Infantile Acute Lymphoblastic Leukemia Research Articles

Endocrine late effects in survivors of infantile acute lymphoblastic leukemia.

Infantile acute lymphoblastic leukemia (ALL) is a rare disease. In survivors, endocrine late effects, such as growth disorder and hypothyroidism, have been reported, but gonadal function remains unclear. Infantile ALL frequently requires transplantation and higher doses of alkylating agents, even in the absence of transplantation. Some studies in childhood cancer survivors reported that a cyclophosphamide equivalent dose (CED) of > 20 g/m2 was associated with testosterone deficiency in boys and > 8 g/m2 with ovarian dysfunction in girls. We retrospectively reviewed the treatment and endocrine function of 6 infantile ALL survivors treated at our hospital using their medical records. The patients' age at the time of the study was between 12 and 26 yr. One patient had 0 transplant, four of them had 1 transplant, and one had 2 transplants, with CEDs of 3, 9-11, and 24 g/m2 respectively. Two patients had short stature, and two patients experienced hypothyroidism. All three girls with a CED of 9-11 g/m2 had primary hypogonadism, and the boy with a CED of 24 g/m2 had high LH and FSH levels, suggesting testosterone deficiency and spermatogenesis disorders. In conclusion, gonadal function, growth and thyroid function should be carefully monitored in infantile ALL, and CED may be useful for predicting the development of hypogonadism.

Comparison of Dexamethasone Versus Prednisolone Prephase in Induction Therapy of Pediatric Acute Lymphoblastic Leukemia: A Single-Center, Randomized Controlled Study from India

Background: Acute lymphoblastic leukemia (ALL) is the commonest cancer in children. Despite advances in treatment, approximately 20% of pediatric ALL patients still relapse. Although the use of dexamethasone in induction regimen has been reported to significantly decrease CNS relapse risk & improve event-free survival (EFS) compared to prednisolone, there are concerns of significant toxicities like infection & osteonecrosis with dexamethasone. Objectives: The aim of this single-center randomized study was to compare the efficacy and safety of dexamethasone prephase versus prednisolone prephase during the initial seven days (days 1 - 7) of induction chemotherapy in newly diagnosed pediatric ALL patients treated with ALL IC-BFM 2009 protocol,in terms of day 8 steroid response, day 15 bone marrow minimal residual disease (MRD) response, and day 33 morphological complete remission (CR) rates. Methods: The study enrolled total 62 newly diagnosed pediatric ALL patients (age > 1 year & ≤ 18 years) between June 2019 and April 2021, after obtaining informed consent and with institutional ethics committee approval. Patients with lymphoblastic lymphoma (LBL) and infantile ALL (age < 1 year) were excluded. Patients who were randomized to dexamethasone prephase group received intravenous dexamethasone 10 mg/m2/day on days 1-7 of induction,& those in prednisolone prephase group received prednisolone 60 mg/m2/day p.o. in three divided doses on days 1-7 of induction therapy .All the patients subsequently received prednisolone 60 mg/m2/day p.o. in three divided doses on days 8 - 28 of induction, followed by prednisolone taper over next 7 days. Induction regimen of ALL IC-BFM 2009 protocol was given. The cut-off values for day 15 BM Flow-MRD were <0.1%, 0.1-10%, and >10% as per ALL IC-BFM 2009 protocol. Morphological complete remission on day 33 was defined as bone marrow blasts < 5% of total nucleated cells, with normocellular or mildly hypocellular marrow. Steroid-related toxicities in the two treatment groups were compared as per NCI-CTCAE version 5. Results: Out of total 62 patients, 33 patients (53%) received dexamethasone prephase and 29 patients (47%) received prednisolone prephase. Forty-six patients (75%) had B-cell ALL, and 25% had T-cell ALL. The distribution of patients in standard-risk, intermediate-risk & high-risk groups as per ALL IC-BFM 2009 protocol risk stratification were 18%, 34% and 48% respectively. Twenty-nine out of 33 patients (88%) in dexamethasone prephase group achieved good steroid response on day 8 (peripheral blood absolute blast count < 1000/µl) compared to 17/29 patients (59%) in prednisolone prephase group [p = 0.018]. Day 15 bone marrow MRD assessment by flowcytometry was available in 57 patients (31/33 in dexamethasone prephase group & 26/29 in prednisolone prephase group). Nineteen out of 31 patients (61%) in dexamethasone prephase group achieved day 15 MRD < 0.1% compared to 6/26 patients (23%) in prednisolone prephase group [p = 0.02]. Twenty-eight out of 30 patients (93%) in dexamethasone group achieved morphological CR on day 33 of induction compared to 18/24 patients (75%) in prednisolone prephase group [p = 0.135]. Day 33 bone marrow Flow-MRD < 0.1% in the dexamethasone & prednisolone prephase groups were 82% and 50% respectively [p = 0.12]. At the time of analysis, 3/30 patients (10%) in dexamethasone group who achieved CR has disease relapse, compared to 8/24 patients (33%) in prednisolone prephase group [p = 0.04]. The event-free survival (EFS) at the end of study (18 months) was found to be significantly higher in the dexamethasone prephase group compared to prednisolone prephase group (p = 0.002). The incidence of steroid-related toxicities of any grade was similar in the two treatment groups. Conclusion: In the present study, the replacement of prednisolone with dexamethasone for a relatively shorter duration in the 7-day steroid prephase of ALL IC-BFM 2009 induction regimen was associated with significantly improved day 8 steroid response, day 15 bone marrow Flow-MRD response, day 33 morphological CR rates, and EFS at 18 months, without significant increase in steroid-related toxicity in induction. To our knowledge, this is the only study to compare dexamethasone versus prednisolone prephase in pediatric ALL induction, in the context of ALL IC-BFM 2009 regimen. Long-term follow up and enrollment of larger number of patients is planned. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clofarabine-Based Chemotherapy for KMT2Ar Infantile Acute Lymphoblastic Leukemia

