scholarly journals Genomic and Clinical Characterization of Adult Ph-Negative B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2821-2821
Author(s):  
Takahiko Yasuda ◽  
Dai Nishijima ◽  
Shinya Kojima ◽  
Masahito Kawazu ◽  
Toshihide Ueno ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Fusion Genes ◽  
Free Survival ◽  
Chromosome Translocations ◽  
Otsuka Pharmaceutical ◽  
Genetic Events ◽  
Disease Free

Abstract Although survival rate for children with Acute Lymphoblastic Leukemia (ALL) now exceeds about 90%, the outcome of adult patients with ALL is extremely poor. These differences might be attributed to the lack of insights into pathogenesis and clinical behavior of adult-ALL. Gross chromosomal alterations including chromosome translocations and aneuploidy are considered as early events in ALL and constitute disease subtypes. To identify chromosome translocations underlying adult with Ph-negative B-ALL, we performed RNA-seq analysis on RNA from individuals with B-ALL who had been treated on the Japan Adult Leukemia Study Group (JALSG) ALL202-O protocol (n = 149). We successfully identified chromosome translocations in 100 patients (67.1%). ZNF384 fusions were most frequently detected in 30 patients (20.1%) and they had wide range of fusion partners. DUX4- and MEF2D- fusions were also recurrently found in 7 (4.7%) and 9 (6.0%) patients, respectively. Chromosome translocations activating kinase and cytokine receptor were found in 25 patients (16.8%) with Ph-like gene expression profile. These alterations were almost completely mutually exclusive indicating these are likely to be primary genetic events. For simplicity, here we define (1) fusions involving ZNF384, DUX4, MEF2D, CEBP and PAX5 as well as TCF3-PBX1 and ETV6-RUNX1 as Transcription Factor fusions (TF fusions; 49% of patients), (2) fusions involving CRLF2, JAK2, PDGFRB, EPOR and ABL as Kinase/cytokine-receptor Activating fusions (KA fusions; 15%) and (3) non-recurrent fusions or the absence of fusions/aneuploidy as B-others (30%). First, we analyzed impact of the patient age on types of fusion genes, based of combined data of ALL202-O cohort, childhood B-ALL cohort (Lilljebjörn H, et al. 2016: n = 189) and ALL202-U cohort (Yasuda T, et al. 2016: n = 54). We found that incidence of ZNF384-, CEBP- fusions and B-others increases as patients age, whereas ETV6-RUNX1 and PAX5 fusions were more prevalent in younger patients, exhibiting negative association with age. DUX4 fusions and TF fusions were most prevalent in Adolescent and Young Adult (AYA) generation. JAK2-, PDGFRB-, EPOR- and KA- fusions were positively correlated with age. Next, we analyzed association between patient survival and types of fusions. In Japanese adult B-ALL cohort (ALL202-O and ALL202-U cohort), we observed ZNF384-, DUX4- fusions and TCF3-PBX1 were associated with better disease-free survival than B-others. Furthermore, when combined, MEF2D- (n = 14), CEBP- (n = 4), PAX5- fusions (n = 2) and ETV6-RUNX1 (n = 2) exhibited significantly better disease-free survival than B-others, indicating TF fusions were associated with an improved outcome. In contrast, KA fusions were associated with poorer disease-free survival than B-others. KMT2A fusions were comparable with B-others regarding to patient disease-free survival. These results allowed us to develop a prognostic schema to identify three distinct risk profile groups, based on types of fusion genes and cytogenetics (Table1); favorable-risk (5-year rate of disease-free survival 67.4%), intermediate-risk (5-year rate of disease-free survival 42.5%) and adverse-risk (5-year rate of disease-free survival 9.6%). This prognostic schema predicted the outcome independently of age, sex and methotrexate dose in multivariate analysis (p < 0.001). In conclusion, we promoted a better understanding of the genetic basis of adult B-ALL by focusing on fusion genes. Each chromosome translocations were closely associated with age. ZNF384-, KA fusions and B-others were characteristic for older-adult patients (40-65 years old) with B-ALL. We clearly demonstrated specific primary chromosome abnormalities are strong prognostic marker. Functional properties of primary genetic events (TF fusions vs. KA fusions) might be a key determinant of biological characteristics and clinical outcome. Disclosures Kiyoi: Novartis Pharma K.K.: Research Funding; Celgene Corporation: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; FUJIFILM Corporation: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Bristol-Myers Squibb: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Sanofi K.K.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Phizer Japan Inc.: Research Funding; Eisai Co., Ltd.: Research Funding. Naoe:Astellas Pharma Inc.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Pfizer Japan Inc.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding.

