evaluate CD71 expression on acute lymphoblastic leukemia (ALL) cells and to follow its possible clinical correlations. Sixty one patients, aged 1-17 years and diagnosed with ALL, were enrolled in the study. CD71 expression was analyzed on the bone marrow blastic cells by flow cytometry. CD71 expression on the leukemic blasts was diversified; in most patients, all blastic cells showed expression of CD71, but levels of expression varied. CD71 expression was statistically higher on T-lineage leukemias. Within the B lineage ALL, a significant difference in CD71 expression existed between precursor B ALL and mature B-ALL, which showed higher CD71 expression. CD71 expression positively correlated with Hgb concentration at diagnosis. Initial risk group assessment and therapy response were not correlated with CD71 expression, although disease free and overall survival times tended to be shorter in patients with B-lineage leukemias with initial high CD71 expression.

[Long-term observations of children with acute lymphoblastic leukemia and high leukocytosis treated according to modified "New York" protocols (1987-2003)]. / Wieloletnie obserwacje dziec z ostra bialaczka limfoblastyczna i wysoka liczba krwinek bialych leczonych wedlug zmodyfikowanych protokolow "Nowy Jork" (1987-2003).

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Due to new therapeutic schedules and cooperation between oncological centers it is curable in more than 80% of affected children. For the optimalization of the therapy there is necessary to assess the risk criteria that have influence on the treatment results in the certain groups of patients. Hyperleukocytosis and the age (less than 1 year and more than 10 years) are known as unfavorable risk factors. The study was designed to assess the long-term treatment results in children with ALL and the initial leukocytosis over 50 000/mm3 with the use of the modified "New York" protocols. We present the treatment results of 340 children with ALL treated in nine centers of Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG) according to three consecutive versions of modified "New York" protocol (group I, II, and III) between 1987 and 2003. Within the analyzed groups the first complete remission (I CR) was achieved in 91%, 95% and 96% of the patients, respectively. Relapses occurred in 37%, 21.5% and 26% of the patients and 3.7%, 1.8% and 5.7% of children died in the I CR due to complications, in the I, II and III therapeutic group, respectively. Obtained 5-and 10-year event-free survival (EFS) were 56% and 53.5% for the group I and 73% and 73% for the group II. Five-year EFS for the group III was 67%. The implementation of the New York protocol in 1987 and New York I in 1997 has improved the treatment results in children with ALL and initial leukocytosis over 50 000/mm3. Protocol New York II did not further improve the treatment results. Among analyzed parameters (age, gender, the initial leukocytosis, the blast cells immunophenotype) only age had the statistical significance. The implementation of modified "New York" protocols has improved the treatment results in children with ALL and initial leukocytosis over 50 000/mm3 compared to previous results.

P-glycoprotein activity predicts outcome in childhood acute lymphoblastic leukemia.

Treatment of children with acute lymphoblastic leukemia (ALL) is based on P-glycoprotein (P-gp)-dependent cytostatics. We assessed the P-gp function in blast cells as a possible prognostic factor and its influence on the overall survival. P-gp function was measured using the verapamil-sensitive Rhodamine efflux. Cell samples from 7 of 45 (16%) patients revealed rhodamine-efflux positive blasts. There were no relations between the presence of P-gp, clinical characteristics (age, sex, hepatomegaly, and splenomegaly) and initial laboratory parameters (immunophenotype, white blood cells count, and serum lactate dehydrogenase) in ALL. P-gp activity plays a negative role, both for a remission achieved on day 33 and for susceptibility to steroid therapy. Children bearing rhodamine-efflux positive blasts had a significantly shorter 5-year overall survival of 35%, as compared with 74% in those negative for P-gp function. Lack of any association with clinical characteristic and initial laboratory parameters suggests that presence of P-gp is an independent prognostic factor.

Additional genetic risk factor for death in children with acute lymphoblastic leukemia: a common polymorphism of the MTHFR gene.