Rearrangements in KMT2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis, with an event-free-survival (EFS) of 33.6-36.9%. In the context of the remarkable improvements in the treatment of childhood ALL, the dismal outcome of infantile KMT2Ar ALL and the lack of any significant progress for more than two decades are striking . The St. Jude Total Therapy 16 study (the most recently reported study of a program for childhood ALL that begun in 1962) yielded a 5-year EFS of 88.2% overall. Total 16 enrolled all subtypes of newly diagnosed pediatric ALL patients including infants, with intensity of treatment adapted to presenting clinical and genomic features, and early treatment response as determined by minimal/measurable residual disease (MRD). KMT2Ar infants were treated on an intensified high-risk arm and received clofarabine in combination with cyclophosphamide and etoposide (CCE) at two points during treatment: Induction days 22-25 and Reinduction I. Infants who lacked KMT2Ar and KMT2Ar patients who were one year of age or older received the same risk-directed treatment plan given to all other patients enrolled on study. A total of 28 patients with KMT2Ar were enrolled on Total 16; the 19 patients > 1 year of age received standard-risk therapy, and the 9 patients < 1 year of age received high-risk therapy on the infant arm with CCE. The probabilities of 5-year EFS and overall survival in KMT2Ar patients > 1 year of age and those < 1 year of age were 73.3% vs. 44.4% (p=0.071) and 84.2% vs. 55.6% (p=0.060), respectively. Six of the nine infants were MRD-positive on Induction day 15 prior to CCE (MRD-positive range, 0.012% to 13.7%; median, 2.13%) with MRD negative status (<0.01%) achieved post CCE in six of the eight patients with data (MRD was 0.011% and 0.07% in the remaining two patients). The trend towards superior outcomes in older KMT2Ar patients was not due to a lower incidence of relapse, as the 5-year cumulative incidence of relapse was 26.7% in patients > 1 year of age and 12.5% for those < 1 year of age (p=0.454). Five infants remain alive (four in CR1, one in CR2), while four expired in CR1. Three deaths were secondary to infection, including a multi-drug resistant soft tissue bacterial infection during Induction days 1-21, a respiratory syncytial virus pneumonia during Reinduction II, and a chronic parainfluenza 3 infection during Continuation weeks 70-101 that led to chronic pneumonitis and interstitial fibrosis. The fourth patient developed grade 5 pulmonary hypertension following induction, a complication potentially compounded by their presenting WBC count of 905 x 10 9/L and pulmonary leukostasis. A comparison of 3-year cumulative risk of selected major toxic effects of treatment revealed that high-risk infants had a lower incidence of asparaginase allergic reactions, osteonecrosis, hyperglycemia, and pancreatitis; in contrast, the incidence of fever and neutropenia, hepatic toxicity and seizures, was similar in high-risk patients regardless of age. Infants had a higher risk of thrombosis (46.7% vs. 23.1%, p<0.001) and of severe infection (70% vs. 19.7%, p<0.001). To further study the contribution of clofarabine to severe infections, we looked at the incidence in high-risk patients > 1 year of age that received one or more clofarabine-containing Reintensification chemotherapy cycles prior to hematopoietic stem cell transplant in first remission (CR1). This revealed a higher frequency of infections in infants, suggesting a greater susceptibility to this complication independent from clofarabine exposure (mean number of episodes, 2.39 vs. 1, p<0.001, Poisson regression modeling). In conclusion, treatment of infants with KMT2Ar ALL with chemotherapy including high-intensity clofarabine leads to a lower cumulative incidence of relapse but a higher risk of treatment-related mortality. Severe infections were a major cause of morbidity and mortality. DisclosuresGruber: Kura Oncology: Consultancy. Coustan-Smith: Juno Therapeutics: Patents & Royalties; Nkarta Therapeutics: Current holder of individual stocks in a privately-held company; Medisix Therapeutics: Current holder of individual stocks in a privately-held company. Campana: Nkarta Therapeutics: Current holder of stock options in a privately-held company; Medisix Therapeutics: Current holder of stock options in a privately-held company; Juno: Other: patent licensing payments; Juno Therapeutics (a Bristol-Myers Squibb company),: Other: patents on methods for minimal residual disease detection.. Evans: St. Jude Children's Research Hospital, Emeritus Member (began Jan 2021): Ended employment in the past 24 months; BioSkryb, Inc.: Membership on an entity's Board of Directors or advisory committees; Princess Máxima Center for Pediatric Oncology, Scientific Advisory Board, Chair: Membership on an entity's Board of Directors or advisory committees. Pui: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Data Monitoring Committee.

Comprehensive Immunophenotyping Panel in Japan Enables to Detect Rare Subtypes in Childhood Leukemia

