scholarly journals Understanding the Role of Hyperdiploidy in Burkitt Lymphoma of Childhood: Biological and Clinical Correlates

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5296-5296
Author(s):  
Georgia Avgerinou ◽  
Stefanos Papadhimitriou ◽  
Kalliopi Stefanaki ◽  
Antonis Kattamis ◽  
Katerina Katsibardi ◽  
...  
Keyword(s):  
Burkitt Lymphoma ◽  
Chromosome Region ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Molecular Cytogenetics ◽  
Myc Gene ◽  
Numerical Aberrations ◽  
Chromosome Regions

Abstract Background: Burkitt lymphoma (BL) is the most common high-grade lymphoma in childhood. BL is typically associated with rearrangement of the MYC gene, on 8q24 chromosome region, and often accompanied by other aberrations, some of which are known to adversely influence the clinical behavior and prognosis of the disease. However, hyperdiploidy, though frequently detected cytogenetically, has not been convincingly linked to specific biological and clinical features of BL. We present here our experience with 8 pediatric hyperdiploid BL cases detected with molecular cytogenetics in the course of routine genetic investigation. Materials and methods: The study included 44 children (35 boys, 9 girls), aged 1 to 15 years (median 6), diagnosed with histologically documented BL. In all cases, interphase FISH was performed on infiltrated bone marrow smears or touch imprints from samples of involved sites. FISH probes employed included sets of the detection MYC, BCL2, BCL6, IGH, IGK, and IGL rearrangement, -17/del(17p13), -9/(del9p21) and del(13q14)/del(13q34). Cases with over-representation of any of the chromosome regions targeted were further tested with the use of the appropriate centromeric/chromosome enumeration probe. Thus, this line of testing allowed for the detection of numerical aberrations of chromosomes 2, 3, 8, 9, 13, 14, 17, 18 and 22. Over-representation of at least three chromosomes, without evidence for any monosomy, was considered a hyperdiploidy criterion. Results: MYC was found rearranged in all cases, in 38 together with IGH and in 6 of them with IGK or IGL rearrangment. 17p-, 13q- and 9p- were detected in 3, 4 and 2 cases, respectively. There were no cases with BCL2 or BCL6 rearrangements. With a median follow-up of 5.5 years, 4 relapses/deaths were observed. Hyperdiploidy was detected in 8 patients (18.2%), with involvement of at least 7 of the 9 chromosomes tested, at the level of trisomy to hexasomy. Hyperdiploid and non-hyperdiploid cases were comparable with regard to sex and age. However, all cases with IGK/IGL involvement, 17p-, 13q- or 9p-, and relapse/death were seen exclusively in the non-hyperdiploid group. Conclusions: From the observations on this small group of patients, it seems that hyperdiploidy is rather common in childhood BL and, perhaps, represents a distinct clonal evolution pathway of the standard t(8;14)+ disease. It appears to be associated with a favorable prognosis. Further study on a larger number of cases is required to fully elucidate the clinical significance of the hyperdiploidy and whether it may be used as a marker of "low-risk" disease, by analogy to acute lymphoblastic leukemia. Disclosures Kattamis: Novartis: Consultancy, Honoraria; Vifor Pharma: Consultancy; CELGENE: Consultancy, Honoraria; ApoPharma: Honoraria.

scholarly journals Intensified Therapy of Acute Lymphoblastic Leukemia in Adults: Report of the Randomized GRAALL-2005 Clinical Trial

2018 ◽  
Vol 36 (24) ◽  
pp. 2514-2523 ◽  
Author(s):  
Françoise Huguet ◽  
Sylvie Chevret ◽  
Thibaut Leguay ◽  
Xavier Thomas ◽  
Nicolas Boissel ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Standard Dose ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Treatment Phase ◽  
Free Survival ◽  
Treatment Tolerance ◽  
To Receive

