scholarly journals S1618 TISAGENLECLEUCEL APPEARS EFFECTIVE AND SAFE IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH RELAPSED/REFRACTORY ACUTE LYMPHOBLASTIC LEUKEMIA WITH HIGH-RISK CYTOGENETIC ABNORMALITIES

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 746-747 ◽  
Author(s):  
S. Grupp ◽  
S. Maude ◽  
A. Baruchel ◽  
T.W. Laetsch ◽  
T. Driscoll ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Young Adult ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Cytogenetic Abnormalities

scholarly journals Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia

Blood ◽  
2015 ◽  
Vol 125 (16) ◽  
pp. 2486-2496 ◽  
Author(s):  
Nathalie Dhédin ◽  
Anne Huynh ◽  
Sébastien Maury ◽  
Reza Tabrizi ◽  
Kheira Beldjord ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Key Points ◽  
First Complete Remission

Key Points SCT in first complete remission is associated with 69.5% 3-year overall survival in high-risk ALL adult patients treated with intensified pediatric-like protocol. Poor early MRD response is a powerful tool to select patients who may benefit from SCT in first complete remission.

Fludarabine and Targeted Busulfan Is Safe and Effective Conditioning Before Hematopoietic Stem Cell Transplantation in Adult Patients with Acute Lymphoblastic Leukemia in First Remission

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 891-891
Author(s):  
Ghada M Kunter ◽  
Janelle Perkins ◽  
Lia Perez ◽  
Joseph Pidala ◽  
Teresa Field ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Older Patients ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Unrelated Donor ◽  
Risk Of Relapse

Abstract Abstract 891 Background: Chemotherapy for adult patients with acute lymphoblastic leukemia (ALL) is associated with high risk of relapse and an overall 2-year survival of 40 to 50%. Allogenic hematopoietic cell transplantation (HCT) in first complete remission (CR1) decreases the risk of relapse and improves outcome over chemotherapy for adult ALL pts, but non-relapse mortality (NRM) is a drawback especially in older patients. In the MRC UKALL XII/ECOG E2993 trial, the 2 year NRM of patient with an allogenic donor was 19% in standard risk patients and 36% in patients over 35 years or those with high risk leukemia. We tested safety and efficacy of a non-irradiation regimen consisting of fludarabine (FLU) and pharmacokinetically-targeted busulfan (BU) for adults with ALL in CR1. Methods: We report the outcomes of 42 consecutive patients with ALL in CR1, 21 positive for the Philadelphia chromosome (Ph+). All patients were in complete morphologic remission before HCT. The median age was 33 (range: 19–62) years, 19 were females and 23 males. Median time from diagnosis to HCT was 6 (range: 3–45) months. Thirty patients were treated to achieve an average daily BU area under the curve (AUC) of 5300 microM-min for 4 days, and 12 patients were treated on a clinical trial to achieve an average daily BU AUC of 6000 to 7500 microM-min for 4 days. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus in all patients, in combination with either methotrexate (88%) or sirolimus (12%). Twenty (48%) patients received grafts from matched related donor, 16 (38%) from matched unrelated donor and 6 (14%) from a mismatched unrelated donor. The median follow-up of surviving patients is 2 (median 1.2–4.3) years. Results: Overall survival at 2 years was 66% (95% CI 52%–81%) for all patients, 70% (95% CI 51%–88%) for Ph- and 63% (95% CI 41%–85%) for Ph+ patients (p=0.59). Overall survival did not differ by age, above or below 35 years (p=0.39). Disease-free survival at 2 years was 59% (95% CI 44%–74%) for all patients, 65% (95% CI 45%–84%) for Ph- and 52% (95% CI 28%–74%) for Ph+ pts (p=0.49). The cumulative incidence of relapse at 2-year was 27% (95% CI 16%–45%). The cumulative incidence of acute GVHD grades II–IV was 64% (95% CI 51%–81%) and grades III–IV GVHD was 25% (95% CI 13%–47%). The cumulative incidence of non-relapse mortality (NRM) was 5% (95% CI 1%–18%) at 100 days and 14% (95% CI 7%–30%) at 2 years. Conclusions: These data show that FLU with myeloablative doses of PK targeted BU is an effective alternative to total body irradiation and etoposide or cyclophosphamide for conditioning patients with ALL without an increased risk of relapse after HCT. The low NRM allows to safely delivering myeloablative chemotherapy and allogenic HCT to older patients. This HCT regimen should be prospectively compared to chemotherapy for adult patients with ALL. Disclosures: No relevant conflicts of interest to declare.

