Childhood Acute Myelogenous Leukemia Research Articles

Twenty years of Polish experience with three consecutive protocols for treatment of childhood acute myelogenous leukemia

Until 1983, results of treatment of acute myelogenous leukemia (AML) in Poland with different regimens were very poor. In 1983, the Polish Pediatric Leukemia/Lymphoma Study Group introduced a unified treatment protocol--a modified version of BFM-83 protocol. This led to an increase in the curability of AML from 15% to approximately 32%. In 1994, a modification was made: the high-risk patients (>5% blasts in bone marrow on day 15 of therapy and all M5 cases) received two additional cycles with intermediate-dose cytarabine (ID-ARAC). This led to a nonsignificant improvement in the 5-year event-free survival (EFS) rate from 32 to 36%. A new treatment protocol employing idarubicin in place of daunorubicin was introduced in 1998 and produced better initial responses, increase in the number of patients attaining remission after induction therapy and proportional increase of standard-risk patients. The probability of 5-year EFS (pEFS) for the whole group of patients increased from 36 to 47%. In standard- and high-risk groups, the 5-year pEFS was 62 and 33%, respectively. The probability of 5-year disease-free survival was 58% in the whole group, and there were no differences between risk groups. Unsatisfactory treatment results in children classified into the high-risk group are principally due to the low remission rate.

Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype

AbstractNucleophosmin (NPM) is a nucleocytoplasmic shuttling protein involved in leukemia-associated chromosomal translocations, and it regulates the alternate reading frame (ARF)-p53 tumorsuppressor pathway. Recently, it has been demonstrated that mutations of the NPM1 gene alter the protein at its C-terminal, causing its cytoplasmic localization. Cytoplasmic NPM was detected in 35% of adult patients with primary non-French-American-British (FAB) classification M3 acute myeloid leukemia (AML), associated mainly with normal karyotype. We evaluated the prevalence of the NPM1 gene mutation in non-M3 childhood AML patients enrolled in the ongoing Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP-AML02) protocol in Italy. NPM1 mutations were found in 7 (6.5%) of 107 successfully analyzed patients. NPM1- mutated patients carried a normal karyotype (7/26, 27.1%) and were older in age. Thus, the NPM1 mutation is a frequent abnormality in AML patients without known genetic marker; the mutation may represent a new target to monitor minimal residual disease in AML and a potential candidate for alternative and targeted treatments. (Blood. 2005;106:1419-1422)

Gene Expression Profiling Identifies Genes Associated with In Vitro Resistance to Daunorubicin and Cytarabine in Children with De Novo Acute Myelogenous Leukemia (AML) from the Pediatric Oncology Group (POG) Study # 9421.

Daunorubicin and cytarabine are the most effective chemotherapeutic agents for AML. Using MTT (3,[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assays as an in vitro test for sensitivity to these agents, investigators have found that leukemia cells from pediatric AML patients with Down Syndrome, which are more sensitive to cytarabine than blasts from non-Down Syndrome AML patients, have been associated with an increased ratio of deoxycytidine kinase to cytidine deaminase and an increased level of cystathionine-beta-synthetase [Ge, Jensen, Stout et al. Cancer Res 2004; 64, 728–35]. Looking for related findings in non-Down syndrome AML, leukemic blasts from non-Down syndrome children with AML were examined utilizing gene expression profiling and MTT assays. Expression signatures from cDNA arrays were related to the drug sensitivity results to daunorubicin and cytarabine by supervised clustering. These results will then be analyzed to look for relationships to the patient's clinical outcomes and identify genes that may be potential therapeutic targets for drug resistance reversal.Bone marrow or blood specimens from 103 patients registered on the Pediatric Oncology Group (POG) protocol 9421 were studied. The diagnostic specimens were tested using MTT assays to measure the IC50 (drug concentration that causes 50% of the cells to die) for both daunorubicin and cytarabine. Samples from ninety-three de novo childhood AML patients were analyzed with a 43,760 element spotted array (containing 41,751 unique genes and expression sequence tags [ESTs]) from the Stanford University Microarray Core Facility. We selected the gene expression profile from 10 samples with the highest and lowest IC50's for each drug. Then, we used Significance Analysis of Microarrays (SAM) to find significant differences in the gene expression between samples sensitive and resistant to each drug. A cluster of 118 overexpressed genes was associated with resistance to daunorubicin (e.g., BCL6, BAPX1, BCL2A1, MBD2, RAB31 and CDKN1A). A cluster of 24 overexpressed genes was associated with resistance to cytarabine (e.g., RIT1, SH3BP2, BCL2A1, NFKBIA, and PTPRE).In summary, MTT assays and gene expression profiling have identified genes that correlate with daunorubicin and cytarabine resistance. Study of the relationship among drug resistance patterns, gene expression profiles and clinical outcome may allow us to better predict patients' prognoses at diagnosis and also can be used to identify novel targets for drug resistance reversal.