Purpose To evaluate randomly the role of hyperfractionated cyclophosphamide (hyper-C) dose intensification in adults with newly diagnosed Philadelphia chromosome–negative acute lymphoblastic leukemia treated with a pediatric-inspired protocol and to determine the upper age limit for treatment tolerability in this context. Patients and Methods A total of 787 evaluable patients (B/T lineage, 525 and 262, respectively; median age, 36.1 years) were randomly assigned to receive a standard dose of cyclophosphamide or hyper-C during first induction and late intensification. Compliance with chemotherapy was assessed by median doses actually received during each treatment phase by patients potentially exposed to the full planned doses. Results Overall complete remission (CR) rate was 91.9%. With a median follow-up of 5.2 years, the 5-year rate of event-free survival (EFS) and overall survival (OS) was 52.2% (95% CI, 48.5% to 55.7%) and 58.5% (95% CI, 54.8% to 61.9%), respectively. Randomization to the hyper-C arm did not increase the CR rate or prolong EFS or OS. As a result of worse treatment tolerance, advanced age continuously affected CR rate, EFS, and OS, with 55 years as the best age cutoff. At 5 years, EFS was 55.7% (95% CI, 51.8% to 59.4%) for patients younger than 55 years of age versus 25.8% (95% CI, 19.9% to 35.6%) in older patients (hazard ratio, 2.16; P < .001). Patients ≥ 55 years of age, in whom a lower compliance to the whole planned chemotherapy was observed, benefited significantly from hyper-C, whereas younger patients did not. Conclusion No significant benefit was associated with the introduction of a hyper-C sequence into a frontline pediatric-like adult acute lymphoblastic leukemia therapy. Overall, tolerability of an intensive pediatric-derived treatment was poor in patients ≥ 55 years of age.

scholarly journals Clinical Implications of Inflammation in Acute Myeloid Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Christian Récher
Keyword(s):  
Acute Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Leukemic Cells ◽  
Prognostic Impact ◽  
Acute Myeloid

Recent advances in the description of the tumor microenvironment of acute myeloid leukemia, including the comprehensive analysis of the leukemic stem cell niche and clonal evolution, indicate that inflammation may play a major role in many aspects of acute myeloid leukemia (AML) such as disease progression, chemoresistance, and myelosuppression. Studies on the mechanisms of resistance to chemotherapy or tyrosine kinase inhibitors along with high-throughput drug screening have underpinned the potential role of glucocorticoids in this disease classically described as steroid-resistant in contrast to acute lymphoblastic leukemia. Moreover, some mutated oncogenes such as RUNX1, NPM1, or SRSF2 transcriptionally modulate cell state in a manner that primes leukemic cells for glucocorticoid sensitivity. In clinical practice, inflammatory markers such as serum ferritin or IL-6 have a strong prognostic impact and may directly affect disease progression, whereas interesting preliminary data suggested that dexamethasone may improve the outcome for AML patients with a high white blood cell count, which paves the way to develop prospective clinical trials that evaluate the role of glucocorticoids in AML.

scholarly journals Outcomes of Acute Lymphoblastic Leukemia with KMT2A (MLL) rearrangement - The MD Anderson Experience

2021 ◽  
Author(s):  
Guillaume Richard-Carpentier ◽  
Hagop M Kantarjian ◽  
Guilin Tang ◽  
C. Cameron Yin ◽  
Joseph D. Khoury ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Poor Prognosis ◽  
Stem Cell Transplant ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cell Transplant ◽  
Md Anderson ◽  
The Impact

Acute lymphoblastic leukemia (ALL) with t(4;11)(q21;q23) - KMT2A-AFF1 is associated with a poor prognosis. The impact of KMT2A rearrangements other than t(4;11) is uncertain and the benefit of allogeneic stem cell transplant (HSCT) is unclear. We reviewed adult patients with ALL treated at our institution from 1984 to 2019 and identified 50/1102 (5%) with KMT2A rearrangement: 42 (84%) with t(4;11)/KMT2A-AFF1 and 8 (16%) with other gene partners. The median age was 45 years old (range, 18 - 78 years); median white blood cell count was 109.0 x 109/L (range, 0.5 - 1573.0). The complete remission (CR) rate was 88% and the rate of measurable residual disease negativity by flow cytometry at CR was 41% (76% overall during follow-up). At the last follow-up, 14 patients were alive. The 5-year overall survival (OS) rate was 18% (95% CI, 9 - 35%) with no difference between t(4;11) and other KMT2A rearrangements (p=0.87). In a 4-month landmark analysis, the 5-year OS rate was 32% (95% CI, 14 - 70%) in patients who underwent HSCT versus 11% (95% CI, 3 - 39) in others (p=0.10). Our study confirms the poor prognosis of ALL with any KMT2A rearrangement and the role of HSCT in these patients.