[Background] Although the development of genome wide screening for risk stratification in childhood leukemia, immunophenotyping is still essential to decide initial treatment because of quick duration to make diagnosis. Immunophenotyping is also very useful to detect rare subtypes in leukemia. From 2011, Japanese pediatric leukemia/lymphoma study group (JPLSG) started nation-wide immunophenotyping with comprehensive panel including more than 50 antigens for childhood hematological malignancy. This panel led easier diagnosis not only for typical leukemia subtypes such as acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML), but for rare subtypes including mixed phenotype acute leukemia (MPAL), acute undifferentiated leukemia (AUL), and blastic plasmacytoid dendritic cell neoplasms (BPDCN). We report here the significance of comprehensive immunophenotyping panel, then clinical manifestations and immunophenotypic peculiarity of rare subtypes in childhood leukemia.[Methods] Immunophenotyping was done with comprehensive panel (Table 1) and diagnosis was done according to WHO 2008 classification. Briefly, determination of lineage was usually decided by major lineage specific markers such as myeloperoxidase (MPO), CD19, and cytoplasmic CD3. Then, more detailed categorization was done by analysis with other lineage, differentiation, or activation markers.[Result] In 4,033 case from January 2012 to December 2016, major immunophenotypes were as follows; B-precursor/pre-B (BCP-) ALL was 2,141, T cell (T-) ALL 348, AML 842, B-ALL 74, Lymphomas 171, transient myeloproliferative disorder (TAM) 244, chornic myelogenous leukemia (CML) 72. Out of other 141 cases, we also found 32 MPAL, 16 AUL, and 7 BPDCN. According to detailed immunophenotyping, MPAL cases could be divided into 3 distinct clusters, T-ALL/ AML-M1 biphenotypic subtype (8 cases), BCP-ALL/AML-M5 bilineal subtype (11), and BCP-ALL with MPO expression subtype (13). Furthermore, distinct cluster, ‘early T cell progenitor ALL (ETP)-like subtype’ was also distinguished from AUL.[Discussion] Acute leukemia of ambiguous lineage and BPDCN are both rare subtypes of acute leukemia. According to WHO 2008 classification, acute leukemia of ambiguous lineage is further classified as MPAL, AUL and natural killer lymphoblastic leukemia. In this study, we evaluate 32 MPAL, 16 AUL and 7 BPDCN. It is of note that we could not identify no natural killer lymphoblastic leukemia in this childhood leukemia cohort. We also evaluate 32 MPAL cases, which showed 3 distinct subgroups. T-ALL oriented cases indicate only one subtype ‘T-ALL/AML-M1 biphenotypic’, which indicated relatively older age, usually diagnosed as AML-M1 with morphologic FAB classification, and received mostly myeloid oriented therapy. BCP-ALL related cases were also divided into two groups, BCP-ALL/AML-M5 bilineal, and BCP-ALL with MPO expression. Bilineal leukemia often found in infantile ALL with MLL gene rearrangement (4 out of 11 cases), but still found 7 older cases without MLL gene rearrangemnt. Bilineal leukemia occasionally cause lineage-switch relapse, so diagnosis of bilineal leukemia seems to be very significant. Recent studies showed leukemia with ZNF384 fusion indicate CD10 negative or low BCP-ALL, and tended to express MPO. Our cases also tended to indicate negative or low CD10 expression. In addition, ETP-ALL like cases were positive for T cell antigens such as CD2 and/or CD7 and also some myeloid antigens but lacked cytoplasmic CD3 expression.In conclusion, we identified a spectrum of rare subtypes in childhood leukemia, including MPAL, AUL, and BPDCN by adoption of comprehensive immunophnotyping panel. In most of childhood MPAL cases were divided into 3 distinct clusters. It must be useful information for detection of genetic abnormality. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A case of infantile acute lymphoblastic leukemia (white blood cell count, 1,730×103/μL) rescued by exchange transfusion

A case of infantile acute lymphoblastic leukemia (white blood cell count, 1,730×10³/μL) rescued by exchange transfusion

Detection of Pathogenic Isoforms of IKZF1 in Leukemic Cell Lines and Acute Lymphoblastic Leukemia Samples: Identification of a Novel Truncated IKZF1 Transcript in SUP-B15.

Simple SummaryAbnormal RNA splicing plays a fundamental role in leukemogenesis in acute lymphoblastic leukemia (ALL). Many cases of high-risk B-cell ALL cases, including BCR-ABL1+ and BCR-ABL1-like ALL, share a common molecular mechanism of aberrant fusion transcripts involving tyrosine kinase genes combined with dysregulation of the transcription factor and lymphocyte differentiation factor IKZF1. Dysfunction of IKZF1 in ALL is caused by mutation and gene deletion but also alternative splicing resulting in exon skipping with production of aberrant IKZF1 proteins. We report here an assay to detect aberrantly spliced isoforms of IKZF1 in ALL to assist in diagnosis, outcome prediction, and therapy selection in ALL and the identification of a novel altered IKZF1 product in a model ALL cell line.Leukemia-associated alternative splicing of IKZF1 can result in proteins with loss of one to four copies of its N-terminal zinc finger domains (N-ZnF). The best characterized pathogenic splice isoforms, Ik-6 and Ik-8, have been commonly found in BCR-ABL1+ acute lymphoblastic leukemia (ALL) and a subset of BCR-ABL1-like ALL. Infantile and childhood ALL that express these pathogenic IKZF1 isoforms have shown inferior clinical outcomes and can be resistant to tyrosine kinase inhibitors. Using ALL cell lines, we designed and validated a method to detect abnormal IKZF1 transcripts. In the SUP-B15 leukemia cell line, we noted novel IKZF1 transcripts that include both an Ik-6 splice and a transcript with a 14 base pair insertion at the C-terminus. There was also increased IKZF2 protein in SUP-B15 as compared to other ALL lines. Expression of Ik-6 could be suppressed by treatment with the pro-apoptotic type II histone deacetylase inhibitor givinostat. In 17 adult ALL samples, we noted the Ik-6 isoforms in 6 of 15 BCR-ABL1−, and 1 of 2 BCR-ABL1+ cases, with Ik-8 also expressed in one case. Cases with Ik-6 expression showed inferior survival as well as older age at presentation, lower expression of CD10 and more commonly a diploid karyotype.