Intensive Asparaginase Therapy in Young Adult Patients with Acute Lymphoblastic Leukemia: Treatment Patterns and Barriers to Asparaginase Use

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4913-4913
Author(s):  
Leonard S Sender ◽  
Tina Doede ◽  
Megan P. Hall ◽  
Celine Bernard
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Young Adult ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Employment Equity ◽  
Term Survival ◽  
The Past ◽  
Equity Ownership

Abstract Background : Although considerable progress has been made in treating acute lymphoblastic leukemia (ALL) in the pediatric population, with long-term survival exceeding 80%, the prognosis for adolescents, young adult, and adult patients with ALL remains poor, with only 30%-45% of patients achieving long-term survival. Several studies suggest that young adult patients have superior overall survival when treated with intensive "pediatric-inspired" regimens that include the use of asparaginase [Dombret H, et al. Curr Hematol Malig Rep. 2014;9(2):158-164]. Despite these results, many young adult patients with ALL continue to be treated with chemotherapy regimens that include little or no asparaginase. The goal of this study was to assess the views and practices of hematologists and oncologists with respect to asparaginase use in young adult patients with ALL. Methods : This study was conducted between May 14 and June 22, 2015, and consisted of a 10-minute online quantitative survey, with a 10-minute per-patient chart audit component for up to 4 charts provided by participating physicians. The survey targeted physicians treating young adult patients (aged 18-40 years) with ALL. To be included in the final analysis, physicians were required to be board certified with 2-30 years in practice, with ≥75% of their time spent in direct patient care and ≥20% of their time spent in an academic setting (NCCN/NCI or academic/teaching hospital). Inclusion criteria also required that physicians' total ALL patient volume (young adults and adults aged >40 years) was greater than 5 over the past 2 years, that the physician primarily treats adult patients, and has personally managed and treated at least 1 young adult ALL patient in the past 2 years. Results: The study included results reported by a total of 63 practicing physicians for 189 young adult patients with ALL (62% were aged 25-40 years). Sixty percent (114/189) of young adult patients were treated with a protocol that included asparaginase, and only 29% (55/189) on a pediatric-inspired protocol. The most common protocols reported for patients receiving asparaginase included the pediatric-inspired CALGB 10403 (18%, 21/114), as well as regimens with more limited asparaginase use, including augmented hyper-CVAD (29%, 33/114) and CALGB 8811 (12%, 14/114). Overall 40% (75/189) of young adult patients were treated with protocols that did not include asparaginase, most commonly hyper-CVAD (77%, 58/75). Fifty percent (18/36) of responding physicians using hyper-CVAD reported the perception of similar outcomes with nonasparaginase regimens as with asparaginase-intensive regimens. When questioned about the greatest barrier to the use of intensive asparaginase-containing regimens, 88% (7/8) of responding physicians reported safety and tolerability concerns. Conclusion: Only 6 out of 10 patients in the study were treated with an asparaginase-containing regimen; of all patients, less than 1 out of 3 received a pediatric-inspired regimen. Fifty-three percent (60/114) of asparaginase-receiving patients were treated on a regimen that structures asparaginase dosing intermittently between alternating courses. Pediatric-inspired regimens include intensive asparaginase therapy and have consistently shown improvements in overall survival when compared with traditional adult protocols in clinical trials [Dombret H, et al. Curr Hematol Malig Rep. 2014;9(2):158-164]. Support: This study was funded by Jazz Pharmaceuticals. Disclosures Sender: Jazz Pharmaceuticals: Research Funding, Speakers Bureau. Doede:Jazz Pharmaceuticals: Employment, Equity Ownership. Hall:Jazz Pharmaceuticals: Employment, Equity Ownership. Bernard:Jazz Pharmaceuticals: Employment, Equity Ownership.

scholarly journals High-Risk Subtype of Ph-like Acute Lymphoblastic Leukemia (ALL) in Adults: Dismal Outcomes of CRLF2+ ALL Patients Treated with Intensive Chemotherapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1082-1082 ◽  
Author(s):  
Nitin Jain ◽  
Kathryn G. Roberts ◽  
Elias J. Jabbour ◽  
Keyur Patel ◽  
Karina Eterovic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Hispanic Ethnicity ◽  
Oncology Research