scholarly journals Long-term follow-up of residual disease in acute lymphoblastic leukemia patients in complete remission using clonogeneic IgH probes and the polymerase chain reaction

Blood ◽  
1993 ◽  
Vol 82 (5) ◽  
pp. 1618-1625 ◽  
Author(s):  
Y Nizet ◽  
S Van Daele ◽  
P Lewalle ◽  
JL Vaerman ◽  
M Philippe ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Chain Reaction ◽  
Polymerase Chain

Abstract We sequentially studied bone marrow (BM) samples of 25 patients in complete remission of an acute lymphoblastic leukemia (ALL) using a simplified polymerase chain reaction (PCR) strategy (direct use of the PCR product as a clonogenic probe recognizing rearranged Ig heavy chain sequences) as a first approach. BM aspirates were serially investigated after obtention of a complete response. When sensitivity was less than 1:10(4), the PCR fragment was sequenced and a specific oligonucleotide was synthetized and used as a probe (five cases). Cases in which minimal residual disease (MRD) became undetectable were cross- controlled using either TCR delta rearrangement or a specific translocation to circumvent the problem of false-negative results arising from clonal evolution. The median follow-up was 30 months (3 to 51 months). Within the first 3 months of complete remission, MRD was detectable in 22 of 23 investigated patients and remained so in 19 of 21 patients examined at 6 months, regardless of the long-term clinical outcome. In patients remaining in complete remission at 30 months or more, two patterns of MRD emerged during the follow-up. Either it continuously decreased to ultimately become undetectable (five patients) or remained detectable (five patients) with an increase after discontinuation of treatment in two. In the eight patients who relapsed, MRD persisted throughout the clinical course, and eventually increased 3 to 12 months before relapse was clinically detectable. In one case, clonal evolution of the VDJ heavy chain region was observed and recurrence of MRD shown by the use of TCR delta rearrangement as a control. We conclude that the use of this simplified methodology is a valuable tool for the follow-up of MRD in a majority of ALL patients, though in a few cases, sequencing needs to be performed to achieve a relevant sensitivity. The possibility of clonal evolution requires a cross-control of any sample becoming negative whatever the initial rearrangement used to generate a probe. In patients on therapy, sequential search for MRD seems to be a good tool for predicting the long-term outcome. In addition, patients remaining positive at the time treatment is discontinued or with a high tumor burden after a few months therapy may be at a higher risk of subsequent relapse, although a longer follow-up is needed to answer this question.

The Superiority of Allogeneic Hematopoietic Stem Cell Transplantation From Unrelated Donor Over Chemotherapy As Post-Remission Treatment for Patients with High-Risk Acute Lymphoblastic Leukemia in First Remission

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1986-1986
Author(s):  
Jiong Hu ◽  
han-Bo Dou ◽  
Ling Wang ◽  
Wei Tang
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Relapse Rate ◽  
Lymphoblastic Leukemia ◽  
P Value ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Chemotherapy Group