Corrigendum

Pediatric Blood & CancerVolume 67, Issue 11 e28380 CORRIGENDUMFree Access Corrigendum This article corrects the following: Using CD19 chimeric antigen receptor-T cell therapy in a 4-month-old patient with infantile acute lymphoblastic leukemia David C. Shyr, Amy A. Homsombath, Priya P. Chan, Michael W. Boyer, Andrew C. Harris, Volume 67Issue 4Pediatric Blood & Cancer First Published online: January 11, 2020 First published: 22 August 2020 https://doi.org/10.1002/pbc.28380AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat In the article by David C. Shyr et al.,1 the authors wish to add some text in the acknowledgement section: The amended acknowledgement section is as follows: Close collaboration between Novartis Apheresis Operations, which included a medical science liaison, strategic account manager, and medical director, and the treatment center, which included medical team, apheresis team, and stem cell lab, helped ensure successful and safe cell collection. Early communication prior to collection significantly helped in terms of planning and minimizing the number of days until collection and the duration of temporary pheresis catheter, which is especially important in these young infants. We acknowledge that medical writing support was provided by Ina Nikolaeva, PhD, of Healthcare Consultancy Group, and this activity was funded by Novartis Pharmaceuticals Corporation REFERENCE 1Shyr DC, Homsombath AA, Chan PP, Boyer MW, Harris AC. Using CD19 chimeric antigen receptor-T cell therapy in a 4-month-old patient with infantile acute lymphoblastic leukemia. Pediatric Blood & Cancer. 2020; 67(4):e21855. Volume67, Issue11November 2020e28380 ReferencesRelatedInformation

Chemotherapy Curability in Leukemia, Lymphoma, Germ Cell Tumors and Gestational Malignancies: A Reflection of the Unique Physiology of Their Cells of Origin.

Cytotoxic DNA damaging chemotherapy brings clinical benefits in the treatment of many metastatic malignancies. However routine curative treatment remains restricted to a small number of malignancies including acute leukemia, high grade lymphoma, germ cell tumors, gestational malignancies and some of the rare childhood cancers. The detailed explanation for this dramatic divergence in outcomes remains to be elucidated. However, we have previously argued that there is a strong correlation between presence of the unique genetic events of immunoglobulin gene variable/diversity/joining (VDJ) recombination, somatic hypermutation (SHM), meiosis, nuclear fusion and gastrulation occurring in cells of origin of these malignancies and their high sensitivity to DNA damaging chemotherapy. In this study we have reviewed some of the basic physiological information relating to the specialized activity and sensitivity to DNA damage mediated apoptosis of normal cells undergoing these processes. In each of unique genetic events there are dramatic changes in apoptotic sensitivity. In VDJ recombination and somatic hypermutation over 95% of the cells involved undergo apoptosis, whilst in meiosis and nuclear fusion there are dramatic short term increases in the apoptotic sensitivity to DNA damage. It is apparent that each of the malignancies arising during these processes retains some of the unique phenotype associated with it. The impact of the physiological differences is most clearly seen in the two non-mutational malignancies. Gestational choriocarcinoma which arises shortly after nuclear fusion is routinely curable with chemotherapy whilst CIMP-positive ependymomas which is not linked to any of the unique genetic events is highly resistant. A similar pattern is found in a pair of malignancies driven by a single driver mutation. Infantile acute lymphoblastic leukemia (ALL) arises in a cell undergoing the early stages of VDJ recombination and has a 40% cure rate in contrast pediatric rhabdoid malignancy which is not linked to a unique genetic event responds very poorly to chemotherapy treatment. The physiological changes occurring in cancer cells at the time of the malignant transformation appear to have a major impact on the subsequent sensitivity to chemotherapy and curability. New therapies that impact on these pathways may be of therapeutic value.

Cytogenetic and molecular aberrations in childhood B lineage acute lymphoblastic leukaemia

Background: Acute Lymphoblastic Leukemia (ALL) is a common hematological malignancy in children and is characterized by genetic changes such as mutations and chromosomal translocations. These cytogenetic and molecular abnormalities have got diagnostic and prognostic significance. Identification of these abnormalities helps in risk categorization and appropriate therapy. Aim of the study was to assess the cytogenetic/molecular abnormalities associated with B Lineage ALL in children.Methods: It was a hospital based retrospective observational study of 79 children diagnosed with B Lineage ALL by Bone marrow aspirate morphology and flow cytometry. Bone marrow samples or Peripheral blood were sent for cytogenetic/molecular analysis by Fluorescent in situ Hybridization technique. Descriptive data analysis was done using SPSS software.Results: Out of 199 cases 163(82%) were B Lineage ALL. 79(48%) undergone molecular analysis. Out of 79 cases of B lineage ALL, Translocation t(9;22) BCR-ABL1 was positive in 2(2.5%) cases , Translocation t(12;21) TEL/AML1 was positive 9(11%) cases and MLL (KMT2A) Gene Rearrangements was seen in 6(7.6%) children. Out of 79 cases of B lineage ALL, 6(7.6%) were Infantile ALL (Males 1(17%); Females 5(83%)). 4(67%) cases were positive for MLL (KMT2A) Gene Rearrangement, all of them were female children. Over all 17(22%) cases (Males 4(24%); Females 13(76%)) were positive for molecular abnormalities.Conclusions: Many children with ALL have got Cytogenetic and Molecular abnormalities. The highest percentage of cytogenetic and molecular genetic abnormalities was related to t(12;21)TEL/AML1 in B Lineage ALL children, if present confer favourable prognosis. MLL (KMT2A) Gene Rearrangement was the common molecular abnormality in Infantile B ALL, presence of it leads to high risk categorization and confer poor prognosis. The evaluation of cytogenetic and molecular genetic abnormalities in children is essential in estimating the prognosis in B Lineage ALL children, which will be a great contribution to offer appropriate therapeutic approaches.

Chemosensitivity is differentially regulated by the SDF-1/CXCR4 and SDF-1/CXCR7 axes in acute lymphoblastic leukemia with MLL gene rearrangements

Although recent advances in chemotherapy have markedly improved outcome of acute lymphoblastic leukemia (ALL), infantile ALL with MLL gene rearrangements (MLL+ALL) is refractory to chemotherapy. We have shown that specific cytokines FLT3 ligand and TGFβ1 both of which are produced from bone marrow stromal cells synergistically induced MLL+ALL cells into chemo-resistant quiescence, and that treatment of MLL+ALL cells with inhibitors against FLT3 and/or TGFβ1 receptor partially but significantly converts them toward chemo-sensitive. In the present study, we showed that MLL+ALL cells expressed CXCR4 and CXCR7, both receptors for the same chemokine stromal cell derived factor-1 (SDF-1), but their biological events were differentially regulated by the SDF-1/CXCR4 and SDF-1/CXCR7 axes and particularly exerted an opposite effect for determining chemo-sensitivity of MLL+ALL cells; enhancement via the SDF-1/CXCR4 axis vs. suppression via the SDF-1/CXCR7 axis. Because cytosine-arabinoside-induced apoptosis of MLL+ALL cells was inhibited by pretreatment with the CXCR4 inhibitor but rather accelerated by pretreatment with the CXCR7 inhibitor, an application of the CXCR7 inhibitor may become a good treatment option in future for MLL+ALL patients. MLL+ALL has a unique gene profile distinguishable from other types of ALL and AML, and should be investigated separately in responses to biological active agents including chemokine inhibitors.

