Comparison of allogeneic transplant versus chemotherapy for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial

Background:Although reinduction rates are good for children withrelapsed acute lymphoblastic leukaemia there is no consensus on whether bonemarrow transplantation (BMT) is the most effective treatment to prolong secondremission. Patients and methods:Analyses comparing the outcome of relateddonor allogeneic BMT (related allograft) with chemotherapy are unreliablebecause of selection biases. To avoid these biases, the MRC UKALL R1 trial wasanalysed by HLA-matched donor availability. Results:No significant difference in outcome was found betweenthe donor and no donor groups. The donor group had a non-significanteight-year event-free survival (EFS) advantage of 8% (95%confidence interval = –9%–24%) over the no donorgroup. Patients with a first remission less than two years appeared to benefitmost from having a donor, although the effect was only marginallysignificantly different from patients with longer first remission. Analysisby treatment received gave similar results, with BMT patients having a5% (P= 0.8) eight-year EFS advantage over patients whoreceived chemotherapy. Conclusions:Related allograft was not found to be significantlybetter than chemotherapy, but there was the possibility of a moderate EFSbenefit with related allograft, especially in patients with a short firstremission.     

Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database

BACKGROUND:

Sarcoma is the index diagnosis of Li‐Fraumeni syndrome (LFS), a familial predisposition to cancer that also includes brain cancer, breast cancer, and adrenal cortical carcinoma. Germline mutations in the TP53 gene are detected in approximately 80% of families that fulfill LFS criteria and in 15% to 25% of families that fulfill criteria for Li‐Fraumeni‐like syndrome (LFS), a group of related syndromes with broader clinical criteria.

METHODS:

The authors of this report used the International Agency for Research on Cancer TP53 database to analyze the types, age at onset and mutation patterns of sarcoma in TP53 mutation carriers. Those data were compared with sarcoma types in the general population of Caucasians using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program.

RESULTS:

Overall, sarcomas represented 25% of tumors in TP53 mutation carriers, and 95.6% occurred before age 50 years compared with 38.3% before age 50 years in the SEER data set. Sarcomas were more likely to be rhabdomyosarcoma in carriers aged <5 years (odds ratio [OR], 11.6; 95% confidence interval [CI], 6.1‐21.9) and osteosarcoma in carriers at any age (aged <20 years: OR, 1.41; 95% CI, 1.02‐1.94; age >20 years: OR, 4.61; 95% CI, 2.72‐7.83). Early sarcoma (at age <20 years) was associated with missense mutations in exons encoding the DNA‐binding domain of p53 protein. Conversely, p53 null mutations (frameshift, splice sites, nonsense) and mutations outside the DNA‐binding domain were associated with leiomyosarcoma (OR, 10.1; 95% CI, 3.4‐29.9), a type of sarcoma that occurred after age 20 years.

CONCLUSIONS:

The current results further demonstrated genotype‐phenotype correlations and age‐dependent variations in sarcoma types in carriers of germline TP53 mutations. Cancer 2012;. © 2011 American Cancer Society.     

Glucocorticoid receptor in childhood acute lymphoblastic leukemia

Glucocorticoid(GC)hasbeenusedinthetreatmentofchildhoodacutelymphoblasticleukenda(ALL)formanyyears.IthasprovedthattheeffectofGCismediatedthroughaglucocortic0idreceptor(GCR)ofthetargetcell.[1]Therefore,manyexpertshaveconcentratdtheirattentiononGCR,butthereisnoreportonthestudyofGCRinchildho0dALLinChina.InununologicalclassificationofALLmaydifferentiatethecelloriginandclustersofdifferentiation(CD)inleukendacell.Itisoneoftheimportantindicatorstoguidecombinationchemotherapyandt0makeapr0gnos…     

Unusual extramedullary relapse of acute lymphoblastic leukemia in a bone marrow transplant patient

An unusual form of relapse of acute lymphoblastic leukemia is described in a woman who developed a solitary large focal mass of lymphoblasts in her liver and an isolated polypoid lymphoblastic mass in her uterus after bone marrow transplantation, despite continued marrow remission. Extramedullary visceral leukemic relapse in the form of such discreet focal masses is highly unusual and to our knowledge has not been described in this setting. Awareness and recognition of atypical forms of relapse are important since such a diagnosis carries critical therapeutic and prognostic implications.     

