Intensified chemotherapy without SCT in infant ALL: Results from COG P9407 (Cohort 3)

Dreyer, ZoAnn E.; Hilden, Joanne M.; Jones, Tamekia L.; Devidas, Meenakshi; Winick, Naomi J.; Willman, Cheryl L.; Harvey, Richard C.; Chen, I‐Ming; Behm, FG; Pullen, Jeanette; Wood, Brent L.; Carroll, Andrew J.; Heerema, Nyla A.; Felix, Carolyn A.; Robinson, Blaine W.; Reaman, Gregory H.; Salzer, Wanda L.; Hunger, Stephen P.; Carroll, William L.; Camitta, Bruce M.

doi:10.1002/pbc.25322

Cited by 60 publications

(64 citation statements)

References 42 publications

(72 reference statements)

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“…Cooperative studies showed long-term EFS of less than 50%751). Important prognostic factors found in these studies include the presence of MLL rearrangement, hyperleukocytosis, age less than three to six months, and poor response to prednisone prophase as having a clear adverse impact on outcome.…”

Section: Treatment Of Specific Subgroupsmentioning

confidence: 99%

Prognostic factors and treatment of pediatric acute lymphoblastic leukemia

Lee

Cho

2017

Korean J Pediatr

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The event-free survival (EFS) for pediatric acute lymphoblastic leukemia (ALL) has shown remarkable improvement in the past several decades. In Korea also, a recent study showed 10-year EFS of 78.5%. Much of the improved outcome for pediatric ALL stems from the accurate identification of prognostic factors, the designation of risk group based on these factors, and treatment of appropriate duration and intensity according to risk group, done within the setting of cooperative clinical trials. The schema of first-line therapy for ALL remains mostly unchanged, although many groups have now reported on the elimination of cranial irradiation in all patients with low rates of central nervous system relapse. Specific high risk subgroups, such as Philadelphia chromosome-positive (Ph+) ALL and infant ALL continue to have significantly lower survival than other ALL patients. The introduction of tyrosine kinase inhibitors into therapy has led to enhanced outcome for Ph+ ALL patients. Infant ALL patients, particularly those with MLL rearrangements, continue to have poor outcome, despite treatment intensification including allogeneic hematopoietic cell transplantation. Relapsed ALL is a leading cause of mortality in pediatric cancer. Recent advances in immunotherapy targeting the CD19 of the ALL blast have shown remarkable efficacy in some of these relapsed and refractory patients. With improved survival, much of the current focus is on decreasing the long-term toxicities of treatment.

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Section: Treatment Of Specific Subgroupsmentioning

confidence: 99%

Prognostic factors and treatment of pediatric acute lymphoblastic leukemia

Lee

Cho

2017

Korean J Pediatr

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“…36 The Children's Oncology Group (COG) in North America also showed in the COG P9407 study that an EFS of 43.8% was achieved for infants >90 days old at onset of MLL-r ALL with only chemotherapy. 13 Given the experience in Europe and North America, a strategy omitting the indication of allogeneic hematopoietic stem cell transplantation (HSCT) but with the introduction of the Interfant induction followed by COG post-remission chemotherapy for MLL-r infants ≥6 months old without CNS involvement, is currently being evaluated in the Japanese nationwide MLL-10 Treatment progress in infant ALL 813 trial (UMIN000004801) conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG).…”

Section: Chemotherapymentioning

confidence: 99%

“…[2][3][4][5] The progress in the treatment of infant ALL (diagnosed at age <12 months), however, is lagging behind compared with the treatment of children ≥1 year: EFS and OS remain at 41.7-50.9% and 44.8-60.5%, respectively (Table 1). 9,[11][12][13] In this review, advances in the pathobiology and clinical management of ALL in infants is described. …”