Profile of Acute Lymphoblastic Leukemia in Children Under 2 Years of Age

Abstract Context: Acute lymphoblastic leukemia (ALL) shows substantial differences in clinical and laboratory features and treatment responsiveness in different subgroups. Pediatric ALL &lt;2 years is associated with worse outcome. Infantile ALL is characterized by high white blood cell (WBC) counts, bulky extramedullary disease, translocations of 11q23 locus. There is paucity of data on ALL under 2 years of age. Aims: This study aims to analyze clinical, hematological, biochemical, immunophenotypical parameters, and treatment responsiveness of ALL under 2 years. Settings and Designs: It is a retrospective data analysis conducted at a Tertiary Care Cancer Centre in South India. The study population includes all pediatric ALL, registered at this institute during January 2009 to December 2013, who were under 2 years at the time of presentation. Materials and Methods: There were 122 cases of ALL under 2 years of age of whom 48 refused treatment, and four were lost to follow-up. Thus, 70 cases are eligible for analysis. Details on clinical, hematological, biochemical, radiological, immunophenotypical, and cytogenetic features were collected from case records, hospital cancer registry, and analysis done using SPSS version 20. Kaplan–Meier curves plotted for survival analysis. Results:: Male:female ratio was 1.26:1 (infants - 1:1; 1–2 years group - 1.3:1). The most common clinical features were hepatomegaly (95%) and fever (89%). Hemoglobin level &gt;11 gm% was seen in 12%, WBC counts above 50,000 in 26% and platelets below 20,000 in 20%. Elevated lactate dehydrogenase presents in 64% and uric acid in 12%. Immunophenotype done in 44 children; precursor-B ALL-41, precursor-T ALL-3. Central nervous system -positive disease and 11q23 translocation were noted in one infant each. Conclusions: Infants with ALL are associated with poor prognosis. Children in the 1–2 years are associated with significantly better outcome. WBC counts &gt;50,000 are associated with poor prognosis among infants. Treatment refusal/abandonment rate is 43% in the study population which is comparable to that in literature.

Viral surveillance using PCR during treatment of AML and ALL.

While viral surveillance of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus using PCR is routine in patients undergoing hematopoetic stem cell transplant and solid organ transplant, the utility in the nontransplant pediatric leukemia population is unknown. Our institution screens patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) for viral DNAemia by PCR as part of clinical care. This retrospective chart review included patients treated for newly diagnosed or relapsed AML or ALL between April 2010 and September 2014. We retrieved data for viral PCR screening, detection and quantification, duration of positivity, and prophylaxis or treatment. One hundred eleven patients were included in analyses. Forty (36.0%) had at least one blood PCR positive for EBV, CMV, or adenovirus. Patients with ALL had significantly higher rates of persistent viral detection and treatment than those with AML (P < 0.02, P < 0.01, respectively). International patients had significantly higher rates of viral detection (P < 0.01), persistence (P < 0.01), any treatment (P < 0.03), and antiviral treatment (P < 0.01); 16.9% of patients who received intravenous immunoglobulin (IVIG) prophylactically had viral detection compared to 63% of patients who did not receive prophylactic IVIG (P = 0.0008). Patients with ALL were more susceptible than those with AML to viral reactivation that was persistent or resulted in treatment. Patients with relapsed ALL, refractory ALL, or infantile ALL are most likely to benefit from asymptomatic screening for CMV and adenovirus. International patients are at higher risk for reactivation and may merit screening. EBV reactivation was not significant and does not warrant screening.

Molecular studies reveal MLL-MLLT10/AF10 and ARID5B-MLL gene fusions displaced in a case of infantile acute lymphoblastic leukemia with complex karyotype.

The present report describes a unique infantile acute lymphoblastic leukemia (ALL) case with cryptic mixed-lineage leukemia (MLL) rearrangements with 11q23 chromosomal translocation. MLL break-apart signals were identified by fluorescence in situ hybridization, and transcriptome sequencing revealed MLL-myeloid/lymphoid or mixed-lineage leukemia; translocated To, 10 (MLLT10)/AF10 fusion transcripts. Analysis also revealed a previously unreported MLLT10/AF10-homeobox protein Mohawk (MKX) transcript, where the 5′ portion of MLLT10/AF10 at 10p12.31 was fused out-of-frame with the 3′ portion of MKX at 10p12.1, which is closely located to MLLT10/AF10. Furthermore, the reciprocal 3′-MLL gene segment was fused in-frame to AT-rich interaction domain (ARID)5B at 10q21. Previously, common allelic variants in ARID5B, which are directly associated with hematopoietic differentiation and development, have been repeatedly and significantly associated with childhood ALL. The heterozygous genotype in ARID5B (RefSNP: rs10821936) increased the risk for leukemia with MLL-rearrangement. In particular, single nucleotide polymorphisms of ARID5B conferred increased risk for MLL-MLLT3/AF9. Based on these findings, the authors propose that while the presence of reciprocal MLL alleles has been detected in this patient, different pathological disease mechanisms may be at play due to individual recombination events.