Abstract Abstract 1986 For adult patients with acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) from HLA-matched related donor (MSD) is recommended for standard and high-risk patients. The role of unrelated donor transplantation (URD) is not fully determined. In this single-center retrospective analysis, we included all consecutive adult patients with high-risk ALL in 1st complete remission (CR) without sibling donor between Jan 2007 to June 2012. Overall, 74 patients were included in the analysis in which 32 patients received URD allo-HSCT during 1st CR with busulfan-cyclophophamide preparation regimen and in vivo T cell depletion with anti-T-lymphoglobulin (ATG). The median time from remission to transplantation was 4.5 months (3∼13). Forty-two patients in the chemotherapy group with 1st CR more than 6 months received consolidation chemotherapy alone either due to lack of suitable URD (n=21), refuse to URD search (n=14), unwillingness to undergo transplantation with available URD (n=5) and donor refuse to donate (n=2). Salvage allo-HSCT was allowed after relapse and actually 5 patients in the chemotherapy group received transplantation from URD donor (n=2) or haplo-identical donor (n=2) in the subsequent remission. The clinical characteristics such age, sex, initial WBC, and Philadelphia chromosome are all distributed equally in the two groups. With a median follow-up of 18 months for the whole group, 30 patients relapsed with estimated 3-year relapse rate (RR) at 58.1±8.5%. The 3-year event-free survival (LFS), non-relapse mortality (NRM) and overall survival (OS) were 38.0±7.9%, 11.1±4.4% and 46.0±9.0% respectively. In the URD allo-HSCT group, RR was 30.6±11.4% which was significantly lower than chemotherapy group (80.5±10.1%, p<0.001) while NRM was higher (16.4±6.7% vs. 0, p=0.028). Overall, 3-year LFS was superior in URD allo-HSCT group compared to chemotherapy (57.8±10.6% vs. 19.5±10.5%; median not reached vs. 13 months, p=0.002) and 3-year OS was also improved in URD allo-HSCT group (63.5±13.3%, median not reached versus 31.6±10.6%, median 24 months, p=0.016). Based on our data, URD allo-HSCT significantly reduced the relapse rate in high-risk ALL and the benefit translated into improvement in both LFS and OS. Prospective randomized study based on availability of HLA matched URD is warranted to confirm the exact role of URD transplantation in adult ALL. Table 1. Patient's characteristics Chemotherapy URD-allo-HSCT P value No of patients N=42 N=32 Median Follow-up (months) 15 (7.7∼48) 22 (8.2∼49) Sex (M/F) 19/23 21/11 0.08 Age 24.5 (16∼60) 25 (16∼57) 0.10     >35 14 9 0.61     <=35 28 23 Initial WBC (×109/L) 80.3 (15.3∼97.9) 61.5 (3.2∼98.4) 0.12 Cytogenetics     Ph+ 8 10 0.33     Ph− 33 22 Table 2. Clinical outcome in different treatment strategies Chemotherapy URD-allo-HSCT P value No of patients N=42 N=32 OS 31.6 ± 10.6% 63.5 ± 13.3% 0.016     median 24.9 months not reached LFS 19.5 ± 10.5% 57.8 ± 10.6% 0.002     median 13.2 months not reached Relapse rate 80.5 ± 10.1% 30.6 ± 11.4% <0.001 NRM 0% 16.4 ± 6.7% 0.028 Disclosures: No relevant conflicts of interest to declare.

Impactof NOTCH1, FBXW7 and SETD2 Mutations On Early Treatment Response In Childhood T-Cell Acute Lymphoblastic Leukemia：A China Children’s Leukemia Group Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4937-4937
Author(s):  
Wei Wei ◽  
Xiaojuan Chen ◽  
Yao Zou ◽  
Lixian Chang ◽  
Zhu Xiaofan
Keyword(s):  
T Cell ◽  
High Risk ◽  
Treatment Response ◽  
Lymphoblastic Leukemia ◽  
High Risk Group ◽  
Missense Mutations ◽  
Early Treatment Response ◽  
Notch1 Mutations