Abstract Background:Ph-like acute lymphoblastic leukemia (ALL) is a high-risk subtype of ALL in children. There are limited and conflicted data on the incidence and prognosis of Ph-like ALL in adults. Methods:Patients with newly-diagnosed B-ALL who received frontline chemotherapy at MD Anderson Cancer Center underwent gene expression profiling of leukemic cells to identify Ph-like ALL. Gene expression profiling was performed on 148 RNA samples using either U133 Plus 2.0 microarrays, or a customized Taqman low density array (LDA) card to identify patients with the Ph-like ALL gene signature (Roberts et al. NEJM 2014). An additional 7 previously untreated patients were found to have CRLF2 overexpression by multicolor flow-cytometry (MFC), and received induction chemotherapy at MDACC were included in the outcome analysis (but not for subtype frequency calculation). We performed targeted sequencing of 303 recurrently mutated genes (L300 panel, MDACC) in 40 patients with CRFL2 rearrangements (15 with matched germline control). Minimal residual disease (MRD) was assessed by MFC, with a sensitivity of 0.01%. Results:Of 148 patients, 49 (33.1%) were Ph-like, 46 patients (31.1%) were Ph+, and 53 patients (35.8%) were of other B-ALL subtypes (B-other). The median age of Ph-like cohort was 33.5 years (range, 15-71), Ph+ cohort was 49 years (range, 22-84), and B-other was 38 years (range, 15-79). Within the Ph-like ALL cohort, 61% had overexpression of CRLF2. Patients received hyper-CVAD (80%) or an augmented-BFM regimen (20%). The rate of CR/CRp was similar in the 3 disease subgroups (Ph-like ALL 89%, Ph+ ALL 93%, B-other 94%, p = 0.57). However, patients with Ph-like ALL were significantly less likely to achieve MRD-negative remission (30% vs. 56% for Ph+ ALL vs. 87% for B-other, p <0.001). Patients with Ph-like ALL had significantly worse overall survival (OS) and event-free survival (EFS) compared to B-other with a 5-year survival of 23% (vs. 59% for B-other, p=0.006) (Figure 1A). The poor outcomes of Ph-like ALL were also observed when only hyper-CVAD treated patients were considered. Interestingly, 68% of the patients with Ph-like ALL (78% among the CRLF2+ cohort) were of Hispanic ethnicity. This was significantly higher compared to Ph+ ALL (35%) and B-other (30%), p <0.001. Patients with CRLF2 overexpression had significantly inferior OS, EFS, and remission duration when compared to other genomic subgroups, including the Ph-like non-CRLF2 group (Figure 1B). Notably, 5-year survival in the CRLF2+ group was <20%. The following were independently associated with inferior OS on multivariable analysis: age (hazard ratio [HR] 2.474, p<0.001); WBC count (HR 1.183, p=0.007); platelet count (HR 4.283, p<0.001) and Ph-like ALL (HR 1.579, p=0.04) (Table 1). The most common mutations by L300 sequencing of 40 patients with CRLF2 were JAK2 (n=19, 47.5%), KRAS (n=10, 25%), CRLF2 (n=7, 17.5%), NRAS (n=5, 12.5%), PAX5 (n=5, 12.5%), JAK1 (n=4, 10%) (Figure 2). The CRLF2 F232C mutation, noted in 7 (17.5%) patients in this study, appears more frequent than in pediatric patients (3/134, 2.2%, Chen et al. Blood 2012), and in range with a smaller adult series (3/14, 21.4%, Yoda et al. PNAS 2010). CRLF2 F232C mutations were mutually exclusive with JAK2/JAK1 mutations (except in one patient). Conclusions:Our findings show a high frequency of Ph-like ALL in adults; an increased frequency of Ph-like ALL in adults with Hispanic ethnicity; significantly inferior outcomes of adult patients with Ph-like ALL; and significantly worse outcomes in Ph-like ALL patients with CRLF2 overexpression. The frequency of CRLF2 F232C mutation appears to be higher in adult patients with B-ALL than in the children. Ph-like ALL represents a high-risk disease subtype of adult B-ALL. Novel strategies are needed to improve the outcome of these patients. Disclosures Jain: Pharmacyclics: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Incyte: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Infinity: Research Funding; Novimmune: Consultancy, Honoraria. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Mullighan:Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Loxo Oncology: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.