Genome-Wide Mutational Landscape of Infant Acute Lymphoblastic Leukemia

[Background] Mixed lineage leukemia (MLL also called KMT2A) rearrangement-positive leukemia is one of the most aggressive types of leukemia. It is diagnosed predominantly in infants and typically shows a multi-lineage phenotype. Since current chemotherapy fails in more than 50% of infantile acute lymphoblastic leukemia (ALL) with MLL-rearrangement, a better understanding of biological features of the disease is important in order to develop more specific and successful treatment strategies. Despite the evident biological and clinical significance of MLL-rearrangement, it has also been shown in vitro and in vivo that MLL-rearrangement is not sufficient to induce full leukemic transformation, indicating additional hits are required for complete leukemogenesis.Recently, sequencing-based genome-wide studies have suggested collaborative involvement of RAS-PI3K pathway in infant leukemogenesis through identification of recurrent mutations affecting RAS-PI3K pathway genes, in infant ALL with or without MLL-rearrangement. However, genetic basis of infant ALL with MLL-rearrangement are not fully elucidated.[Materials and Methods] Here, we performed whole exome sequencing in leukemia samples with matched peripheral blood T lymphocyte from 46 cases of infant ALL including 3 cases with germline MLL. Our cohort included samples from the Infant Leukemia Sub-committee, Japan Children's Cancer Group. For mapping and mutation calling, we used publicly available "Genomon Pipeline".[Results] In total, 198 somatic non-silent mutations (4.3 mutations per case) were identified, including 125 missense, 4 nonsense, 8 splice site mutations, 49 frameshift indels, and 12 in-frame indels. Thirteen genes were recurrently affected, among which RAS-PI3K pathway mutations were the most frequent: KRAS (10/46 cases, 21.7%), NRAS (4/46 cases, 8.7%) and PTPN11 (3/46 cases, 6.5%). In addition, novel recurrent mutations were detected in HSP90AB1 (5/46 cases, 10.9%), MAPRE3 (2/46 cases, 4.3%) and SRCAP (2/46 cases, 4.3%), as well as known candidate driver mutations in FLT3 (7/46 cases, 15.2%), TP53 (3/46 cases, 6.5%), CHD4 (2/46 cases, 4.3%) and PAX5 (2/46 cases, 4.3%). HSP90AB1 is a member of Heat shock protein90 (Hsp90) family that encodes a group of molecular chaperones involved in stabilization and activation of multiple oncogenic proteins and pathways. Overexpression of Hsp90 is observed in ALL, chronic myeloid/lymphocytic leukemia and several non-hematological malignancies. Another recurrently mutated gene, SRCAP, encodes the core component of chromatin-remodeling Snf2-related CREBBP activator protein complex. Recurrent mutations in this gene have recently been reported in FLT3-ITD positive acute myeloid leukemia with significantly high co-occurrence of MLL3 mutations. Overall, RAS-PI3K pathway mutations were detected in 19/46 cases of infant ALL (41.3%). In our cohort, none of 3 germline MLL cases contained RAS-PI3K pathway mutations; one case had a PAX5 mutation, another had a SRCAP mutation, and the other had no candidate driver mutations. In the germline MLL case without candidate drivers, G-banding had identified a structural abnormality, t(5;15)(p15;q11.2), that is rare but reported to be predominant in infant ALL rather than other hematological/non-hematological malignancies.[Conclusion] Our results demonstrated that aberrations of cell proliferation signaling, transcription factors, as well as cell cycle/epigenetic regulators are co-operative oncogenic events in MLL-rearrangement cases. The mutation spectrum is similar to myeloid malignancies rather than lymphoid cancers. Intriguingly, we identified novel recurrent mutations in the oncogenic proteins, such as HSP90AB1, MAPRE3, and SRCAP,suggesting that these are potentially targetable by small-molecule therapy. In addition, we also illustrated the genetic differences between MLL-rearrangement and germline MLL. Thus, our mutational landscape provides a novel insight into the molecular mechanisms of infant ALL and may contribute to improving the clinical outcome of infant patients suffering from the intractable ALL. DisclosuresOgawa:Kan research institute: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding; Sumitomo Dainippon Pharma: Research Funding.

Severe Hyperphosphatemia Resulting in Acute Renal Failure and Ischemic Encephalopathy in a Patient with Infantile Leukemia

Tumor lysis syndrome (TLS), hyperleukocytosis, and disseminated intravascular coagulation (DIC) are representative oncological emergencies that overlap mutually at the beginning of therapy for aggressive leukemia. Lately recombinant urate oxidase (rUO) enables to control uric acid level and its crystallization, the most frequent risk factor for clinical TLS; therefore, hyperphosphatemia appears to be the main risk in the rUO era. We here report an infantile leukemia patient who developed severe hyperphosphatemia, resulting in acute renal failure and ischemic encephalopathy. A 9-month-old female baby was adynamic with a bulging anterior fontanel, and was diagnosed as infantile acute lymphoblastic leukemia with a mixed lineage leukemia gene rearrangement. A laboratory examination revealed leukocytosis, bicytopenia, hyperuricemia, a prolonged prothrombin time, activated partial thromboplastin time, and elevated lactate dehydrogenase level. Soon after a reduced dose of prednisolone was administered, she developed hypoxia caused by systemic inflammatory response syndrome and heart failure. Her white blood cell count decreased sharply, leading to acute renal failure due to hyperphosphatemia, which required continuous hemodiafiltration for 48 hours. Although renal function subsequently recovered, severe ischemic encephalopathy remained. She achieved morphological remission once, however, relapsed and passed away soon after. We have to pay attention to the progression of hyperphosphatemia, hyperkakemia and DIC, although hyperuricemia was controlled using rUO. Changes in electrolyte levels must be continuously monitored, and TLS, DIC and/or hyperleukocytosis should be promptly managed especially in patients who are sensitive to therapy.