Abstract T-cell lymphoblastic leukemia (T-ALL) is an aggressive malignancy accounting for about 15% of newly diagnosed acute lymphoblastic leukemia (ALL) in children. Although the prognosis has been improved by intensified therapies, the outcome of high risk patients is still not optimistic. Activating NOTCH1 and/or FBXW7 mutations have been reported to be the leading genetic abnormality in T-ALL with good prognosis but few studies about the role of NOTCH1 and FBXW7 in T-ALL were conducted in China and their mutation distributions and clinical prognosis are still unclear. On the other hand, loss of function mutations of SETD2, a histone methyltransferase specific for trimethylation of histone H3 on Lys36 (H3K36me3), has been found in renal cell carcinoma, gliomas and early T cell precursor ALL (ETP-ALL). SETD2 is a potential tumor suppressor gene and may play a deleterious role in human cancer. We attempted to investigate the role of these mutations in Chinese T-ALL children. Thirty-seven bone marrow samples from childhood patients with newly diagnosed T-ALL (26 boys and 11 girls; age＜14 years) enrolled into the China Children’s Leukemia Group (CCLG) ALL-2008 trail from September 2010 to December 2012 were analyzed for SETD2, NOTCH1, FBXW7 mutations. All exons of SETD2, exons 25-28, 34 of NOTCH1 and exons 5, 7-12 of FBXW7, including intron-exon boundaries, were sequenced by Sanger method. NOTCH1 mutations were observed in 43.2% (n=16) of the T-ALL patients. Thirteen missense mutations were found in HD-N domain, HD-C domain and TAD domain of NOTCH1 while only frameshift insertions and deletions were identified in PEST domain. Besides missense mutations, five inframe insertions were also observed in HD-N domain of NOTCH1. We only found one FBXW7 synonymous mutation in our patients, which was extremely low compared with that in other studies. SETD2 somatic mutations were found in 8.1% (n=3, one female and two males) of 37 T-ALL patients. Of the three patients, two patients had truncated SETD2 protein because of nonsense mutation (c.6229 C＞T) and frameshift insertion (c.7516_7517insTTATA) respectively. Both SETD2 and NOTCH1 mutations were found in one patient. In our study, no significant relationships between NOTCH1 status and age, sex, mediastinal or Central Nervous System (CNS) involvement, immunophenotype and cytogenetics were observed. However, White Blood Cell (WBC) count at diagnosis in patients without NOTCH1 mutation were much higher (221×109/L vs 76.95×109/L, P=0.015). Patients with NOTCH1 mutations had a better early treatment response: higher prednisone good response rate (81.2% vs 47.6%, p=0.048), higher incidence of bone marrow M1 status (blast cell＜5%) on day 15 (73.3% vs 33.3%, p=0.04), and higher rate of favorable minimal residual disease (MRD) level on day 88 (100% vs 59.9%, p=0.012). In contrast, patients without NOTCH1 mutations were more likely to fall into the high risk group (71.4% vs 21.4%, p= 0.006) according to our treatment protocol. After a median follow-up of 11 months, 1 patient did not reach complete remission (CR), 2 patients died during induction and 2 patients relapsed in 6 months. Patients who suffered relapse and induction failure are all in the NOTCH1 wild type group. SETD2 mutations seemed to have no relationship to sex, age, WBC, cytogenetics, CNS and mediastinal involvement. In contrast to previous study that found SETD2 mutations only in EPT ALL patients, none of our SETD2 mutated patients were ETP ALL, two were cortical-T ALL and one was pre-T ALL. All of the patients with SETD2 mutations were alive without the disease at the last follow-up. However, all of the patients were in the high risk group. The patient who had both NOTCH1 and SETD2 mutations responded poorly to prednisone. Although the other two patients without NOTCH1 mutations had good response to prednisone, favorable BM status on day 15 and low MRD on day 33, they had very high MRD levels (0.21% and 0.44% respectively) on day 88. NOTCH1 activating mutations were found in 43.2% of pediatric T-ALL patients enrolled in the CCLG ALL-2008 study with good treatment response while FBXW7 mutation rate was much lower. SETD2 mutation was a recurrent event in pediatric T ALL not only in ETP ALL. It seems that patients with SETD2 mutations have high risk of poor response to chemotherapy regardless of NOTCH1 status. Further studies are needed to find out the prognostic significance of SETD2 mutation in pediatric T ALL. Disclosures: No relevant conflicts of interest to declare.

Paired Immunophenotype Comparison Of Diagnosis and Relapse Samples In B-Lineage Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4954-4954
Author(s):  
Marion Eveillard ◽  
Richard Garand ◽  
Nelly Robillard ◽  
Soraya Wuilleme ◽  
Caroline Thomas ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Leukemic Cells ◽  
Aberrant Expression ◽  
Blast Cells ◽  
B Lineage