Mutation of the TP53 gene in acute lymphoblastic leukemia does not affect survival outcomes after haploidentical hematopoietic stem cell transplantation

Previous studies have demonstrated that TP53 mutation is correlated with insufficient therapy response and unfavorable prognosis in acute lymphoblastic leukemia (ALL). Few studies have investigated the impact of TP53 mutation in ALL patients after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We completed a retrospective study of 65 ALL patients with available TP53 status who underwent haplo-HSCT. They were divided into a TP53 mutation group (TP53^mut) and a TP53 wild-type (TP53^wt) group. TP53^mut showed comparable 2-year cumulative incidence of relapse (CIR) rates (13.1% vs 12.5%, P = .96) and 2-year leukemia-free survival (LFS) (74.2% vs 77.4%, P = .80) with TP53^wt. No significant differences in 2-year overall survival (OS) rates (82.9% vs 87.3%, P = .61) or 2-year NRM rates (12.7% vs 10.2%, P = .69) were observed in TP53^mut and TP53^wt patients. Multivariate analysis suggested that white blood cell (WBC) count at initial diagnosis (>50 × 10⁹/L: hazard ratio [HR] = 3.860, P = .016) and age (>40 years old: HR = 4.120, P = .012) are independent risk factors for 2-year LFS. Our study showed that TP53 mutations may not be related to the unfavorable impact on survival in ALL patients after treatment with haplo-HSCT. The present results suggested that haplo-HSCT may eliminate the poor prognosis effect of TP53 mutation in ALL.     

Prognostic value of BCL2 and TP53 genetic alterations for diffuse large B-cell lymphoma patients treated with R-CHOP

Objective:Limited data about the prognostic significance of BCL2 mutations and BCL2 copy number variations in diffuse large B-cell lymphoma (DLBCL) are available. This study aimed to comprehensively describe BCL2 genetic alterations in DLBCL patients, and examine correlation of BCL2, TP53 and other genetic alterations with outcomes in patients treated with R-CHOP.Methods:Probe capture-based high-resolution sequencing was performed on 191 patients diagnosed with de novo DLBCL. MYC, BCL2, and BCL6 protein expressions were detected by immunohistochemistry.Results:The presence of BCL2 alterations significantly correlated with poor progression-free survival (PFS) (5-year PFS: 13.7% vs. 40.8%; P = 0.003) and overall survival (OS) (5-year OS: 34.0% vs. 70.9%; P = 0.036). Importantly, patients who harbored BCL2 gain/amplifications (BCL2^GA/AMP) also had a remarkably inferior 5-year PFS (11.1% vs. 38.3%; P < 0.001) and OS (22.1% vs. 69.6%; P = 0.009). In contrast, neither BCL2 mutations nor BCL2 translocations were significantly prognostic for survival. Multivariable analyses showed that the presence of BCL2 alterations, especially BCL2^GA/AMP, TP53 mutations, and International Prognostic Index (IPI) were significantly associated with inferior PFS and OS. Novel prognostic models for OS were constructed based on 3 risk factors, including BCL2 alterations (Model 1) or BCL2^GA/AMP (Model 2), TP53 mutations, and IPI, to stratify patients into 4 risk groups with different survival outcomes.Conclusions:This study showed that DLBCL patients treated with R-CHOP, BCL2 alterations, especially BCL2^GA/AMP and TP53 mutations were significantly associated with inferior outcomes, which were independent of the IPI. The novel prognostic models we proposed predicted outcomes for DLBCL patients treated with R-CHOP, but further validation of the prognostic models is still warranted.     