scholarly journals Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report

Blood ◽  
1991 ◽  
Vol 78 (11) ◽  
pp. 2814-2822 ◽  
Author(s):  
CA Linker ◽  
LJ Levitt ◽  
M O'Donnell ◽  
SJ Forman ◽  
CA Ries
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Remission Induction ◽  
Cell Phenotype ◽  
Free Survival ◽  
Prognostic Features ◽  
Adult Acute Lymphoblastic Leukemia ◽  
Disease Free

Abstract We treated 109 patients with adult acute lymphoblastic leukemia (ALL) diagnosed by histochemical and immunologic techniques. Patients were excluded only for age greater than 50 years and Burkitt's leukemia. Treatment included a four-drug remission induction phase followed by alternating cycles of noncrossresistant chemotherapy and prolonged oral maintenance therapy. Eighty-eight percent of patients entered complete remission. With a median follow-up of 77 months (range, 48 to 111 months), 42% +/- 6% (SEM) of patients achieving remission are projected to remain disease-free at 5 years, and disease-free survival for all patients entered on study is 35% +/- 5%. Failure to achieve remission within the first 4 weeks of therapy and the presence of the Philadelphia chromosome are associated with a 100% risk of relapse. Remission patients with neither of these adverse features have a 48% +/- 6% probability of remaining in continuous remission for 5 years. Patients with T-cell phenotype have a favorable prognosis with 59% +/- 13% of patients achieving remission remaining disease-free compared with 31% +/- 7% of CALLA-positive patients. Intensive chemotherapy may produce prolonged disease-free survival in a sizable fraction of adults with ALL. Improved therapy is needed, especially for patients with adverse prognostic features.

Allogeneic bone marrow transplantation for children with acute lymphoblastic leukemia in first remission: a cooperative study of the Groupe d'Etude de la Greffe de Moelle Osseuse.

1989 ◽  
Vol 7 (6) ◽  
pp. 747-753 ◽  
Author(s):  
P Bordigoni ◽  
J P Vernant ◽  
G Souillet ◽  
E Gluckman ◽  
D Marininchi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Marrow Transplantation ◽  
Lymphoblastic Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Disease Free Survival ◽  
Allogeneic Bone ◽  
Free Survival ◽  
Disease Free

Thirty-two children ranging in age from 1.5 to 16 years with poor-prognosis acute lymphoblastic leukemia (ALL) were treated with myeloablative immunosuppressive therapy consisting of cyclophosphamide (CPM) and total body irradiation (TBI) followed by allogeneic bone marrow transplantation (BMT) while in first complete remission (CR). The main reasons for assignment to BMT were WBC count greater than 100,000/microL, structural chromosomal abnormalities, and resistance to initial induction therapy. All children were transplanted with marrow from histocompatible siblings. Twenty-seven patients are alive in first CR for 7 to 82 months post-transplantation (median, 30 months). The actuarial disease-free survival rate is 84.4% (confidence interval, 7.2% to 29%) and the actuarial relapse rate is 3.5% (confidence interval, 0.9% to 13%). Four patients died of transplant-related complications, 16 developed low-grade acute graft-v-host disease (GVHD), and six developed chronic GVHD. The very low incidence of relapse (one of 28 long-term survivors) precluded the determination of the prognostic significance of the different poor-outcome features. Moreover, two infants treated with busulfan, CPM, and cytarabine (Ara-C) relapsed promptly in the marrow. In summary, as a means of providing long-term disease-free survival and possible cure, BMT should be considered for children with ALL presenting poor-prognostic features, particularly certain chromosomal translocations [t(4;11), t(9;22)], very high WBC counts, notably if associated with a non-T immunophenotype, and, perhaps, a poor response to initial therapy with corticosteroids (CS), or infants less than 6 months of age.