BACKGROUND: The presence of metabolically important genetic polymorphisms may affect treatment efficacy in patients with malignancies. The objective of this prospective multicenter study was to evaluate the role of selected polymorphisms of genes associated with metabolism of chemotherapeutic drugs as prognostic markers in children with acute lymphoblastic leukemia. PROCEDURE: Genotyping for the presence of 7 genetic variants in 403 patients and analysis of death cases were performed. RESULTS: Thirty-one children died before reaching remission maintenance phase. Genetic analysis revealed in this group increased frequency of homozygosity for c.677C>T polymorphism of the MTHFR gene (26% vs. 8% in the survivors; OR 4.09; 95% CI 1.67-10; adjusted for multiple testing P = 0.028). CONCLUSION: Our data suggest that modification of anti-leukemic treatment should be considered in patients homozygous for c.677C>T polymorphism.

[Second neoplasms in children with solid tumours in the years 1992-2007. Experiences of Gdansk medical academy]. / Drugie nowoteory u dzieci z guzami litymi w latach 1992-2007. Doswiadczenia osrodka gdanskiego

UNLABELLED: The occurrence of a second tumour is a severe complication of neoplastic disease and its treatment, and it reduces the patient's chances to survive. The aim of the study was to assess the frequency of a second neoplasm and its clinical course in children treated in Gdansk in the years 1992-2007. PATIENTS AND METHODS: There were 420 children and young adults included in the study. They were treated for malignant tumours in this period in the Department of Paediatrics, Haematology, Oncology and Endocrinology Medical Academy of Gdansk. The medical records of these patients were analysed. RESULTS: The second neoplasm was diagnosed in 9 patients, aged 9 to 23 years. They were treated for nephroblastoma - 3 cases, soft tissue sarcoma - 2, Ewing's sarcoma - 1, medulloblastoma - 1, retinoblastoma - 1 and neuroblastoma - 1 case. The second neoplasms were: acute non lymphoblastic leukaemia - 2, soft tissue sarcoma - 2, osteosarcoma - 2, chondrosarcoma - 1, renal cell carcinoma - 1 and glioblastoma multiforme - 1 case. Time between the first and second diagnosis was from 3 and 11/12 to 19 years. Treatment failed in 5 out of 9 children treated for osteosarcoma (2/2), chondrosarcoma (1/1), soft tissue sarcoma (1/2) and acute non lymphoblastic leukaemia (1/2). These patients died of progression of neoplastic disease during 2 to 20 months after the diagnosis of the second tumour. CONCLUSIONS: The diagnosis of the second tumour worsens the prognosis. It is difficult to define the factors that predispose to the second neoplasm. In 5 cases the second neoplasm occurred in the region which was previously irradiated.

[Treatment results in children with the standard risk acute lymphoblastic leukemia treated with high dose of methotrexate (5.0 g/m2). 11 years of the Polish Pediatric Leukemia/Lymphoma Study Group experience]. / Wyniki leczenia ostrej bialaczki limfoblastycznej grupy standardowego ryzyka (ALL-SR) u dzieci z zastosowaniem wysokich dawek metotreksatu (HD-MTX 5,0 g/m2)--11 lat doswiadczen Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczek i Chloniaków.

Since 01.07.1993 to 30.09.2004, 675 children with ALL-SR were diagnosed and treated according to the modified ALL-BFM 90 protocol. Subject to statistical analysis (Kaplan-Meier method) were thus 197 children with ALL-SR treated with HD-MTX in a dose 5.0g/ m2. Among them, 21 patients failed to respond to therapy: 2 (1.0%) early deaths, 2 (1.0%) deaths during I complete remission, 16 (8.2%) relapses, 1 (0.5%) second neoplasm. Relapses occured: 12 (6.2%) in bone marrow, 2 (1.0%) in central nervous system, 1 (0.5%) in testicle and in 1 (0.5%) child combined relapse was observed. Probability rates for 11-year event free survival (EFS) was 0.80 (0.03). Application of high dose of methotrexate is safety and effective in prevention of relapses, especially meningeal and testicular involvement.