Allelotype analysis in relapsed childhood acute lymphoblastic leukemia

We performed for the first time the allelotype of relapsed childhood acute lymphoblastic leukemia (ALL). A total of 38 cases were screened for loss of heterozygosity (LOH) using 71 markers. In all, 26 (68%) patients showed LOH on at least one chromosomal arm, indicating that LOH is a frequent event at relapse. The most frequent loss was found on chromosomal arm 9p at the p16/INK4a locus (39%). LOH at the TEL gene locus on chromosomal arm 12p also occurred often (25%). Frequent loss was observed on chromosome arms 4q (20%), 6q (21%), and 17q (20%). Sequential analysis (i.e. samples obtained from both initial diagnosis and relapse) shows that some patients (63%) have the identical LOH status at both phases, suggesting the presence of the same clone. Other samples (37%) showed distinct LOH alterations, indicating clonal evolution at relapse. Despite the heterogeneous and complex changes, some shared LOH loci occurred in these matched samples, suggesting that many of the same tumor-suppressor genes are aberrant at both phases. In summary, novel tumor-suppressor genes on chromosome arms 4q, 6q, and 17q, as well as the p16 and TEL genes, have an important role in the relapse of childhood ALL.     

Testicular relapse in acute childhood leukemia

The successful induction and maintenance of hematologic remission in childhood acute leukemia has led to the recognition of extramedullary leukemia as a major clinical problem [1–6]. The central nervous system is the most common site of extramedullary relapse [1,7–12], A more recently recognized form of extramedullary relapse is the testis [13–22]. This paper will review a series of patients with childhood acute leukemia who suffered testicular relapse. Modes of therapy for testicular relapse and research conducted into the etiology of testicular relapse will be discussed.     

Clofarabine for the treatment of acute lymphoblastic leukemia

A marked improvement in the outcome of patients with acute lymphoblastic leukemia has been achieved with chemotherapeutic agents developed between the 1950s and 1970s. As the limits of optimizing the use of old drugs are reached, most adults with acute lymphoblastic leukemia still succumb to their disease and leukemia remains the leading cause of nonaccidental death in children. Salvage regimens, based mostly on different combinations of the same agents used in front-line therapy, carry a high incidence of morbidity and dismal long-term survival rates. New therapeutic strategies are needed. Clofarabine, a next-generation deoxyadenosine analog, has demonstrated significant activity in children and adults with refractory lymphoid and myeloid leukemia in early clinical trials and was granted approval for use in children with acute lymphoblastic leukemia in second or higher relapse. This is the only anticancer drug to receive primary indication for use in children over the past decade. Ongoing studies are exploring the benefit of clofarabine combinations in less heavily pretreated patients and the use of different dose schedules in a variety of hematological malignancies.     

Germline TP53 alterations in Finnish breast cancer families are rare and occur at conserved mutation-prone sites

We have screened for germline TP53 mutations in Finnish BRCA1 and BRCA2 mutation-negative families. This study represents the largest survey of the entire protein-encoding portion of TP53, and indicates that mutations are only found at conserved domains in breast cancer families also meeting the criteria for Li-Fraumeni/Li-Fraumeni-like syndrome, explaining only a very small additional fraction of the hereditary breast cancer cases.     

Outcome of children treated for relapsed acute lymphoblastic leukemia in Central America

BACKGROUND:

Outcomes for relapsed childhood acute lymphoblastic leukemia (ALL) have not been documented in resource‐limited settings. This study examined survival after relapse for children with ALL in Central America.

METHODS:

A retrospective cohort study was performed and included children with first relapse of ALL in Guatemala, Honduras, or El Salvador between 1990 and 2011. Predictors of subsequent event‐free survival (EFS) and overall survival (OS) were examined.