scholarly journals Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report

Blood ◽  
1991 ◽  
Vol 78 (11) ◽  
pp. 2814-2822 ◽  
Author(s):  
CA Linker ◽  
LJ Levitt ◽  
M O'Donnell ◽  
SJ Forman ◽  
CA Ries
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Remission Induction ◽  
Cell Phenotype ◽  
Free Survival ◽  
Prognostic Features ◽  
Adult Acute Lymphoblastic Leukemia ◽  
Disease Free

We treated 109 patients with adult acute lymphoblastic leukemia (ALL) diagnosed by histochemical and immunologic techniques. Patients were excluded only for age greater than 50 years and Burkitt's leukemia. Treatment included a four-drug remission induction phase followed by alternating cycles of noncrossresistant chemotherapy and prolonged oral maintenance therapy. Eighty-eight percent of patients entered complete remission. With a median follow-up of 77 months (range, 48 to 111 months), 42% +/- 6% (SEM) of patients achieving remission are projected to remain disease-free at 5 years, and disease-free survival for all patients entered on study is 35% +/- 5%. Failure to achieve remission within the first 4 weeks of therapy and the presence of the Philadelphia chromosome are associated with a 100% risk of relapse. Remission patients with neither of these adverse features have a 48% +/- 6% probability of remaining in continuous remission for 5 years. Patients with T-cell phenotype have a favorable prognosis with 59% +/- 13% of patients achieving remission remaining disease-free compared with 31% +/- 7% of CALLA-positive patients. Intensive chemotherapy may produce prolonged disease-free survival in a sizable fraction of adults with ALL. Improved therapy is needed, especially for patients with adverse prognostic features.

scholarly journals Improved results of treatment of adult acute lymphoblastic leukemia

Blood ◽  
1987 ◽  
Vol 69 (4) ◽  
pp. 1242-1248 ◽  
Author(s):  
CA Linker ◽  
LJ Levitt ◽  
M O'Donnell ◽  
CA Ries ◽  
MP Link ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Remission Induction ◽  
Induction Phase ◽  
Free Survival ◽  
Results Of Treatment ◽  
Kaplan Meier ◽  
Wbc Count ◽  
Disease Free

Abstract We designed a treatment program to improve the outcome for adults with acute lymphoblastic leukemia (ALL). Treatment included a remission- induction phase followed by intensive alternating cycles of non-cross- resistant chemotherapy and prolonged oral maintenance therapy. Eighty- one consecutive previously untreated patients were entered on this study. Ninety-four percent of patients entered complete remission. A Kaplan-Meier analysis predicts that 53% +/- 9% (SEM) of patients in remission will remain free of disease at 3 years. Neither age, sex, WBC count, nor immunophenotype had a significant effect on remission duration. This program of intensive cyclical chemotherapy has improved the disease-free survival of patients with adult ALL.

General Outcome of Four Years Experience in the Treatment of Acute Lymphoblastic Leukemia in the National Hospital Edgardo Rebagliati Martins. Lima- Peru.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4105-4105
Author(s):  
Mariela Moreno ◽  
Sergio Murillo ◽  
Jackeline Rodriguez ◽  
Juan Ramon JN Navarro ◽  
Lourdes Aranda ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
National Hospital ◽  
Free Survival ◽  
Disease Free ◽  
Very High