[Acute lymphoblastic leukemia in children with initial leucocytosis above 50,000/mm3: summary of treatment results of Polish Pediatric Leukemia/Lymphoma Study Group]. / Ostra bialaczka limfoblastyczna u dzieci ze wstepna leukocytoza powyzej 50,000/mm3: podsumowanie wyników leczenia Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczek i Chloniaków.

Initial leucocytosis, presence of t(9;22) and t(4;11) translocations and poor response to therapy with steroids or induction chemotherapy are still included to poor risk factors group. From 1981 to 1986, children with acute lymphoblastic leukemia (ALL) and initial WBC above 50,000/mm3, achieved significantly worse treatment results than children with lower WBC: over 6-year disease-free survival were respectively 33% and 60%. In attempt to improve treatment results in children with hyperleucocytosis, modified American protocols called: New York (1987), New York I (1997), and New York II (1999) were introduced consecutively in the centers of Polish Pediatric Leukemia/ Lymphoma Study Group. Actually treatment results obtained with those protocols in three groups of patients: group I: 214 children (1987-1996), group II: 58 children (1997-1999), and group III: 77 children (1999-2001) are presented. The observation was completed in March 31, 2004. In evaluated groups the first complete remissions (CR) were achieved in 91%, 95%, and 96% of patients, respectively. Relapses occurred in 72 patients of group I (37%), in 12 patients of group II (21%), and in 13 patients of group III (18%). The 5-year overall survivals were: 62%, 79%, and 78% (p=0.05) respectively; 5 year event-free survivals (EFS) were: 52%, 74%, and 69% (p=0.01) respectively. A significant improvement in treatment results in second compared with first group was achieved. Treatment results obtained with New York II are comparable with results obtained with New York I. The analysis of treatment results achieved shows the improvement of the prognosis in children with ALL and initial WBC above 50 000/mm3 in comparison with patients treated before 1987. There is strong necessity of unification of risk group qualification criteria in childhood ALL in term of comparable estimation treatment results achieved in different centers all over the world.

RNA and protein evidence for haplo-insufficiency in Diamond-Blackfan anaemia patients with RPS19 mutations.

The genetic basis of Diamond-Blackfan anaemia (DBA), a congenital erythroid hypoplasia that shows marked clinical heterogeneity, remains obscure. However, the fact that nearly one-quarter of patients harbour a variety of mutations in RPS19, a ribosomal protein gene, provides an opportunity to examine whether haplo-insufficiency of RPS19 protein can be demonstrated in certain cases. To that end, we identified 19 of 81 DBA index cases, both familial and sporadic, with RPS19 mutations. We found 14 distinct insertions, deletions, missense, nonsense and splice site mutations in the 19 probands, and studied mutations in 10 patients at the RNA level and in three patients at the protein level. Characterization of the mutations in 10 probands, including six with novel insertions, nonsense and splice site mutations, showed that the abnormal transcript was detectable in nine cases. The RPS19 mRNA and protein in CD34+ bone marrow cells identified haplo-insufficiency in three cases predicted to have one functional allele. Our data support the notion that, in addition to rare DBA patients with the deletion of one allele, the disease in certain other RPS19 mutant patients is because of RPS19 protein haplo-insufficiency.

[Non-Hodgkin lymphomas of the nasopharynx in children--diagnostic and therapeutic difficulties]. / Chloniaki nieziarnicze nosogardla u dzieci--trudnosci diagnostyczne i terapeutyczne.