Prognostic implications of t(10;11) translocations in childhood acute myelogenous leukemia: a report from the Children's Cancer Group.

This was a retrospective analysis of outcome based on cytogenetics for a Children's Cancer Group phase 3 trial of acute myelogenous leukemia (AML) (CCG-2891). A retrospective analysis of outcome for newly diagnosed children with AML and myelodysplastic syndrome (MDS) was performed using data collected from CCG-2891. The authors identified 11 patients whose blasts carried t(10;11) reciprocal translocations or other complex rearrangements involving 10p and 11q among 470 eligible patients entered with acceptable, centrally reviewed cytogenetics. A bone marrow specimen was used for each case of cytogenetic analysis in which 20 banded (either G-banded or Q-banded) metaphases were completed on each subject. All 11 patients had characteristic monocytoid morphology (M4 or M5) and tended to be young (0.1-7.9 years; median 0.9 years). All 11 patients entered remission, but remissions tended to be short; 9 patients relapsed within 12 months (median 4 months). The relapse rate of 82% was significantly higher for this group of patients compared with 46% for the group at large. The relapse rate for this group of patients having t(10;11) reciprocal translocations or other complex rearrangements involving 10p and 11q was also significantly higher compared with subjects with other 11q23 chromosomal abnormalities. The CNS relapse rate of 55% was higher for this group of patients compared with 3% for all other patients in the study. The CNS relapse rate was higher for the subjects who had t(10;11) reciprocal translocations or other complex rearrangements involving 10p and 11q compared with subjects with all other chromosome 11 abnormalities. Three children survived, two in second remissions (4.7 and 6.3 years after relapse) and one in first remission (7.0 years after diagnosis). Survival and event-free survival for the patients with t(10;11) reciprocal translocations or other complex rearrangements involving 10p and 11q was 27 +/- 27% and 9 +/- 17% at 6 years, respectively, and was not statistically different from all other patients with cytogenetics. Similarly, the survival and event-free survival for the patients with t(10;11) translocations and other rearrangements of chromosomes 10 and 11 was 27 +/- 27% and 9 +/- 17% at 6 years, respectively, and was not statistically different from the 11q23 group of subjects. Further research is needed to determine the various changes that are occurring at the molecular level for patients with t(10;11) translocations and other rearrangements of chromosomes 10 and 11 to gain insight into the mechanisms causing this clinical phenotype associated with a poor prognosis.

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 novo 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.

Granulocytic Sarcoma in MLL-Positive Infant Acute Myelogenous Leukemia : Fluorescence in Situ Hybridization Study of Childhood Acute Myelogenous Leukemia for Detecting MLL Rearrangement

