scholarly journals MLL gene rearrangements in infant leukemia vary with age at diagnosis and selected demographic factors: A Children's Oncology Group (COG) study

2011 ◽  
Vol 58 (6) ◽  
pp. 836-839 ◽  
Author(s):  
Thien N. Sam ◽  
John H. Kersey ◽  
Amy M. Linabery ◽  
Kimberly J. Johnson ◽  
Nyla A. Heerema ◽  
...  
Keyword(s):  
Demographic Factors ◽  
Age At Diagnosis ◽  
Gene Rearrangements ◽  
Oncology Group ◽  
Mll Gene ◽  
Infant Leukemia

406: Birth Weight and the MLL Gene in Infant Leukemia: A Children's Oncology Group Study

2005 ◽  
Vol 161 (Supplement_1) ◽  
pp. S102-S102
Author(s):  
L G Spector ◽  
S M Davies ◽  
L L Robison ◽  
M Roesler ◽  
J A Ross
Keyword(s):  
Birth Weight ◽  
Oncology Group ◽  
Oncology Group Study ◽  
Mll Gene ◽  
Infant Leukemia

scholarly journals Analysis of the Role of Hematopoietic Stem-Cell Transplantation in Infants With Acute Lymphoblastic Leukemia in First Remission and MLL Gene Rearrangements: A Report From the Children's Oncology Group

2011 ◽  
Vol 29 (2) ◽  
pp. 214-222 ◽  
Author(s):  
ZoAnn E. Dreyer ◽  
Patricia A. Dinndorf ◽  
Bruce Camitta ◽  
Harland Sather ◽  
Mei K. La ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Gene Rearrangements ◽  
Oncology Group ◽  
Hematopoietic Stem ◽  
Mll Gene

Purpose Although the majority of children with acute lymphoblastic leukemia (ALL) are cured with current therapy, the event-free survival (EFS) of infants with ALL, particularly those with mixed lineage leukemia (MLL) gene rearrangements, is only 30% to 40%. Relapse has been the major source of treatment failure for these patients. The parallel Children's Cancer Group (CCG) 1953 and Pediatric Oncology Group (POG) 9407 studies were designed to test the hypothesis that more intensive therapy, including dose intensification of chemotherapy, and hematopoietic stem-cell transplantation (HSCT) would improve the outcome for this group of patients. Patients and Methods One hundred eighty-nine infants (CCG 1953, n = 115; POG 9407, n = 74) were enrolled between October 1996 and August 2000. For infants with the MLL gene rearrangement and an appropriate donor, HSCT was the preferred treatment on CCG 1953 and investigator option on POG 9407 after completion of the second phase of therapy. Fifty-three infants underwent HSCT. Results The 5-year EFS rate was 48.8% (95% CI, 33.9% to 63.7%) in patients who received HSCT and 48.7% (95% CI, 33.8% to 63.6%) in patients treated with chemotherapy alone (P = .60). Transplantation outcomes were not affected by the preparatory regimen or donor source. Conclusion Our data suggest that routine use of HSCT for infants with MLL-rearranged ALL is not indicated. However, limited by small numbers, this study should not be considered the definitive answer to this question.

Nation-Wide Survey of Infant Leukemia in Japan: A Report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 896-896
Author(s):  
Takako Miyamura ◽  
Katsuyoshi Koh ◽  
Daisuke Tomizawa ◽  
Kanji Sugita ◽  
Koji Kato ◽  
...  
Keyword(s):  
Wide Spectrum ◽  
Lymphoblastic Leukemia ◽  
Age At Onset ◽  
Mixed Lineage Leukemia ◽  
Gene Rearrangements ◽  
Monocytic Leukemia ◽  
Pediatric Leukemia ◽  
Mll Gene ◽  
Nation Wide Survey ◽  
Infant Leukemia