scholarly journals Structure and significance of cytogenetic abnormalities in adult patients with Ph-negative acute lymphoblastic leukemia

2018 ◽  
Vol 90 (7) ◽  
pp. 30-37 ◽  
Author(s):  
I S PISKUNOVA ◽  
T N OBUKHOVA ◽  
E N PAROVICHNIKOVA ◽  
S M KULIKOV ◽  
V V TROITSKAYA ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Structural Changes ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Long Term Results ◽  
Serum Lactate Dehydrogenase ◽  
Cytogenetic Abnormalities ◽  
Fish Technique ◽  
Study Results ◽  
Cdkn2a Deletion

Objective. To evaluate occurrence, variety, structural peculiarities and prognostic meaning of cytogenetic abnormalities in adult patients with Ph-negative acute lymphoblastic leukemia (ALL) receiving therapy according to ALL-2009 protocol. Materials and methods. The study included 115 adult patients with firstly diagnosed Ph-negative ALL: 58 male and 57 female aged from 15 to 61 years (mean age 26.5 years), who underwent treatment from September 2009 to September 2015 in National Medical Research Center for Hematology MH RF (n=101) and in hematology departments of regional hospitals (n=14). All patients received therapy of ALL-2009 protocol (ClinicalTrials.gov, NCT01193933). The median follow-up was 24.5 months (0.2-94.4 months). As a part of the study results of a standard cytogenetic assay (SCA) were analyzed and fluorescence hybridization in situ (FISH) with the use of DNA-probes was performed on archived biological material for structural changes in gene locuses MLL/t(11q23), с-MYC/t(8q24), TP53/ deletion 17p13, CDKN2A/ deletion 9p21, translocation t(1;19)/E2A-PBX1 и t(12;21)/ETV6-RUNX1; iAMP21 identification. Results. Karyotype was defined using SCA in 86% of patients. Normal karyotype was found in 48.5% of them, chromosome aberrations in 51.5% (structural changes were found in 19.2%, hyperploidy in 27.2%, and hypoploidy in 5.1%). In 17.2% of patients complex karyotype abnormalities were found. With the use of FISH technique aberrations were found in 67% of patients: 9p21/CDKN2A deletion in 24.3%, MLL/t(11q23) gene abnormalities in 7.8%, 17p13/TP53 deletion in 5.2%, abnormalities of c-MYC/t(8q24) in 1.7%, t(1;19)/E2A-PBX1 in 0.8%, and iAMP21 in 0.8%, other abnormalities (additional signals/absence of signals from gene locuses) in 26.4%, t(12;21)/ETV6-RUNX1 was not found. FISH technique use in addition to SCA allows to increase aberrant karyotype location from 51.5 to 67%. A statistically significant correlation of 9p21/CDKN2A deletion with high serum lactate dehydrogenase activity (p=0.02); MLL/t(11q23) gene abnormalities - with leucocytosis and high blast cells level in blood (p=0.0016), hyperploidy - with normal leukocyte count (p=0.02) was shown. In groups with different cytogenetic abnormalities no statistically significant differences of treatment with ALL-2009 protocol were found (in terms of complete remission, early mortality and treatment resistance). When connection of cytogenetic abnormalities and their combinations with long-term results were analyzed according to ALL-2009 protocol, only two characteristics - MLL/t(11q23) and c MYC/t(8q24) gene abnormalities had a statistically significant influence on disease-free survival (HR - 176.9; p

Genomic Characterization and Experimental Modeling Of BCR-ABL1-Like Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 232-232 ◽  
Author(s):  
Kathryn G. Roberts ◽  
Yongjin Li ◽  
Debbie Payne-Turner ◽  
Richard C. Harvey ◽  
Jinjun Cheng ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Young Adult ◽  
High Risk ◽  
Tyrosine Kinase ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Hematopoietic Progenitor Cell ◽  
Oncology Group ◽  
Genomic Landscape ◽  
Primary Mouse