Abstract Although great progress has been made in the treatment of acute lymphoblastic leukemia (ALL), relapse remains a major issue in the follow-up of these patients. Recent data about the emergence of subclones during haematological malignancies suggest that relapses could result from resistant cells initially in minority or from cells driven to resistance by previous treatments. Among the tools allowing for the characterization of leukemic cells, flow cytometry (FCM) is an essential approach. Increasingly used to evaluate minimal residual disease (MRD) based on the immunophenotypic features of the blasts at diagnosis, it can also allow to identify immunophenotypic shifts related to clonal evolution. Such an approach would be best studied by comparing follow-up samples from the same patients. In order to be thorough, this would however require that conditions as similar as possible are applied to both types of cells. This work was designed 1) to compare the immunophenotypic features of B-ALL blast cells with those of normal hematogones, 2)to assess potential immunophenotypic shifts at relapse 3)to determine the stability of markers not classically used at diagnosis during follow-up and their potential utility for MRD. FCM was performed simultaneously on thawed paired samples from 15 patients (9 children aged between 1 and 12 years old and 6 adults aged between 23 and 71 years old) with B-lineage ALL. With a three-tubes 8 colours panel comprising a backbone of CD45, CD34, CD22 and CD10, the expression of 8 markers was examined and compared to that observed on normal hematogones contained in 29 bone marrow samples from healthy donors. These 8 markers were CD7, CD19, CD20, CD24, CD38, CD58, CD81, CD123. Moreover, an additional four colours panel was used to examine the more recently described antigens CD44, CD200, CD304 and Her2Neu. The presence of leukemia associated immunophenotypes (LAIP) was defined as a difference in mean fluorescence intensity (MFI) between hematogones and blasts of at least 2 standard deviations. At diagnosis, the expression of each marker was at variance from that on hematogones yielding LAIP in all patients, with at least 4 aberrant markers (up to 11). Antigens with the most abnormal expression were CD10 (100%), CD24 (93.3%), CD81 (80%), CD38 (60%) and CD58 (53.3%). Antigens with the least aberrant expression were CD19 (20%), CD22 (20%), CD123 (20%), CD34 and CD20 (46,7%). CD44 which is at a low level on hematogones, was present for 80% of the patients at diagnosis and overexpressed in ALL with MLL rearrangement (3/15 cases). CD200 was overexpressed in 73% of the patients while CD304 was present in only 40% of the patients. A single patient was positive for Her2Neu, which remained present at relapse. All patients retained at relapse the same global immunophenotype without any change in the EGIL classification (3 B-I, 8 B-II, 4 B-III) and the difference with hematogones remained. The expression of most markers was similar at diagnosis and relapse. There was no change at all for the expression of CD38 which therefore appears as the most interesting marker for follow-up and MRD in ALL. Only one patient each showed a change in the expression of CD44, CD58 or CD123. As a whole, stable markers were CD58, CD44, CD200, CD81 and CD24 in contrast with CD19, CD22, CD123, CD304, CD24 and CD20 which changed in 27 to 67% of the patients. Four patients displayed no immunophenotypic change at relapse while 3 showed a modification of a single marker. For 5 patients, with respectively 6 and 7 LAIP, two markers were modified at relapse. Three markers changed for the patient with Her2Neu expression. Finally, only two patients (13%) showed major changes possibly associated with the emergence of a new clone. This study confirms that B-ALL blast cells differ immunophenotypically from hematogones, although the latter have been reported to possibly be their normal counterpart. These data moreover comfort the interest of using LAIP in the detection of MRD in multiparameter FCM. Finally, since molecular targets of therapeutic monoclonal antibodies do not shift sensibly, their use can also be considered at relapse. Disclosures: No relevant conflicts of interest to declare.

Clonal Evolution Underlying the Progression from Myelodysplastic Syndromes to Ph-Positive Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5514-5514
Author(s):  
Masataka Taguchi ◽  
Tomoko Kohno ◽  
Hiroyuki Mishima ◽  
Hiroaki Taniguchi ◽  
Takeharu Kato ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Myelodysplastic Syndromes ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Intron 1