Abstract Infant leukemia consists of wide spectrum of disease phenotype which includes acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and mixed lineage leukemia, and has unique biological and clinical features. However, there are few studies which have focused on its diversity from the cross-sectional view of this specific age group. We here conducted a nation-wide survey to analyze the disease distribution, characteristics, clinical courses, and outcomes of these patients in Japan. Questionnaires were sent to 170 institutions participating in the JPLSG which covers more than 95% of the hospitals in Japan, and total of 225 cases with infant leukemia and related disorders aged less than 24 months at onset who were diagnosed between 2004 and 2007 were registered. Median age at onset was 12 months, ranged from 0 to 22 months. No gender differences were observed (male, 118 cases; female, 107 cases). Thirty-nine were diagnosed as ALL with positive MLL gene rearrangements (MLL-R ALL), 74 as ALL with germline MLL (MLL-G ALL), 83 as AML, 9 as mixed lineage leukemia, and 20 as other disorders. In MLL-R ALL group, the frequency of t(4;11) was high in patients of <12 months of age (18/29 cases), whereas hyperdiploidy was detected in 20% of cases of MLL-G ALL group (12/61 cases). In AML, positive MLL gene rearrangements were detected in only 15% (13/83 cases), while t(1;22)(p13q13) or OTT-MAL was detected in 4 cases. Regardless of disease groups, early infant group of <6 months of age showed poor prognosis compared with other age groups. Particularly, all cases of ALL diagnosed at <4 weeks after birth harbored MLL gene rearrangements and either died or relapsed, indicating that more appropriate strategy is needed to improve the outcome for this specific group. Patients with MLL-G ALL less than 12 months old showed a favorable prognosis compared to those with MLL-R ALL. In AML, majority of cases were myelomonocytic/monocytic leukemia (M4/M5) or megakaryoblastic leukemia (M7), and showed favorable outcome. In conclusion, infant leukemia is still a challenging disease harboring diverse features, therefore, it is necessary to keep on-going the prospective trials, to register and follow-up these cases systematically and to standardize its treatment including supportive cares, especially for those with younger age onset.

Genetic Susceptibility Loci and Risk of Infant Leukemia by Subtype and MLL status: A Children's Oncology Group Report

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 749-749
Author(s):  
Julie A. Ross ◽  
Amy M. Linabery ◽  
Crystal Blommer ◽  
Erica Langer ◽  
Logan G. Spector ◽  
...  
Keyword(s):  
Genetic Susceptibility ◽  
Myeloid Leukemia ◽  
Strong Association ◽  
Variant Allele ◽  
Gene Rearrangements ◽  
Genome Wide Association Studies ◽  
Susceptibility Loci ◽  
Older Children ◽  
Mll Gene ◽  
Infant Leukemia

Abstract Abstract 749 Introduction. Leukemia in infancy is extremely rare and etiologically distinct from leukemia arising in older children. Infant leukemia cases likely arise in utero, typically involve rearrangements of the mixed lineage leukemia (MLL) gene, and have a much poorer survival than older children with leukemia. Since genetic determinants of susceptibility to infant leukemia are likely different from those in older children, we aimed to evaluate genetic variants previously identified by genome wide association studies of childhood acute lymphoblastic leukemia (ALL). Methods. We genotyped candidate susceptibility loci in 171 Caucasian infants less than 12 months of age with acute leukemia (including 102 ALL, 67 acute myeloid leukemia (AML), and 2 biphenotypic cases) diagnosed during the period 1996–2006. Controls consisted of 384 healthy Caucasian blood donors. Associations between genetic polymorphisms in IKZF1, ARID5B, and CEBPE and infant leukemia were evaluated using logistic regression and were further stratified by leukemia subtype and presence or absence of MLL gene rearrangements. Results. We observed a statistically significant association with two copies of the IKZF1 rs11978267 variant allele in infant leukemia overall (Odds Ratio (OR)=2.3, 95% Confidence Interval (CI)=1.3-4.2), but not with the other susceptibility loci. The association with IKZF1 was concentrated in the AML group, with an increased risk associated with two copies of the variant allele (OR=3.9, 95%CI=1.8-8.4), but not one copy. The association was similarly strong in those with and without a MLL gene rearrangement. In contrast, a strong association with the IKZF1 variant was seen in infants with ALL lacking a MLL rearrangement (OR=5.1, 95%CI=1.8-14.5), but not in those with MLL rearrangements (OR=0.7, 95%CI=0.2-2.2). Moreover, infants with ALL and no MLL rearrangement had a strong association with a genetic variant in the gene, ARID5B (rs10821936, OR=7.2, 95%CI=2.5-20.6), which was also not seen in those with ALL and a MLL rearrangement. Discussion. IKZF1 (IKAROS)is expressed in early hematopoiesis, and its role in lymphopoiesis and lymphoid leukemia is well-described. IKAROS is also expressed in precursor myeloid cells, and our report is the first evidence that IKZF1 is important in the etiology of infant myeloid leukemia, irrespective of MLL gene rearrangements. Moreover, our data indicate striking differences in genetic susceptibility to infant ALL with and without rearrangements of the MLL gene. This knowledge could provide important new etiologic insights into this extremely rare but heterogeneous hematopoietic malignancy. Supported by NIH CA079940, T32 CA099936, K05 CA157439 and the Children's Cancer Research Fund, Minneapolis, MN. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Infant leukemia and parental infertility or its treatment: a Children's Oncology Group report

2010 ◽  
Vol 25 (6) ◽  
pp. 1561-1568 ◽  
Author(s):  
S. E. Puumala ◽  
L. G. Spector ◽  
M. M. Wall ◽  
L. L. Robison ◽  
N. A. Heerema ◽  
...  
Keyword(s):  
Oncology Group ◽  
Group Report ◽  
Infant Leukemia