Effect of KIR Ligand Mismatched SCT for Infantile ALL with MLL gene Rearrangement: A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)

AbstractAbstract 4543 Introduction:Acute lymphoblastic leukemia (ALL) in infants with MLL gene rearrangement shows poor prognosis and its treatment strategy has not been established. The MLL03 study in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) consisted of the HLA-identical related bone marrow transplantation (BMT) or unrelated cord blood transplantation (CBT) within 4 months after intensive chemotherapy. However, it has not been elucidated whether the stem cell transplantation (SCT) at the early stage of treatment could improve the prognosis of infantile ALL. Recently, the graft- versus- leukemia (GVL) effect in KIR ligand mismatched SCT has been reported in several hematologic malignancies. The purpose of this study is to clarify the effect of KIR ligand mismatched SCT for infantile ALL. Subjects and Methods:Twenty-three of the 63 infants with MLL gene rearranged ALL who were registered in the MLL03 study and undergone SCT from February 2004 to January 2009, were evaluated. The prognosis and SCT-related complications were analyzed in patients with KIR ligand matched (n=18) and mismatched (n=5) SCT. Results:Overall survival rate (OS) in the KIR ligand matched group was 58.3% (95% CI, 31.3 – 77.8%), while all of the KIR ligand mismatched group have survived (p=0.10). Event free survival (EFS) was 44.4% (95% CI, 21.5 – 65.1%) in the KIR ligand matched group and 80.0% (95% CI, 20.3 – 96.9%) in the KIR ligand mismatched group (p=0.18). Acute GVHD (grade 2 to 4) was detected in 3 patients in the KIR ligand matched group, and 2 in the KIR ligand mismatched group (p=0.54). Two patients in the KIR ligand matched group and 1 in the KIR ligand mismatched group showed chronic GVHD, but it was all mild. Three patients who relapsed after KIR matched first SCT underwent second SCT with KIR mismatched cord blood, and all have survived without relapse. Discussion:Our study suggests the effect of KIR ligand mismatched SCT to prevent relapse and improve prognosis of infantile ALL, although no significant difference was observed because of small number of patients in each group. In addition, serious adverse events including GVHD were not detected in KIR ligand mismatched group. We conclude that NK cell mediated GVL effect associated with KIR ligand mismatch might improve the prognosis of infantile ALL after SCT, and therefore should be evaluated as a front-line treatment strategy to improve the prognosis of infants with MLL gene rearranged ALL. Disclosures:No relevant conflicts of interest to declare.

Abstract 71: Mutational analysis for IDH1 and IDH2 in pediatric leukemia

Abstract Recently, mutational and epigenetic profiling of a large acute myeloid leukemia (AML) patient cohort revealed that NADP+dependent isocitrate dehydrogenase (IDH)1/2-mutated AMLs display global DNA hypermethylation and a specific hypermethylation signature, suggesting a shared proleukemogenic effect. To explore the involvements of IDH1/2 in the pathogenesis in pediatric hematological malignancies. We analyzed mutations that involve the activation sites of IDH1/2 using polymerase chain reaction amplification/sequencing in a total of 244 samples of pediatric myeloid malignancies as well as infantile leukemia including 17 AML-derived cell lines, 115 primary cases of AML, 28 primary cases of MDS, 15 primary cases of juvenile myelomonocytic leukaemia (JMML), 6 chronic myeloid leukemia (CML)-derived cell line, 18 primary cases of CML and 45 infantile leukemia(6 AML and 39 acute lymphoblastic leukemia (ALL) patients). Moreover, to assess whetherIDH1/2 mutations overlap with known gene abnormalities, such as FLT3, c-KIT, and NPM1 mutations, mutational analyses of FLT3, c-KIT, and NPM1 were also performed. The common IDH2 R140Q mutation was detected in a single AML case, whereas no IDH1 mutation was detected in samples of myeloid malignancies. Although no IDH2 mutation was detected in infantile leukemias, novel P127S, H133I and I130V of IDH1 mutations were detected in 4 of 45 (8.9%) infantile ALL cases. No IDH1 and IDH2 mutations were detected in the JMML, MDS, or CML samples examined. Six AML samples including one cell line had c-KIT mutations (D816V, N822K, or D419fs), 12 AML cases had FLT3-ITD and 10 infantile leukemia cases had FLT3 mutations (D835E or I836). The NPM1 mutation was detected in 2 of 132 AML samples. The AML case harboring the IDH2 mutation, Case 39 was a 12-year-old boy diagnosed as AML-M2 according to the French-American-British cooperative group classification system having t(8;21)(q22;q22), showed no abnormalities of NPM1, c-KIT, and FLT3. Remarkably, among 4 infantile ALL cases with IDH1 mutations, 3 cases showed mixed lineage leukemia(MLL) rearrangements with t(4;11). The FLT3-D835 mutation was found in 1 of 4 patients with IDH1 mutations. These results suggest that although the involvements of IDH1/2 mutations in the pathogenesis of pediatric myeloid malignancies are extremely rare, closely positioned to near activation site, R132 IDH1, these IDH1 mutations are the candidate second genetic events in a subset of MLL-leukemia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 71. doi:1538-7445.AM2012-71

臍帯血移植後に血清Eosinophil Cationic Protein値が高値を呈し気管支喘息様症状を呈したBronchiolitis Obliterans Organizing Pneumonia (BOOP) の1症例

臍帯血移植後に血清Eosinophil Cationic Protein値が高値を呈し気管支喘息様症状を呈したBronchiolitis Obliterans Organizing Pneumonia (BOOP) の1症例

Nation-Wide Survey of Relapsed Infantile Acute Lymphoblastic Leukemia In Japan: Treatment and Outcome From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) MLL03 Study.