Abstract BCR-ABL1-like B-progenitor acute lymphoblastic leukemia (B-ALL) accounts for 10-15% of childhood B-ALL and is characterized by alteration of IKZFI, a gene expression profile similar to BCR-ABL1 ALL and poor outcome. Using next-generation sequencing, we have shown that BCR-ABL1-like ALL patients harbor genetic alterations activating kinase pathways that are sensitive to tyrosine kinase inhibitors (TKIs), and have shown that refractory BCR-ABL1-like ALL is responsive to TKIs in vivo (Weston et al., J. Clin. Oncol 2013). Furthermore, the outcome of ALL in adolescent and young adult (AYA) patients is inferior to children, yet the genetic basis underlying treatment failure is poorly understood. To define the frequency and genomic landscape of BCR-ABL1-like ALL in children, adolescents, and young adults we have extended our studies to include 665 high-risk childhood (<16 years, 14% BCR-ABL1-like), 370 adolescent (16-21 years, 21% BCR-ABL1-like) and 161 young adult (21-39 years; 26% BCR-ABL1-like) B-ALL cases from the Children's Oncology Group, St Jude Children's Research Hospital, Eastern Cooperative Oncology Group, MD Anderson Cancer Center and the Alliance - CALGB trials. Event-free survival (EFS) for BCR-ABL1-like cases was inferior to non BCR-ABL1-like cases with 5-year EFS rates of 40.0±7.1 vs 85.0±3.3 (p<0.0001) for adolescent cases and 16.1±8.5 vs 57.9±8.0 (p=0.006) for young adult cases. In each age group, 50-60% of BCR-ABL1-like cases harbored rearrangements of CRLF2 (IGH@-CRLF2 or P2RY8-CRLF2) (Fig. 1). To characterize the full spectrum of kinase lesions in the remaining BCR-ABL1-like ALL cases we performed mRNA-seq on pediatric (n=39), adolescent (n=21) and young adult (n=22) cases, and whole genome (WGS; n=18) or exome sequencing (n=10) on cases with matched tumor and normal material. Fusion transcripts were identified using deFuse and CICERO, a novel assembly-based structural variation detection method specifically designed for mRNA-seq analysis. We identified 23 different kinase rearrangements involving 7 tyrosine kinase or cytokine receptor genes. These consist of 5 ABL1, 2 PDGFRB, 8 JAK2 fusions and 2 EPOR translocations to IGH@ and IGK@ loci, along with new fusions involving the tyrosine kinases ABL2 (n=3), CSF1R (n=1), AKT2 (n=1) and STAT5B (n=1). We performed frequency testing for 15 of these fusions on 555 cases from the COG AALL0232 trial of high-risk B-ALL. Several alterations were recurrent in BCR-ABL1-like ALL, including NUP214-ABL1, RCSD1-ABL2, SSBP2-CSF1R, PAX5-JAK2 and EPOR translocations. Notably, we did not identify any of these fusions in non BCR-ABL1-like cases. The frequency of ABL1/ABL2 and EPOR translocations was consistent across all age groups (∼16% and 7% of BCR-ABL1-like cases, respectively), while JAK2 rearrangements were more common in young adult than in pediatric and adolescent ALL (12%). Importantly, ∼10% of BCR-ABL1-like ALL cases lacked a kinase-activating alteration on analysis of mRNA-seq data. Notably, we identified two additional cases with IL7R or SH2B3 sequence mutations, indicating the requirement for complementary approaches such as WGS to fully define the genomic landscape of BCR-ABL1-like ALL. Current functional studies include the development of experimental models using the Ba/F3 hematopoietic progenitor cell line, primary mouse pre-B cultures and the generation of xenografts to determine the role of these alterations in leukemogenesis, and to enable testing of targeted therapies. For example, we show that RCSD1-ABL1 and SSBP2-CSF1R confer factor-independent growth and constitutive activation of JAK/STAT pathways in Ba/F3 cells. Furthermore, RCSD1-ABL1 and SSBP2-CSF1R are both sensitive to the TKIs, imatinib (IC50 378nM and 327nM, respectively) and dasatinib (IC50 2.1nM and 2.5nM, respectively). Together, these complementary approaches will further define the genetic landscape of both pediatric and AYA ALL, and facilitate the development of diagnostic and therapeutic strategies to improve the treatment outcome for high-risk BCR-ABL1-like ALL patients. Disclosures: Hunger: Bristol Myers Squibb: Consultancy.

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