UNLABELLED: About 7% of all childhood cancers comprise non-Hodgkin's lymphoma (NHL). NHL are heterogenous group of neoplasms deriving from lymphatic system (cell B and T). B-cell NHL characterize by high malignancy, but coincidentally good reaction for treatment. In about 20% primary tumour is localised within head and neck, and nasopharynx lymphomas comprise 10%. This location maintains the biggest diagnostic and therapeutic difficulties because of tumours of this site proliferate in the region of frequent infections postponing a proper diagnosis and the local control after complete treatment is difficult. AIM OF THE STUDY: The authors analyse clinical symptoms before diagnosis, the incidence of nasopharynx lymphomas, histopathological type of neoplasm, clinical stage, results of treatment. MATERIAL AND METHODS: The study includes 97 patients who were treated because of lymphomas between 1993-2002. The character of clinical symptoms and their duration, histopathological type of lymphomas, results of treatment were analysed. RESULTS: The primary nasopharynx location was assessed in 9 patients (9.3%). Sex: 7 boys, 2 girls, age: 2-17 years. The duration which elapsed from initial clinical symptoms to diagnosis was 2-10 weeks. The histopathological assessment in 6 children was Burkitt lymphoma and in 3 children--Burkitt-like lymphoma. Metastases: CNS--1 patient, bone marrow--1 patient, abdomen--1 patient. Treatment was performed according to LMB-89 protocol. RESULTS: First complete remission--7 patients; second complete remission--2 patients. CONCLUSIONS: Lymphomas of nasopharynx cause diagnostic problems because of their early stage pseudo-inflammatory manifestation. Special attention should be paid to perform imaging studies (MRI/CT), which are useful in the reaching the proper diagnosis. The radiologic evaluation of primary lesion is still difficult. In the doubtful cases, the surgery and histopathological examination are necessary.

[Progress in the treatment of non-Hodgkin's lymphoma (NHL) in children. The report of Polish Pediatric Leukaemia/lymphoma Study Group (PPLLSG)]. / Postep w leczeniu nieziarniczych chloniaków zlosliwych (NHL) u dzieci. Raport Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczek i Chloniaków u Dzieci (PPGLBC).

Treatment results of non-Hodgkin lymphoma (NHL) in children has been shown in this study. From 1979 to 2003 children were registered with the diagnosis of NHL in oncology centers of Polish Pediatric Leukaemia/Lymphoma Study Group, a group of 397 patients with NHL B, 222 pts with NHL T and 54 pts with anaplastic large cell lymphoma (ALCL). The pts with NHL T have been treated according to BFM-90 protocol. The predominant primary site of disease was mediastinum (59.3%). Complete remission (CR) was achieved by 87%. EFS for all NHL T pts was 65% and 56% for pts with extensive tumours and 73% for pts with tumours < 10 cm. Patients with NHL B were treated according to the adopted LMB-89 protocol. The majority were Burkitts type and presented abdominal location (50%). 80% with disseminated disease. CR was achieved by 89% patients, but 94% with LDH < 500 IU/L and 73% with LDH > 500 IU. The median time of follow up was 53 months. EFS was 73% for all patients. The patients with ALCL were treated according to several protocols. Peripheral nodes were the most often primary location (40%), than mediastinum (24%) and abdomen (21%). EFS for all pts was 63%. Despite great progress in the therapy of NHL in children during 20 years of observation, the results are not satisfactory in disseminated stages. It is necessary to look for new prognostic markers which make it possible to improve classification of patients. Major surgery in advanced stages is not recommended since it delays chemotherapy and fails to improve overall survival. Early detection of neoplasm is one of the most important efforts to improve therapy success.

[Treatment results in children with standard-risk acute lymphoblastic leukemia. Report of the Polish Pediatric Leukemia/Lymphoma Study Group]. / Wyniki leczenia ostrej bialaczki limfoblastycznej grupy standardowego ryzyka u dzieci wg zmodyfikowanego programu ALL BFM 90 w materiale Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczek i Chloniaków.