AbstractAbstract 1025 Introduction:Infantile acute lymphoblastic leukemia (ALL) is a rare leukemia subtype in infants with poor prognosis. Its outcome has gradually improved due to the development of treatment, including intensive chemotherapy or hematopoietic stem cell transplantation (SCT). However, prognosis of relapsed patients is extremely poor, which prompt us to establish the new treatment strategy for them. To establish the future treatment strategy for the relapsed cases, we here investigated the incidence of relapse, treatment, prognosis, and possible risk factors of relapsed cases with infantile ALL treated by the Japanese Pediatric Leukemia /Lymphoma Study Group (JPLSG) MLL03 study. Subjects:All relapsed cases with infantile ALL who underwent the MLL03 study between April 2004 and June 2009 were eligible for the study. The questionnaires were sent to all participants, asking the relapsed patients with infantile ALL by the MLL03 study. The questionnaires consisted of the time and site of relapse, treatment after relapse, presence or absence of remission prior to the second SCT, conditioning regimen for the second SCT, and age, white blood cell count, and presence or absence of central nervous system (CNS) infiltration at initial onset. Results:Total 63 patients were treated in this study period (mean follow-up, 31.8 months). Among them, 24 patients relapsed at any site after first complete remission (38%). These include 7 boys and 17 girls. Age at onset was less than 6 months in 19, and 6–12 months in 5. The overall survival (OS) rate of 24 patients was 60.2 ± 11.1% at 3 years; 44.6 ± 12.7% at 4 years, and 23.5 ± 13.4% at 5 years. Twenty-one of 24 patients (87.5%) relapsed after initial SCT; only three patients (12.5%) relapsed before SCT. Two patients relapsed early within 6 months after initial treatment terminally died. All four patients who relapsed at extramedullary site except CNS have survived, suggesting better prognosis. Patients diagnosed at age of less than 6 months also showed poor prognosis after relapse (5 year OS rate was 14.9 ± 13.0%). Presence or absence of remission prior to the second SCT was not a significant prognostic factor (28.3 ± 21.8% versus 15.6 ± 14.2%). Discussion:In the JPLSG MLL03 study, 38% of patients with infantile ALL relapsed. Only four patients relapsed prior to the initial SCT, indicating that the aim of the MLL03 study, to reduce the early relapse rate by performing the early SCT, could have been achieved. On the other hand, 87.5% of the patients relapsed after initial SCT in this study. Most of them were less than 6 months at onset. Several reasons for the high relapse rate after SCT should be considered, which include low graft-versus-leukemia (GVL) effect for infantile ALL, remained minimal residual disease (MRD) before SCT, or inappropriate conditioning regimen in this study. Since we have analyzed MRD before and after SCT in each patient treated by the MLL03 study, one reason could be resolved. In addition, the treatment strategy to induce GVL effect for infantile ALL should be established and we should reconsider the treatment strategy. Finally, appropriate treatment strategy for relapsed cases should be organized in the future. Disclosures:No relevant conflicts of interest to declare.

Mutational Analysis for IDH1 and IDH2 In Pediatric Leukemia

AbstractAbstract 5106NADP+dependent isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) catalyzes the oxidative carboxylation of isocitrate to α-ketoglutarate (α-KG) in citric acid cycle. Recently, recurrent somatic missense mutations in IDH1 at codon R132, as well as IDH2 at codon R172 have been identified in low-grade gliomas/secondary glioblastoma by high throughput sequencing. Subsequent studies also revealed that acquired somatic mutations in IDH1 and IDH2 frequently occurred in adult hematological malignancies, such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), and that these mutations were associated with older age, poor prognosis, cytogenetically normal AML, and the genotype of mutated NPM1 without FLT3-internal tandem duplication (ITD). Tumor-derived IDH1 and IDH2 mutations impair the affinity of the enzymes for the substrates and dominantly inhibit wild-type IDH1 and IDH2 activities through the formation of catalytically inactive heterodimers. However, little is known about the incidence and prognostic values of IDH1 and IDH2 mutations in pediatric hematological malignancies.Here, we analyzed mutations that involve the activation sites of IDH1 and IDH2 using polymerase chain reaction amplification/sequencing in a total of 244 samples of pediatric myeloid malignancies as well as infantile leukemia including 17 AML-derived cell lines, 115 primary cases of AML, 28 primary cases of MDS, 15 primary cases of juvenile myelomonocytic leukaemia (JMML), 6 chronic myeloid leukemia (CML)-derived cell line, 18 primary cases of CML and 45 infantile leukemia(6 AML and 39 acute lymphoblastic leukemia (ALL) patients). Moreover, to assess whether IDH1 and IDH2 mutations overlap with known gene abnormalities, such as FLT3, c-KIT, and NPM1 mutations, mutational analyses of FLT3, c-KIT, and NPM1 were also performed.The common IDH2 R140Q mutation was detected in a single AML case, whereas no IDH1 mutation was detected in samples of myeloid malignancies. Although no IDH2 mutation was detected in infantile leukemias, novel P127S, H133I and I130V of IDH1 mutations were detected in 4 of 45 (8.9%) infantile ALL cases. No IDH1 and IDH2 mutations were detected in the JMML, MDS, or CML samples examined. Six AML samples including one cell line had c-KIT mutations (D816V, N822K, or D419fs), 12 AML cases had FLT3-ITD and 10 infantile leukemia cases had FLT3 mutations (D835E or I836). The NPM1 mutation was detected in 2 of 132 AML samples. The AML case harboring the IDH2 mutation, Case 39 was a 12-year-old boy diagnosed as AML-M2 according to the French-American-British cooperative group classification system having t(8;21)(q22;q22), showed no abnormalities of NPM1, c-KIT, and FLT3. Remarkably, among 4 infantile ALL cases with IDH1 mutations, 3 cases showed mixed lineage leukemia(MLL) rearrangements with t(4;11). The FLT3-D835 mutation was found in 1 of 4 patients with IDH1 mutations. These results suggested that IDH1 mutations are one of the second genetic events in infant ALL with MLL rearrangements; however, it was concluded that the involvements of IDH1 and IDH2 mutations in the pathogenesis of pediatric myeloid malignancies are extremely rare. Disclosures:No relevant conflicts of interest to declare.