Granulocytic sarcoma is considered to be rare and its frequent occurrence is associated with specific genetic changes such as t(8;21). To investigate an association between MLL (mixed lineage leukemia or myeloid-lymphoid leukemia) rearrangement and granulocytic sarcoma, we applied fluorescence in situ hybridization for detection of the 11q23/MLL rearrangements on the bone marrow cells of 40 patients with childhood acute myelogenous leukemia (AML). Nine (22.5%) of 40 patients exhibited MLL rearrangements. Three (33.3%) of these nine patients had granulocytic sarcoma and were younger than 12 months of age. Of these three patients one presented as granulocytic sarcoma of both testes with cerebrospinal fluid involvement, the second case presented in the form of an abdominal mass, and the third as a periorbital granulocytic sarcoma. On the other hand, no granulocytic sarcomas were found among MLL-negative patients. It is likely that MLL-positive infant AML may predispose granulocytic sarcoma. Regarding the findings of our study and those of other reports, we would guess that the incidence of granulocytic sarcoma in pediatric MLL-positive AML may be equal to or greater than the 18 to 24% described in AML with t(8;21). Further investigations designed to identify 11q23/MLL abnormalities of leukemic cells or extramedullary tumor may be helpful for the precise diagnosis of granulocytic sarcoma.

Treatment of childhood acute myelogenous leukemia with an intensive regimen (AML-87) that individualizes etoposide and cytarabine dosages: short- and long-term effects.

The purpose of this study was to assess the feasibility and efficacy of a treatment regimen for pediatric acute myelogenous leukemia (AML) that uses four rotating drug pairs and adjusts dosages of etoposide and cytarabine to target specific plasma concentrations. Thirty-one girls and 27 boys (median age, 9.7 years) with de novo AML were treated on the protocol. Six cycles of chemotherapy were planned. Cycles 1 to 4 comprised the drug combinations cytarabine plus etoposide, cytarabine plus daunomycin, etoposide plus amsacrine, and etoposide plus azacitidine, respectively. For cycles 5 and 6, the first two combinations were repeated. Dosages were adjusted to achieve plasma concentrations of 1.0 microM +/- 0.1 microM cytarabine and 30 microM +/- 0.3 microM etoposide. Forty-four patients (76%) entered complete remission. Of those, 24 have had relapses; 23 remain alive in first or subsequent remission. The 5-year event-free survival (EFS) estimate was 31.0% +/- 5.9%; the 5-year survival estimate was 41.4% +/- 6.3%. Six patients (10%) died of the toxic effects of therapy. Severe neutropenia occurred in all cycles. Long-term complications of therapy included hepatitis C, cardiac insufficiency, and hearing loss. Adjustment of cytarabine and etoposide dosage was feasible for achieving targeted plasma drug concentrations; however, the potential clinical efficacy of this approach was offset by substantial acute and long-term toxicity.

Role of Bone Marrow Transplantation in Childhood Acute Myelogenous Leukemia

Role of Bone Marrow Transplantation in Childhood Acute Myelogenous Leukemia

Prognostic value of internal tandem duplication of the FLT3 gene in childhood acute myelogenous leukemia

Prognostic value of internal tandem duplication of the FLT3 gene in childhood acute myelogenous leukemia

Prognostic value of internal tandem duplication of the FLT3 gene in childhood acute myelogenous leukemia

Prognostic value of internal tandem duplication of the FLT3 gene in childhood acute myelogenous leukemia

Prognostic value of internal tandem duplication of the FLT3 gene in childhood acute myelogenous leukemia.

Recently, an internal tandem duplication of the FLT3 gene (FLT3/ITD) was found in 20% of adult cases of acute myelogenous leukemia (AML), and this length abnormality was suggested to be associated with leukemic progression. We examined the mRNA expression of the FLT3 gene by using reverse transcription-polymerase chain reaction (RT-PCR) in 64 children with AML, and further abnormal transcripts were cloned and sequenced. An unexpected longer product was found in seven patients (11%) by RT-PCR of the FLT3 gene. Sequence analysis of these abnormal products revealed the presence of tandemly duplicated fragments in all seven patients. Three factors were identified to be associated with high incidence of FLT3/ITD; older patients (> or = 10 years) (P = 0.049), high WBC count (> or = 50,000/microl) at presentation (P = 0.002), and M3 in FAB subtypes (P = 0.002). Induction failure was observed in 3 (43%) of 7 patients with FLT3/ITD. Only FLT3/ITD was identified as a significant risk factor for induction failure by univariate analysis (P = 0.013), although it was not significant by multivariate analysis (P = 0.11). The Kaplan-Meier estimate of event-free survival rate at 5 years was 14% for patients with FLT3/ITD, which was significantly lower in comparison with 69% for patients without FLT3/ITD (P = 0.003). This finding was also identified by multivariate analysis (P = 0.01). In this study, FLT3/ITD was observed in 11% of childhood AML and identified to be associated with poor prognosis. A large prospective study with uniform treatment is necessary to confirm our results.