Abstract Abstract 4105 Considering our Pediatric Hematology Unit (PHU), as a social security national reference Unit, one third of the hospitalized children population have acute leukemia in the Pediatrics Department of the National Hospital Hospital Edgardo Rebagliatti Martins- ESSALUD, Lima - Perú. PURPOSE: To analyze survival outcome and behavioral of the disease in children with acute lymphoblastic leukemia (ALL) in a Social Security Hospital of a Developing country. PATIENTS AND METHODS: We analyze 100 pediatrics patients (less than 14 years old) diagnosed with acute lymphoblastic leukemia (ALL) since 2005 to 2008. Disease-free survival (DFS) was computed according to the Kaplan-Meier method and long rank test, using the SPSS 15.0. RESULTS: A total of 100 children were evaluated. The major incidence according to age was in the group of children between 1 and 9 years old (76%); there were no difference between gender: 51% females and 49% males. The B type was the most common diagnosed leukemia: The B CALLA positive (CD10, CD19, HLA, DR) was the most frequent inmunophenotype, present in 87 children (87%). T-cell ALL was seen in 7%, bi-phenotype and Pro B in 3%. According to our risk stratification protocol, 34 patients were in the very high risk group (VHR), 47 patients in the high risk (HR) group and 19 patients in the intermediate-low risk (ILR) group. About Kariotype evaluation, the most common presentations were normal and hyperdiploid kariotype (67%). We achieved Complete Remission in 95% of our patients post 4 weeks Induction therapy (“A” Induction period). The Total 4th year disease free survival was 48.9% (36.3% VHR, 50.4% HR and 75.9% ILR); of these 61.8 ± 6.2% had DFS after 2 years of therapy and 55.9±6.9 % after 3 years. The Disease Free Survival was significantly increased on those with the following risk factors at diagnosis: white blood cell count &lt; 100 000/mm3 (P= 0.002), normal or hyperdiploid kariotype (P&lt;0.0001). However age, gender and type of ALL in our small group do not have statistical significance. The groups of patients not responding to prednisone have identical DFS than the Responding patients, but the no responding patients received treatment as an immediately superior group (High or Very High Risk). All the patients that have more than 1% of Minimal Residual Disease after a 4 week Induction therapy and achieved a Complete Remission with other chemotherapy treatment, had a poor DFS of less than 10 months (P = 0.015). CONCLUSION: The Total DFS was 48.9%. WBC count below 100,000 mm3; normal and hyperdiploid kariotypes, correlate with best DFS. The MDR &gt;1%, was correlated with poor DFS (less than 10 months). The no responding prednisone group must receive a more intensive chemotherapy (the treatment of the immediately superior risk group). The poor DFS at 4 years explain the reason of our therapeutic decision to perform a sibling stem cell Transplant, in those pediatric patients with HR or VHR Acute Lymphoblastic Leukemia (BMT with a 12 year disease free survival of 59.8%). Disclosures: No relevant conflicts of interest to declare.

scholarly journals Allogeneic bone marrow transplantation for patients with acute lymphoblastic leukemia

Blood ◽  
1983 ◽  
Vol 62 (2) ◽  
pp. 381-388 ◽  
Author(s):  
R Dinsmore ◽  
D Kirkpatrick ◽  
N Flomenberg ◽  
S Gulati ◽  
N Kapoor ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Marrow Transplantation ◽  
Lymphoblastic Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Disease Free Survival ◽  
Allogeneic Bone ◽  
Free Survival ◽  
Disease Free ◽  
Relapse Group

Fifty-two patients with acute lymphoblastic leukemia (ALL) underwent allogeneic bone marrow transplantation following cytoreduction with total body irradiation and cyclophosphamide. Twenty-two patients were in second remission, 15 in a later remission, and 15 were in relapse at the time of the transplant. At a median follow-up of 24 mo, 14 of those in second remission survive in continuous remission compared to 5 in later remission and 4 in the relapse group. Statistical analysis showed an improved disease-free survival for the second remission group (p = 0.09). Patients transplanted in later remission or relapse had a similar survival. The improved survival in second remission resulted from a decreased relapse rate posttransplant, as the early mortality from nonleukemic causes was similar among the groups (p = 0.01). In the second remission patients, no characteristics of the initial leukemia were identified that significantly affected outcome. In the combined later remission and relapse group, poor prognosis posttransplant was associated with initial WBC greater than 20K, age at diagnosis older than 10, or initial remission duration less than or equal to 1 yr. These results suggest that extended disease-free survival may be achieved by second remission transplantation and that improved therapy is necessary for later remission or relapse transplants due to the high rate of posttransplant relapse.

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