Since 01.07.1993 to 30.09.2002, 640 children (48.2% girls and 51.8% boys) with ALL-SR were diagnosed and treated according to the modified ALL-BFM 90 protocol. In 29 children the treatment was intensified because of poor corticosteroid response. Subject to statistical analysis (Kaplan-Meier method) were thus 611 children with ALL-SR. Among them, 89 patients failed to respond to therapy: 10 (1.6%) early deaths, 15 (2.5%) deaths during I complete remission, 64 (10.5%) relapses. Relapses occurred: 45 (7.4%) in bone marrow, 11 (1.8%) in central nervous system, 4 (0.7%) in testicular and in 4 (0.7%) children combined relapses were observed. Probability rates for 9-year event free survival (EFS) and relapse free survival (RFS) for all patients were 0.77 (0.02) and 0.79 (0.02), respectively. Application of high dose of methotrexate is effective in prevention of relapses, especially meningeal and testicular involvement.

[Evaluation of systolic and diastolic function of the left ventricle in children with acute lymphoblastic leukaemia before treatment]. / Ocena czynnosci skurczowej i rozkurczowej lewej komory serca u dzieci z ostra bialaczka limfoblastyczna przed rozpoczeciem leczenia.

Between 1995 and 2001 echo-cardiography was performed in 244 children (128 boys, 116 girls) with acute lymphoblastic leukaemia (ALL) before the beginning of therapy with anthracyclines (medium 5.4 days after the diagnosis). The mean age at diagnosis was 5.4 years (range 9 months to 17.7 years). 189 children (97 boys and 92 girls) were included into the standard and medium risk groups and 55 (31 boys and 24 girls) into the high risk group. 29% of ALL children had disturbances in ECG. Changes in the thickness of the intraventricular septum (%IVSTh) and left ventricular posterior wall (%LVPWTh) were statistically lower, especially in children under 7 years of age. Some children showed lowering of shortening fraction (%FS - 8.6%), ejection fraction (%EF - 10.2%) and corrected velocity of fibber-shortening (Vcfc - 25.8%). Children with decreased shortening fraction (%FS) had left ventricular posterior wall thickness (%LVPWTh) impairment. Changes in diastolic function indicate impaired relaxation and compliance of the left ventricle. Decreased peak early filling velocity (E) was found. There were also longer deceleration time (EDecT) and decreased deceleration from peak E velocity (E/Dec) and longer isovolumetric relaxation time in children in standard and medium risk groups. Shorter acceleration time (EAccT) was seen in the high risk group. Evaluation of cardiac function before anthracycline chemotherapy will allow to select patients with pre-existing cardiac impairment for whom cardioprotective treatment is absolutely necessary.

[Advances in the treatment of children with high risk acute lymphoblastic leukemia (ALL) treated with modified "NEW YORK" protocols between 1987 and 2002]. / Postepy w leczeniu dzieci z ostra bialaczka limfoblastyczna (ALL) wysokiego ryzyka wg modyfikowanych programów "NOWY JORK" w latach 1987-2002.

From 1981 to 1986, in children with ALL and initial WBC > or = 50,000/mm3, over 6-year disease-free survival was significantly lower (33%) than in children with WBC < 50,000/mm3 (60%). In attempt to improve this unsatisfactory results, three modified American protocols named: "New York", "New York I", and "New York II", "New York I", and "New York II" were introduced consecutively in the centers of Polish Pediatric Leukemia Lymphoma Study Group (respectively, in 1987, 1997, and 1999). The treatment results achieved in three consecutive therapeutic groups of children with ALL and initial WBC > or = 50,000/mm3: group I--213 children (1987-1996), group II--58 children (1997-1999), and group III--52 children (1999-2001) are presented. The observation was completed in December 31, 2002. In three evaluated groups the first complete remissions (CRs) were achieved in 90.6%. 94.8%. and 94.2% of patients, respectively. Relapses occurred in 71 patients of group I (37%), in 9 patients of group II (16%), and in 6 patients of group III (12%). The complications of treatment caused death in 7 children of group I, in 1 child of group II, and in 2 children of group III. Eighty-one (38%), 11 (18.9%), and 9 (17.3%) patients, respectively, died due to progression of disease. The event-free survival (EFS) in three evaluated groups did not depend on age of children and WBC. The rates of 2-, 5-, and 10-year event-free survival (EFS) in group I were: 69.9%, 55.3%, and 53.6%, respectively and the rates of 2- and 5-year EFS in group II were: 80.7% and 72.7%, respectively. The rate of 2-year EFS in group III was 71.6%. The analysis of achieved treatment results in three evaluated groups shows the gradual improvement of the prognosis in children with ALL and initial WBC > or = 50,000/mm3 treated with the use of modified protocols "New York" and "New York I" in comparison with patients treated before 1987. Longer observation is needed for evaluation of efficacy and complications of "New York II" protocol.