Abstract Introduction: Myelodysplastic syndromes (MDS) are considered as a "stem cell disorders", in which hematopoietic stem cells and lineage-committed progenitor cells acquire genetic and epigenetic alterations and provide aberrant, clonal hematopoiesis, sometimes resulted in the progression to acute myeloid leukemia (Elias HK et al, Oncogene 2014). We previously reported a rare case of which the patient developed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) 2.5 years after being diagnosed with MDS (Kohno T et al, Br J Haematol 1996). p190 BCR-ABL1 mRNA was detected in the Ph+ALL cells. Metaphase cytogenetics showed the karyotypes: 46, XY, 20q- in MDS phase and 46, XY, t(9;22)(q34;q11), 20q- in ALL phase, indicating that MDS and Ph+ALL in this patient were of the same clonal origin. To uncover the detail of the clonal evolution, we analyzed bone marrow samples of MDS and Ph+ALL in this patient by targeted massively parallel sequencing with a panel of 154 genes including known driver genes of hematologic malignancies. Methods: Genomic DNAs (gDNAs) were extracted from the bone marrow mononuclear cells of MDS and Ph+ALL in this patient. Targeted sequencing was performed on the Illumina HiSeq2500 platform. Single nucleotide variants (SNVs) and small insertions and deletions (INDELs) were called using HaplotypeCaller of Genome Analysis Toolkit (GATK) version 3.4-46. We also attempted to detect the breakpoint of BCR-ABL1 translocation from the targeted sequencing data using the computational method, BreaKmer (Abo RP et al, Nucleic Acids Research 2015). The candidates of the mutations and structural variations were validated by amplicon-based deep sequencing and Sanger sequencing. Copy number variations were analyzed using Affymetrix CytoScan HD Array. Results: The mutations in ASXL1 and U2AF1 genes were identified in the MDS sample with variant allele frequencies (VAFs) of about 45%. At the progression of Ph+ALL, the mutations in SETBP1, SMC1A, and SLC5A8 genes were newly acquired while the ASXL1 and U2AF1 mutations were also identified with the same level of VAFs (about 50%) as the other mutations. VAFs of all of the mutations were decreased to about 20% after the chemotherapy for Ph+ALL, and then increased to about 40% at the recurrence of the disease. Furthermore, we identified the breakpoint of BCR-ABL1 translocation at intron 1 of ABL1 genes and intron 1 of BCR genes, that is the well-known cluster region, m-bcr, only among the samples of Ph+ALL. Copy number analysis confirmed that both MDS and Ph+ALL samples harbored the deletion of chromosome 20q. And the deletion of IKZF1 gene, which is frequently identified in Ph+ALL cases (Mullighan CG et al, Nature 2008), was not identified during the progression from MDS to Ph+ALL. These results demonstrated that the MDS clone harboring 20q- and ASXL1 and U2AF1 mutations acquired the mutations in SETBP1, SMC1A, and SLC5A8 genes and the p190 BCR-ABL1, resulted in the development of Ph+ALL in this patient. Conclusion: The alterations of SETBP1, SMC1A, and SLC5A8 genes are usually reported in myeloid malignancies (Makishima H et al, Nat Genet 2013, Kon A et al, Nat Genet 2013, Whitman SP et al, Blood 2008). Previous study in transgenic mouse demonstrated the distinct role of p190 BCR-ABL1 in the development of an ALL (Voncken JW et al, Blood 1995). Recapitulating this scenario, p190 BCR-ABL1 may play a critical role in the development of Ph+ALL from the MDS stem cells in this patient. This study may provide a new insight into the stem cell origin of MDS and the role of p190 BCR-ABL1 in the development of Ph+ALL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Mutational Landscape, Clonal Evolution Patterns and Role of RAS Mutations in Relapsed Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4068-4068
Author(s):  
Koichi Oshima ◽  
Hossein Khiabanian ◽  
Ana Carolina da Silva Almeida ◽  
Gannie Tzoneva ◽  
Francesco Abate ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Disease Progression ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Wild Type ◽  
Ras Mutations ◽  
Recurrent Mutations ◽  
Glucocorticoid Receptor Gene ◽  
Pediatric All