FLT3-Targeted Therapy Selectively Kills MLL-Rearranged Infant and Childhood ALL Blasts In Vitro and in Vivo.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 686-686 ◽  
Author(s):  
Patrick Brown ◽  
Obdulio Piloto ◽  
Mark Levis ◽  
Sheila Shurtleff ◽  
Dario Campana ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Targeted Therapy ◽  
Cell Lines ◽  
Gene Rearrangements ◽  
Human Leukemia ◽  
Childhood All ◽  
Activating Mutations ◽  
Mll Gene ◽  
Flt3 Expression

Abstract The FLT3 receptor tyrosine kinase has been convincingly implicated in the pathogenesis of human leukemia. In childhood acute lymphoblastic leukemia (ALL), FLT3 is expressed in 94% of B-lineage disease and 32% of T-lineage disease. Co-expression of FLT3 ligand (FL) may frequently occur in these cases, as we have observed constitutive activation of the wild type receptor in cell lines and primary samples. A smaller percentage of ALL cases harbor activating mutations of FLT3. Cases of ALL with MLL gene rearrangements are common among infants less than 1 year of age, and have a distinctly poor prognosis, with overall survival rates of approximately 20%. Gene expression studies have revealed that these cases express the highest levels of FLT3, and activating mutations of FLT3 also occur in 18% of MLL-rearranged ALL. We hypothesized that inhibition of FLT3 signaling would be selectively cytotoxic to ALL blasts with high levels of FLT3 expression, particularly if MLL rearrangements were present. We determined the anti-leukemic activity of CEP-701, a potent (IC50=3 nM) and selective small molecule FLT3 inhibitor, in 36 bone marrow samples obtained at diagnosis from infants and children with various subtypes of ALL. FLT3 expression level was determined by RNA microarray analysis or by FLT3 immunoprecipitation and immunoblotting, and FLT3 mutation status was determined by PCR analysis. MTT cytotoxicity assays and annexin V binding apoptosis assays were performed on all samples. CEP-701 induced more pronounced cytotoxicity at all six dose levels (5–100 nM) in samples that expressed high levels of FLT3 (N=23) compared to samples with low levels of expression (N=13). At 50 nM, for example, the MTT mean optical density was 45% that of untreated control in the FLT3 high group vs. 84% in the FLT3 low group (P<0.0001). Cytotoxicity was particularly pronounced in samples with MLL gene rearrangements (N=11, P=0.0006). Seven samples (five with MLL rearrangements) that were sensitive to CEP-701, and six samples that were resistant (none with MLL rearrangements), were examined by FLT3 immunoprecipitation and immunoblotting. All seven sensitive samples demonstrated constitutively phosphorylated FLT3 that was potently inhibited by CEP-701. Conversely, 0 of 6 resistant samples expressed constitutively phosphorylated FLT3. To assess the in vivo activity of FLT3-targeted therapy for MLL-rearranged ALL, six week old NOD/SCID mice were injected with MLL-rearranged primary infant leukemia blasts. Mice were treated with vehicle control, CEP-701 or EB10 (a fully humanized anti-FLT3 monoclonal antibody) for 14 weeks. Bone marrow was then harvested and assessed for engraftment of human cells. Inhibition of engraftment was achieved in the CEP-701-treated mice (mean engraftment 45%, N=5) and EB10-treated mice (mean engraftment 28%, N=4) compared to vehicle controls (mean engraftment 96%, N=9). Finally, in cytotoxicity and apoptosis assays utilizing MLL-rearranged cell lines and primary blast samples, schedule-dependent synergy between CEP-701 and several chemotherapy agents active in ALL was demonstrable, including doxorubicin, dexamethasone, l-asparaginase, etoposide, vincristine and cytarabine. We conclude that FLT3-targeted therapy is a promising novel approach to the treatment of MLL-rearranged ALL, a disease with dismal prognosis with current treatment approaches. Clinical testing is warranted.

Genetic and Clinical Characterization of 45 Acute Leukemia Patients with MLL Gene Rearrangements From a Single Institution.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2477-2477
Author(s):  
Nuno Cerveira ◽  
Susana Lisboa ◽  
Cecília Correia ◽  
Susana Bizarro ◽  
Joana Santos ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Acute Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Consecutive Series ◽  
Gene Rearrangements ◽  
Fusion Partner ◽  
Older Children ◽  
Single Institution ◽  
Mll Gene