In vitro activity of glufosfamide in childhood acute leukemia.

Glufosfamide is a new agent for cancer chemotherapy. The objective of the study was the comparison of the in vitro drug resistance profile of glufosfamide with other oxazaphosphorines in 106 samples of childhood acute leukemia by means of the MTT assay. The following drugs were tested: glufosfamide, 4-HOO-ifosfamide, 4-HOO-cyclophosphamide, mafosfamide cyclohexylamine salt, prednisolone, vincristine, L-asparaginase, daunorubicin and cytarabine. In the group of initial Acute Lymphoblastic Leukemia (ALL) samples, equivalent cytotoxicity values for glufosfamide, 4-HOO-ifosfamide, 4-HOO-cyclophosphamide and mafosfamide were 5.95, 9.92, 4.60 and 3.90 microg/ml, respectively. In comparison to initial ALL samples, the relative resistance for glufosfamide and 4-HOO-ifosfamide in relapsed ALL samples were 1.9 (p=0.049) and 1.3 (ns), and in initial Acute Myeloblastic Leukemia (AML) samples, respectively, 31 (p<0.001) and 5 (p=0.001). All oxazaphosphorines showed highly significant cross-resistance. In conclusion, in vitro activity of glufosfamide is comparable to ifosfamide. Glufosfamide shows high activity against lymphoblasts both on diagnosis and on relapse, however it cannot circumvent resistance to other oxazaphosphorines.

Ex vivo drug resistance profile in childhood acute myelogenous leukemia: no drug is more effective in comparison to acute lymphoblastic leukemia.

Therapy results in childhood acute myelogenous leukemia (AML) differ from those of acute lymphoblastic leukemia (ALL). Cellular drug resistance might be one of the reasons of therapy failure in AML. The aim of the study was the analysis of ex vivo drug resistance profile in childhood initial and relapsed AML in comparison to initial ALL. Fifty-three AML samples were tested for chemosensitivity and results were compared with those of 106 initial ALL samples. Ex vivo drug resistance was tested by means of the MTT assay. Up to 29 cytotoxic drugs were tested for each patient. When compared to de nova ALL samples, myeloblasts from initial AML samples were significantly more resistant to most tested drugs, except cytarabine, mercaptopurine and thioguanine. Relapsed AML samples, in relation to initial AML samples, showed comparable sensitivity to cytarabine, idarubicin, fludarabine and cladribine. Patients, who have died due to refractory or relapsing disease, were already on first diagnosis 2-fold more resistant to cytarabine, 6.4-fold more resistant to cisplatin and 3-fold more resistant to carboplatin, when compared to those who stay in remission. Resistance to prednisolone was observed in 85% initial and all relapsed AML samples, in comparison to 33% of ALL samples. Resistance to cytarabine occurred in 2.1% of ALL and 12% of AML cases while a patient with Down syndrome presented the most sensitive drug resistance profile. In conclusion this study shows that no drug was found which, on average, was more effective in AML than in ALL samples. The sensitivity of myeloblasts to platinum derivatives might have prognostic value.