Abstract Acute Lymphoblastic Leukemia (ALL) is the most common malignancy in children. Altogether 90% of pediatric ALL patients achieve a complete hematologic remission with current high dose combination chemotherapy and 80% of them remain leukemia free. However, the outcome for patients showing refractory disease or those whose leukemia relapses after an initial transient response remains disappointingly poor with cure rates of less than 40%. To investigate genetic drivers of relapse and resistance and explore the specific roles of clonal evolution in disease progression and relapse here we performed whole-exome sequence analysis of matched diagnosis, germline (remission) and relapse DNA samples in a panel of 55 pediatric ALL patients including 33 T-cell ALLs and 22 B-cell precursor ALLs. These analyses identified an average of 9 mutations present in diagnostic samples and 17 mutations in relapsed leukemia DNAs. Phylogenetic tree analysis for each of the 48 cases with optimal variant call parameters analyzing their clonal evolution dynamics during disease progression, combined with whole genome sequencing of targeted samples with low exonic mutation input, showed that branched evolution in which relapse clones contain some, but not all genetic lesions present in the major clone at diagnosis as the primary mechanism driving tumor progression and relapse present in 45/48 (94%) cases. In addition, and consistent with previous reports we identified the presence of chemotherapy associated mutations in NT5C2 (10/55), TP53 (3/55), CREBBP (4/55) and the NR3C1 glucocorticoid receptor gene (2/55). However, and most strikingly, 23/27 (85%) recurrently mutated genes in this series with mutations preferentially selected or retained at the time of relapse (mutation never lost in the relapse clone) were not implicated in relapse ALL before (HTR3A, MED12, USP9X, CACNA1H, ODZ3, AACS, SAMD4A, ANO5, PAPPA, NAALADL2, HIST3H2A, FZD7, TBX15, NEB, GREB1L, PLXNA4, SGK223, TSC1, PTPRG, FGF10, SYCP2, TRPM3 and EYS). A branched pattern of genetic evolution and the presence of recurrent mutations selected at relapse support that chemotherapy imposes a strong Darwinian genetic selection in leukemic cell populations. In this context it is worth noting that RAS-MAPK pathway activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series. Interestingly, some leukemias showed retention or emergence of RAS mutant clones at relapse, while in others, RAS mutant clones present at diagnosis were replaced by RAS wild type populations, supporting a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia. Most notably, and in agreement with this hypothesis, inducible expression of mutant KRAS in human ALL lines demonstrate that oncogenic KRAS G12D induces methotrexate resistance, but also improves leukemia response to vincristine; a phenotype perfectly recapitulated in a isogenic ALL leukemia model generated from a conditional inducible Kras G12D knockin mice. Mechanistically, KRAS G12 expression induces MAPK dependent abrogation of methotrexate induced apoptosis. Moreover, Kras mutant tumors show enhanced G2/M cell cycle arrest and apoptosis upon spindle poisoning with vincristine, a phenotype linked with increased PLK phosphorylation and transcriptional down-regulation of mitotic genes. Finally clonal competition assays demonstrate that the differential response to methotrexate and vincristine in isogenic Kras wild type and Kras mutant ALL cells results in clonal dominance of Kras G12D populations in cultures treated with methotrexate, while Kras wild type cells are selected the context of vincristine treatment. In all these results show novel insight on the genetics and mechanisms of clonal selection, disease progression and relapse in ALL and demonstrate a previously unrecognized dual role of RAS mutations in chemotherapy response. Disclosures Loh: Abbvie: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia

2016 ◽  
Vol 113 (40) ◽  
pp. 11306-11311 ◽  
Author(s):  
Koichi Oshima ◽  
Hossein Khiabanian ◽  
Ana C. da Silva-Almeida ◽  
Gannie Tzoneva ◽  
Francesco Abate ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Mapk Pathway ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Wild Type ◽  
Ras Mutations ◽  
Viral Oncogene ◽  
Mutational Landscape ◽  
Viral Oncogene Homolog

Although multiagent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die because of chemorefractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape at relapse in pediatric ALL cases. These analyses identified numerous relapse-associated mutated genes intertwined in chemotherapy resistance-related protein complexes. In this context, RAS-MAPK pathway-activating mutations in the neuroblastoma RAS viral oncogene homolog (NRAS), kirsten rat sarcoma viral oncogene homolog (KRAS), and protein tyrosine phosphatase, nonreceptor type 11 (PTPN11) genes were present in 24 of 55 (44%) cases in our series. Interestingly, some leukemias showed retention or emergence of RAS mutant clones at relapse, whereas in others RAS mutant clones present at diagnosis were replaced by RAS wild-type populations, supporting a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia. Consistently, functional dissection of mouse and human wild-type and mutant RAS isogenic leukemia cells demonstrated induction of methotrexate resistance but also improved the response to vincristine in mutant RAS-expressing lymphoblasts. These results highlight the central role of chemotherapy-driven selection as a central mechanism of leukemia clonal evolution in relapsed ALL, and demonstrate a previously unrecognized dual role of RAS mutations as drivers of both sensitivity and resistance to chemotherapy.

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