RESULTS:

There were 755 children identified with relapsed disease. The median time from diagnosis to relapse was 1.7 years (interquartile range, 0.8‐3.1 years). Most relapses occurred during (53.9%) or following (24.9%) maintenance chemotherapy, and the majority occurred in the bone marrow (63.1%). Following the initial relapse, subsequent 3‐year EFS (± standard error) and OS were 22.0% ± 1.7%, and 28.2% ± 1.9%, respectively. In multivariable analysis, worse postrelapse survival was associated with age ≥ 10 years, white blood cell count ≥ 50 × 10⁹/L, and positive central nervous system status at the original ALL diagnosis, relapse that was not isolated central nervous system or testicular, and relapse < 36 months following diagnosis. Site and time to relapse were used to identify a favorable risk group whose 3‐year EFS and OS were 50.0% ± 8.9% and 68.0% ± 8.1%, respectively.

CONCLUSIONS:

Prognosis after relapsed ALL in Central America is poor, but a substantial number of those with favorable risk features have prolonged survival, despite lack of access to stem cell transplantation. Stratification by risk factors can guide therapeutic decision‐making. Cancer 2013. © 2012 American Cancer Society.     

Role of CXCL12, TP53 and CYP1A1 gene polymorphisms in susceptibility to pediatric acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common type of childhood leukemia and represents one third of all pediatric malignancies. Epidemiological studies have shown that various genetic factors play a crucial role in leukemogenesis. Recent genetic association studies on cancer risk have focused on the effects of single-nucleotide polymorphisms (SNPs) in genes that regulate inflammation and tumor suppression, such as chemokines, TP53 and cytochrome P450s (CYPs). Genetic polymorphisms in the 3′ untranslated region of the C-X-C motif chemokine ligand 12 (CXCL12; rs1801157) and TP53 (rs1042522) genes have been suggested to influence the risk of ALL in children, while other studies have indicated an association between the CYP1 subfamily A member 1 (CYP1A1)*2C (rs1048943) allele and leukemia risk. The aim of the present study was to investigate the possible association of rs1801157 (CXCL12), rs1042522 (TP53) and rs1048943 (CYP1A1*2C) SNPs with an increased susceptibility of developing ALL. These SNPs were analyzed in 86 children or adolescent patients with ALL and 125 control subjects by PCR-restriction fragment length polymorphism and allelic-specific chain reaction techniques. A higher frequency of CYP1A1*2C heterozygotes and TP53 rare homozygotes, which include the proline (Pro)/Pro genotype, was observed among children with ALL and control subjects, whereas no significant differences were observed for the CXCL12 SNP. Furthermore, the analysis of various allelic combinations of the aforementioned gene polymorphisms demonstrated a markedly increased risk of developing ALL in children. In conclusion, the present study demonstrated that there was a strong association between CYP1A1*2C heterozygotes, as well as the TP53 Pro/Pro genotype, and an increased susceptibility for pediatric ALL in Caucasians.     

Cytogenetic analysis in relapsed childhood acute lymphoblastic leukemia.

The nature of the cytogenetic abnormalities present at relapse of childhood acute lymphoblastic leukemia (ALL) and their relationship to the disease and the karyotype at diagnosis have not been clearly defined. This report describes cytogenetic analyses of 50/51 consecutive relapsed childhood ALL patients. Evolution of the karyotype was common, with structural abnormalities particularly frequent. Rearrangements involving chromosome 1 occurred frequently, particularly in patients with greater than 50 chromosomes. In patients with less than or equal to 50 chromosomes, structural aberrations were often unbalanced, leading to loss of genetic material, but these did not show a predominance of chromosome 1 abnormalities. These differences among the cytogenetic groups of ALL are an indication that the chromosomal abnormalities occurring in ALL reflect different biological events underlying this disease, and that different biological processes are involved in the several cytogenetic groups of ALL patients not only at initiation, but also during the progression and evolution of the disease.     