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confidence: 99%

Recent progress in the treatment of infant acute lymphoblastic leukemia

Tomizawa

2015

Pediatrics International

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Treatment of infants with acute lymphoblastic leukemia (ALL), especially those with mixed lineage leukemia (MLL) rearrangement (MLL-r), which account for approximately 80% of cases, is still a major challenge for pediatric hematologists and oncologists worldwide. Continuing efforts by collaborative clinical study groups in Europe, North America, and Japan have rescued approximately half of the MLL-r ALL patients with intensive chemotherapy with or without allogeneic hematopoietic stem cell transplantation. Recent progress has clarified the unique mechanism of MLL-r ALL: the aberrant methylation and histone modifications via DOT1L and other related molecules by MLL fusion proteins lead to leukemogenetic gene expression, thus to overt leukemia. In order to overcome this dismal subtype of ALL, novel targeted therapy based on leukemia biology is urgently needed. Due to the extreme rarity of the disease, collaboration between the study groups in Europe (Interfant), North America (Children's Oncology Group), and Japan (Japanese Pediatric Leukemia/Lymphoma Study Group) is under way.Key words acute lymphoblastic leukemia, epigenetics, hematopoietic stem cell transplantation, infant, mixed lineage leukemia.Acute lymphoblastic leukemia (ALL), a malignant disorder of lymphoid progenitor cells, is the most common type of malignant neoplasms in children and adolescents, with approximately 444-532 cases diagnosed annually in Japan. 1 Optimal use of "old drugs", developed between the 1950s and 1970s under successive collaborative clinical trials, has improved the outcome of childhood ALL to achieve an event-free survival (EFS) rate of 80.4-87.2% and an overall survival (OS) rate of 91.8-93.5% in recently completed clinical trials. [2][3][4][5] The progress in the treatment of infant ALL (diagnosed at age <12 months), however, is lagging behind compared with the treatment of children ≥1 year: EFS and OS remain at 41.7-50.9% and 44.8-60.5%, respectively (Table 1). 9,[11][12][13] In this review, advances in the pathobiology and clinical management of ALL in infants is described. Epidemiology and characteristicsInfant ALL accounts for <5% of childhood ALL, with 20-25 new cases diagnosed annually in Japan. In children ≥1 year, ALL comprises 75-80% of all childhood leukemia because of the high peak incidence of B-lineage ALL between the age of 2 and 5 years, with a predominance in boys. In contrast, the incidence of ALL in infants is the same as that of acute myeloid leukemia (AML), with a slight predominance in girls. 1,11 Biologically and clinically, infant ALL consists of two distinct subtypes: one involves rearrangements of mixed lineage leukemia (MLL also called KMT2A), which accounts for approximately 80% of infant ALL; and the other with germline MLL. Infant ALL with rearranged MLL (MLL-r) is a highly aggressive leukemia with high white blood cell (WBC) count and frequent involvement of extramedullary sites including the central nervous system (CNS) at diagnosis. 9,11 In addition, MLL-r ALL has a very immature CD10-ne...

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“…Infant MLL-r ALL is often aggressive, and the outcomes remain poor despite intensified chemotherapy or allogeneic hematopoietic stem cell transplantation (74,75). The MLL (KMT2A) gene is a histone methyltransferase located on chromosome 11q23.…”

Section: Infant Mll-r Allmentioning

confidence: 99%

Dysregulation of BCL-2 family proteins by leukemia fusion genes

Brown

Hanna

Khaw

et al. 2017

Journal of Biological Chemistry

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The genomic lesions that characterize acute lymphoblastic leukemia in childhood include recurrent translocations that result in the expression of fusion proteins that typically involve genes encoding tyrosine kinases, cytokine receptors, and transcription factors. These genetic rearrangements confer phenotypic hallmarks of malignant transformation, including unrestricted proliferation and a relative resistance to apoptosis. In this Minireview, we discuss the molecular mechanisms that link these fusions to the control of cell death. We examine how these fusion genes dysregulate the BCL-2 family of proteins, preventing activation of the apoptotic effectors, BAX and BAK, and promoting cell survival. Recurrent fusion genes in acute lymphoblastic leukemiaAcute lymphoblastic leukemia (ALL) 2 is the most common form of childhood malignancy. Therapy for ALL is one of the great success stories of modern chemotherapy, and overall cure rates are now Ͼ90% in developed countries, depending on molecular subtypes and clinical features (1). The extraordinary improvements in outcomes in ALL have unquestionably been driven by the treatment of patients on international collaborative clinical trials (2), which have made it possible to rapidly recruit sufficient numbers of patients to studies of new treatment regimes. The analysis of treatment responses, based on measurement of minimal residual disease, has allowed the early identification of treatment failure or relapse and the consequent adjustment of treatment intensity.The next revolution in our understanding of ALL biology is being driven by many studies, involving thousands of patient samples, characterizing the genomic landscape of ALL through genome and transcriptome sequencing (3-7). This has led to the recognition of novel molecular subtypes of ALL, defined by the genomic lesions that drive them. Characterization of leukemic genomes provides insight into the key molecular pathways involved in ALL subtypes.Many recently identified genomic lesions in ALL are fusion genes, arising from chromosomal translocations (8). These include fusions that activate tyrosine kinases, cytokine receptors, and transcription factors. The presence of these fusions has important prognostic and treatment implications. In this Minireview, we consider how these genomic lesions promote resistance to apoptosis in ALL. Gene fusions in ALLChromosomal translocations, resulting in the expression of fusion genes, are a hallmark of B-cell malignancies. This likely arises as fusion partners are mistakenly juxtaposed during periods of genomic editing and recombinase-activating gene (RAG1 and RAG2) activation or somatic hypermutation during B-cell development (9). Recurrent chromosomal translocations have been recognized and detected in ALL, initially by staining of metaphases and microscopy, and more recently by fluorescent in situ hybridization (FISH). The detection of a small number of recurrent translocations is a standard component of ALL diagnosis and risk assessment. For example, t(12;21) ETV6-RUNX1 ...

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Intensified chemotherapy without SCT in infant ALL: Results from COG P9407 (Cohort 3)

Cited by 60 publications

References 42 publications

Prognostic factors and treatment of pediatric acute lymphoblastic leukemia

Prognostic factors and treatment of pediatric acute lymphoblastic leukemia

Recent progress in the treatment of infant acute lymphoblastic leukemia

Dysregulation of BCL-2 family proteins by leukemia fusion genes

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