Abstract Abstract 2477 Background: MLL gene rearrangements are found in more than 70% of the cases of infant leukemia, both acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML), but are less frequent in leukemia from older children. MLL translocations are also found in approximately 10% of adult AML and in a small proportion of patients with therapy-related leukemia. Independently of their association with other high-risk features at presentation, MLL rearrangements are in most cases predictive of poor clinical outcome. In this study, we report the clinical characterization and frequency and type of MLL rearrangements present in a consecutive series of 45 patients that were diagnosed with acute leukemia in the Portuguese Oncology Institute, Porto, Portugal, over the last 13 years (1998–2011). Patients and Methods: Conventional cytogenetic, fluorescence in situ hybridization (FISH), and molecular genetic studies (RT-PCR and LDI-PCR) were used to characterize the type and frequency of MLL rearrangements in a consecutive series of 45 Portuguese patients with MLL-related leukemia treated in a single institution between 1998 and 2011. Additionally, a detailed patient clinical characterization was also performed and statistical analysis using the Kaplan-Meier method as used to evaluate patient survival. Results: In 43 patients (96% of the cases) we could identify the fusion partner, the most common being the MLLT3, AFF1, MLLT1, MLLT10, ELL, and MLLT4 genes, accounting for 88% of all cases. In the group of patients with acute lymphoblastic leukemia and an identified MLL fusion partner, 47% showed the presence of an MLL-AFF1 fusion, as a result of a t(4;11). In the remaining cases, a MLL-MLLT3 (27%), a MLL-MLLT1 (20%), or MLL-MLLT4 (7%) rearrangement was found. The most frequent rearrangement found in patients with acute myeloblastic leukemia was the MLL-MLLT3 fusion (42%), followed by MLL-MLLT10 (23%), MLL-MLLT1 (8%), MLL-ELL (8%), MLL-MLLT4 (4%), and MLL-MLLT11 (4%). In three patients, fusions involving MLL and a septin family gene (SEPT2, SEPT6, and SEPT9), were identified. The most frequently identified chromosomal rearrangements were reciprocal translocations, but insertions and deletions, some cryptic, were also observed. In our series, patients with MLL rearrangements were shown to have a poor prognosis, regardless of leukemia subtype and treatment protocol. However, patients that received a bone marrow transplant had a better survival than patients that received chemotherapy alone. Interestingly, children with 1 year or less showed a statistically significant better overall survival when compared with both older children and adults. Conclusions: The use of a combined strategy in the initial genetic evaluation of acute leukemia patients allowed us to characterize the pattern of MLL rearrangements in our institution, including our previous discovery of two novel MLL fusion partners, the SEPT2 and CT45A2 genes, and a very rare MLL-MLLT4 fusion variant. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Excess congenital non-synonymous variation in leukemia-associated genes in MLL− infant leukemia: a Children’s Oncology Group report

Leukemia ◽  
2013 ◽  
Vol 28 (6) ◽  
pp. 1235-1241 ◽  
Author(s):  
M C Valentine ◽  
A M Linabery ◽  
S Chasnoff ◽  
A E O Hughes ◽  
C Mallaney ◽  
...  
Keyword(s):  
Oncology Group ◽  
Group Report ◽  
Infant Leukemia

FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 812-820 ◽  
Author(s):  
Patrick Brown ◽  
Mark Levis ◽  
Sheila Shurtleff ◽  
Dario Campana ◽  
James Downing ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Gene Rearrangements ◽  
Childhood All ◽  
Activating Mutations ◽  
Mll Gene ◽  
Flt3 Inhibitor ◽  
Targeted Agent

AbstractFMS-like tyrosine kinase 3 (FLT3) is almost universally expressed in B-precursor childhood acute lymphoblastic leukemia (ALL). Cases of ALL with MLL gene rearrangements and those with high hyperdiploidy (&gt; 50 chromosomes) express the highest levels of FLT3, and activating mutations of FLT3 occur in 18% of MLL-rearranged and 28% of hyperdiploid ALL cases. We determined the antileukemic activity of CEP-701, a potent and selective FLT3 inhibitor, in 8 ALL cell lines and 39 bone marrow samples obtained at diagnosis from infants and children with various subtypes of ALL. CEP-701 induced pronounced apoptotic responses in a higher percentage of samples that expressed high levels of FLT3 (74%, n = 23) compared with samples with low levels of expression (8%, n = 13; P = .0003). Sensitivity to FLT3 inhibition was particularly high in samples with MLL gene rearrangements (82%, n = 11; P = .0005), high hyperdiploidy (100%, n = 5; P = .0007), and/or FLT3 mutations (100%, n = 4; P = .0021). Seven of 7 sensitive samples examined by immunoblotting demonstrated constitutively phosphorylated FLT3 that was potently inhibited by CEP-701, whereas 0 of 6 resistant samples expressed constitutively phosphorylated FLT3. We conclude that the FLT3 inhibitor CEP-701 effectively suppresses FLT3-driven leukemic cell survival. Clinical testing of CEP-701 as a novel molecularly targeted agent for the treatment of childhood ALL is warranted.

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