TP53 mutation and survival in aggressive B cell lymphoma

TP53 is mutated in 20–25% of aggressive B‐cell lymphoma (B‐NHL). To date, no studies have addressed the impact of TP53 mutations in prospective clinical trial cohorts. To evaluate the impact of TP53 mutation to current risk models in aggressive B‐NHL, we investigated TP53 gene mutations within the RICOVER‐60 trial. Of 1,222 elderly patients (aged 61–80 years) enrolled in the study and randomized to six or eight cycles of CHOP‐14 with or without Rituximab (NCT00052936), 265 patients were analyzed for TP53 mutations. TP53 mutations were demonstrated in 63 of 265 patients (23.8%). TP53 mutation was associated with higher LDH (65% vs. 37%; p < 0.001), higher international prognostic index‐Scores (IPI 4/5 27% vs. 12%; p = 0.025) and B‐symptoms (41% vs. 24%; p = 0.011). Patients with TP53 mutation were less likely to obtain a complete remission CR/CRu (CR unconfirmed) 61.9% (mut) vs. 79.7% (wt) (p = 0.007). TP53 mutations were associated with decreased event‐free (EFS), progression‐free (PFS) and overall survival (OS) (median observation time of 40.2 months): the 3 year EFS, PFS and OS were 42% (vs. 60%; p = 0.012), 42% (vs. 67.5%; p < 0.001) and 50% (vs. 76%; p < 0.001) for the TP53 mutation group. In a Cox proportional hazard analysis adjusting for IPI‐factors and treatment arms, TP53 mutation was shown to be an independent predictor of EFS (HR 1.5), PFS (HR 2.0) and OS (HR 2.3; p < 0.001). TP53 mutations are independent predictors of survival in untreated patients with aggressive CD20+ lymphoma. TP53 mutations should be considered for risk models in DLBCL and strategies to improve outcome for patients with mutant TP53 must be developed.     

MicroRNA expression profiles discriminate childhood T‐ from B‐acute lymphoblastic leukemia

MicroRNAs (miRNAs) play a critical role on biological and cellular processes; the search for functional markers may be of importance for differential diagnosis, prognosis, and development of new therapeutic regimens. In this context, we evaluated the bone marrow miRNA profile of Brazilian children exhibiting T‐ or B‐cell acute lymphoblastic leukemia (T‐ALL or B‐ALL), using massive parallel sequencing, using the HiSeq 2500 platform (Illumina). The differential expression analysis was conducted considering a leave‐one‐out approach and FDR ≤ 0.05. Machine learning algorithms were applied to search for the disease subset biomarkers. Target prediction, functional enrichment, and classification of biological categories were also performed. Sixteen miRNAs were differentially expressed between T‐ and B‐ALL, of which 10 (miR‐708‐5p, miR‐497‐5p, miR‐151a‐5p, miR‐151b, miR‐371b‐5p, miR‐455‐5p, miR‐195‐5p, miR‐1266‐5p, miR‐574‐5p, and miR‐425‐5p) were downregulated and six (miR‐450b‐5p, miR‐450a‐5p, miR‐542‐5p, miR‐424‐5p, miR‐629‐5p, and miR‐29c‐5p) were upregulated in childhood T‐ALL. These miRNAs may be used for distinguishing childhood lymphoblastic leukemia subtypes, since it provided the clear separation of patients in these two distinct groups. Six relevant biological pathways were identified according to their role in leukemia, namely, viral carcinogenesis, cell cycle, and B‐cell receptor signaling pathways for induced miRNAs and TGF‐beta signaling, apoptosis, and NF‐kappa B signaling for the repressed miRNAs, of which several miRNA gene targets participate in cell differentiation and hematopoiesis processes. Machine learning analysis pointed out miR‐29c‐5p expression as the best discriminator between childhood T‐ and B‐ALL, which is involved in calcium signaling, critical for B‐cell lymphocyte fate. Further studies are needed to assure the role of the 16 miRNAs and miR‐29c‐5p on acute lymphoblastic leukemia subtypes and on disease prognosis.