#457 Feasibility of timed-sequential induction chemotherapy with high-dose Ara-C on day 14 for childhood acute myelogenous leukemia

Bowers, D. C.; Cho, S. Y.; Higman, M.; McDonough, C.; Chen, A. R.; Civin, C. I.; Cohen, K. J.; Schwartz, C. L.; Small, D.; Friedman, A. D. Author Information

Duration of first remission predicts remission rates and long-term survival in children with relapsed acute myelogenous leukemia.

Although treatment of childhood acute myelogenous leukemia (AML) has substantially improved in the last 15 years, in nearly half of the patients disease recurs. The aim of this study was to establish the prognosis of relapsed childhood AML and to identify prognostic factors for achievement of second remission and survival. From February 1988 to July 1996, 134 children with first relapse of AML were reported to the study center of the AML-BFM group. 102 patients treated intensively to induce second remission were prospectively followed. With various regimens, complete remission was achieved in 52 of 102 patients (51%), 27 children were alive in median 2.5 years (range, 0.4-7 years) after relapse. Disease-free survival was observed in seven of 16 patients transplanted from a matched sibling donor, one of four after matched unrelated bone marrow transplantation, 10 of 22 after autologous transplantation and five of nine patients after chemotherapy alone (two patients were lost to follow-up). Time until relapse reflecting the duration of first remission is the only variable correlating CR and survival rates. Defining early relapse as less than 1.5 years from diagnosis to relapse resulted in a 5-year survival of 10%, s.e. 5% for early relapses and 40%, s.e. 10% for late relapses (P-logrank test, 0.0001). Duration of first remission is a strong predictor for achievement of second CR and survival. It should be considered in reporting results of experimental therapies.

A Phase II study of carboplatin as a treatment for children with acute leukemia recurring in bone marrow

Carboplatin is an analogue of cisplatin with less nonhematologic toxicity and a similar spectrum of antineoplastic activity. Although cisplatin has not been found to be an active agent against leukemia, carboplatin-induced complete remissions have been observed in adults with acute myelogenous leukemia (AML), and antileukemic activity has been observed in a Phase I trial involving children with acute lymphoblastic leukemia (ALL) and AML. Therefore, a pediatric Phase II study was undertaken to determine the degree of activity of carboplatin in childhood ALL and AML. Between October 1991 and November 1994, the Children's Cancer Group conducted a Phase II study of carboplatin given by 5-day continuous intravenous infusion to children with acute leukemia recurring in bone marrow. Minimal antileukemic activity was demonstrated in patients with ALL and AML. One of 21 eligible patients with ALL achieved a partial response. Of 23 eligible patients with AML, including 1 patient with chronic myelogenous leukemia in blast crisis, 1 had hypocellular M1 bone marrow with a platelet count of 15,000/mm3, and 2 achieved partial responses. Nonhematologic toxicities, which were infrequent, included mild hepatic and renal dysfunction. In this pediatric Phase II trial of carboplatin as a treatment for acute leukemia, minimal activity was demonstrated in patients with ALL and AML recurring in bone marrow. Further evaluation of carboplatin as a treatment for childhood leukemia, using the dose schedule of 216 mg/m2/day given by 5-day continuous intravenous infusion, does not appear warranted.

Epidemiology of childhood acute myelogenous leukemia.

Acute myelogenous leukemia (AML) is the second most common leukemia in children, with approximately 400 new cases occurring annually in the United States. Worldwide, the highest rates of childhood AML occur in Asia and the lowest rates are reported from India and South America. Numerous genetic risk factors for childhood AML have been defined, including Down syndrome, neurofibromatosis, and Fanconi anemia. Research into environmental risk factors has been limited by the rarity of this disease; however, studies of AML in adults have implicated ionizing radiation, solvents, and petroleum products as potential etiologic agents. The largest analytic study of childhood AML found that occupational exposures of either parent to pesticides, paternal exposure to petroleum products, and postnatal exposures to pesticides are increased in children with AML. In addition, maternal use of marijuana during pregnancy was associated with an increased risk of AML, especially the monocytic subtypes. Further study of childhood AML, including occurrence of the disease as a second malignancy, is needed in order to confirm these findings and to increase our understanding of this leukemia.

An Overview of the Current Status of Treatment of Acute Myelogenous Leukemia in Children

An Overview of the Current Status of Treatment of Acute Myelogenous Leukemia in Children

High-dose cytarabine for intensification of early therapy of childhood acute myeloid leukemia: a Pediatric Oncology Group study.

In June 1984, the Pediatric Oncology Group (POG) initiated a pilot study (8498) using high-dose cytarabine (HdA; 3 g/m2) for intensification of early therapy in childhood acute myelogenous leukemia (AML) (group I). Remission induction therapy consisted of two courses of daunorubicin, cytarabine (Ara-C), and thioguanine (DAT). Postremission therapy consisted of four sequential courses, each consisting of (1) four doses of HdA (HdA4) followed by asparaginase (L-Asp), (2) etoposide (VP) plus azacytidine (Az), (3) prednisone, vincristine, methotrexate, and mercaptopurine (POMP), and (4) Ara-C daily for 5 days by continuous infusion. Six doses of intrathecal Ara-C were given for CNS prophylaxis. In December 1986, the protocol was amended (group II) to substitute six doses of HdA (HdA6) for the second DAT (two + five) induction course; postinduction, a single course of HdA6 was given instead of four HdA/L-Asp courses, and the remainder of the therapy was unchanged. One hundred forty group I patients and 145 group II patients were assessable. The two groups were similar with regard to clinical prognostic groups. No significant differences were noted in the two groups with regard to remission induction (85% [SE = 2%] in each group), induction deaths (6.5% v 7.0%), or deaths in remission (one in each group). Cerebellar toxicity was reported in three patients in group II (with HdA6) but none in group I (HdA4). At present, patients who received HdA6 (group II) had higher event-free survival than patients in group I (EFS at 3 years, 34% [SE = 11%] v 29% [SE = 4%]), and disease-free survival (DFS at 3 years, 42% [SE = 14%] v 34% [SE = 4%]), but the differences were not statistically significant. In both groups, children less than 2 years and those with WBCs less than 100,000/microL had significantly better outcome (EFS of 55% [SE = 10%] and 36% [SE = 5%] at 3 years, respectively) than children greater than or equal to 2 years and those with WBCs greater than or equal to 100,000/microL (EFS of 27% [SE = 5%] and 20% [SE = 9%] at 3 years, respectively.

Identification of two risk groups in childhood acute myelogenous leukemia after therapy intensification in study AML-BFM-83 as compared with study AML-BFM-78. AML-BFM Study Group

The main difference between the two cooperative studies on therapy of childhood acute myelogenous leukemia AML-BFM-78 and AML-BFM-83 was the addition of an 8-day ADE (cytosine arabinoside, daunorubicin, etoposide) induction treatment in the second study. Due to this intensification, the relapse rate, but not the rate of induction failures, was reduced. The probability of a 6-year event-free survival increased from 38%, SD 4%, in study AML-BFM-78 to 49%, SD 4%, in study AML-BFM-83, P = .08. The improvement of the 6-year event-free interval (EFI) was significant in the second study (61%, SD 4%, versus 47%, SD 5%, P less than .05); it was restricted to the FAB types M1 through M4 (EFI: 67%, SD 5%, versus 45%, SD 5%, P less than .01). The difference in EFI seen in FAB M5 was not statistically significant (EFI: 40%, SD 10%, versus 63%, SD 11%, NS). According to the results of the second study, two different risk groups (low and high) could be identified by combinations of predominantly pretherapeutic parameters. The low risk group, comprising 37% of the patients who achieved complete remission, included the FAB types with granulocytic differentiation and specific additional features: FAB M1 with Auer rods, FAB M2 with white blood cell count of less than 20,000/microL, FAB M3 all patients, and FAB M4 with eosinophilia. The 6-year Kaplan-Meier estimation of EFI is 91%, SD 4%, compared with 42%, SD 6% in the high risk group. In future studies based on the AML-BFM-83 treatment, bone marrow transplantation in first remission should be mandatory only for children of the high risk group.

Identification of Two Risk Groups in Childhood Acute Myelogenous Leukemia After Therapy Intensification in Study AML-BFM-83 as Compared With Study AML-BFM-78

The main difference between the two cooperative studies on therapy of childhood acute myelogenous leukemia AML-BFM-78 and AML-BFM-83 was the addition of an 8-day ADE (cytosine arabinoside, daunorubicin, etoposide) induction treatment in the second study. Due to this intensification, the relapse rate, but not the rate of induction failures, was reduced. The probability of a 6-year event-free survival increased from 38%, SD 4%, in study AML-BFM-78 to 49%, SD 4%, in study AML-BFM-83, P = .08. The improvement of the 6-year event-free interval (EFI) was significant in the second study (61%, SD 4%, versus 47%, SD 5%, P less than .05); it was restricted to the FAB types M1 through M4 (EFI: 67%, SD 5%, versus 45%, SD 5%, P less than .01). The difference in EFI seen in FAB M5 was not statistically significant (EFI: 40%, SD 10%, versus 63%, SD 11%, NS). According to the results of the second study, two different risk groups (low and high) could be identified by combinations of predominantly pretherapeutic parameters. The low risk group, comprising 37% of the patients who achieved complete remission, included the FAB types with granulocytic differentiation and specific additional features: FAB M1 with Auer rods, FAB M2 with white blood cell count of less than 20,000/microL, FAB M3 all patients, and FAB M4 with eosinophilia. The 6-year Kaplan-Meier estimation of EFI is 91%, SD 4%, compared with 42%, SD 6% in the high risk group. In future studies based on the AML-BFM-83 treatment, bone marrow transplantation in first remission should be mandatory only for children of the high risk group.

Prognostic significance of auer rods in childhood acute myelogenous leukemia: Results of the studies AML‐BFM‐78 and −83

The prognostic significance of Auer rods in predicting response rate and remission duration was investigated in 257 patients of the two West German acute myelogenous leukemia (AML) studies BFM-78 and -83. Auer rods were found in 129 children (50%) in the initial bone marrow smear. The incidence was higher in myeloid subtypes M1 (63%) and M2 (78%) compared with subtypes M4 (47%) and M5 (5%) with monocytic differentiation. In both studies, the remission rate was significantly higher in patients with Auer rods (P = 0.01), and in the study AML-BFM-83 a significantly longer remission duration was evaluated for Auer rod-positive patients (P = 0.007). In the M1 type, Auer rods were of high prognostic significance regarding both the induction success (P = 0.003) and the remission duration (P = 0.004), whereas no significant differences between Auer rod-positive and -negative patients in other subtypes were found. Occurrence of Auer rods was independent of hyperleukocytosis, the most powerful prognostic parameter in the studies AML-BFM-78 and -83, whereas absence of Auer rods was associated with the AML risk group M5. In the M1 type, Auer rod-negative leukemias appears to represent cases of poorly differentiated AML. Auer rods were therefore useful in differentiating between patients with a poor and a more favorable prognosis, particularly in the M1 type.