Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) In Adults With Philadelphia Chromosome (Ph)-Negative Acute Lymphoblastic Leukemia (ALL): Results From The Group For Research On Adult ALL (GRAALL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 552-552 ◽  
Author(s):  
Nathalie Dhédin ◽  
Anne Huynh ◽  
Sébastien Maury ◽  
Reza Tabrizi ◽  
Xavier Thomas ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
White Blood Count ◽  
Prognostic Impact ◽  
Allogeneic Hsct ◽  
Post Transplant ◽  
Unrelated Donors ◽  
B Lineage

Abstract Purpose The pediatric-inspired intensified GRAALL protocol yielded a marked improvement in the outcome of adults with Ph-negative acute lymphoblastic leukemia (ALL) (Huguet et al,JCO 2009), raising the issue of the place of allogeneic HSCT in this new context. We report here the results associated with HSCT in first complete remission (CR) in younger adults treated in the GRAALL-2003/2005 trials. Patients and methods In these trials, HSCT was offered in first CR to patients aged 15-55 years with ALL at higher risk of relapse. High-risk factors included white blood count >30 x 109/L for B-lineage ALL, central nervous system (CNS) involvement, t(4;11)/MLL anomalies, t(1;19), low hypodiploidy/near triploidy, complex karyotype, early resistance to the steroid prephase (CsR), early resistance to chemotherapy (ChR) as assessed by poor bone marrow blast clearance at day 8, and late CR. Per protocol, HSC donor should be a matched sibling or an unrelated donor (10/10 or eventually 9/10 HLA matched) and conditioning regimen should include single fraction 10-Gy or fractionated 12-Gy total body irradiation (TBI) and high-dose cyclophosphamide. The role of HSCT was evaluated by HSCT versus no-HSCT cohort comparison (Mantel-Byar time-dependent analysis). Results Among the 522 high-risk patients eligible, 283 (54%) actually received HSCT in first CR (185 B-lineage and 98 T-lineage ALL; median age, 31 years). There were no significant differences in baseline characteristics and early response between HSCT and no-HSCT cohorts, except more HSCT patients with t(4;11)/MLL anomalies. Among the 283 HSCT patients, 46 had t(4;11)/MLL anomalies, 13 had CNS disease, 116 had CsR and 176 had ChR ALL. Origin of HSC was 140 sibling and 143 unrelated donors, including 47 unrelated donors with 1 HLA mismatch. The following HSCT protocol violations were observed: a) conditioning did not include TBI in 17 patients; b) 10 patients received reduced-intensity conditioning (RIC); and c) 13 patients received cord blood HSCT. These patients remained in the HSCT cohort for the analysis. With a median post-transplant follow-up of 3.5 years, post-HSCT cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and relapse-free survival (RFS) were estimated respectively at 19% (95% CI, 15-25), 16% (95% CI, 12-21) and 64% (95% CI, 58-70) at 3 years, without any RFS difference between sibling and unrelated donors. A marked trend for a higher NRM was observed in patients aged 45 years or more (26% versus 13% at 3 years; HR, 1.6; p=0.059), while post-transplant CIR was similar in older and younger patients. Mantel-Byar RFS estimations showed no significant difference between both HSCT and no-HSCT cohorts (HR, 0.80; p=0.13), meaning that the risk factors used in these protocols failed to identify patients who could significantly benefit from HSCT in first CR. As minimal residual disease (MRD) had a major prognostic impact, we retrospectively analyzed the effect of HSCT in the 278/522 patients evaluated for 6-week Ig/TCR MRD level (154 HSCT and 124 no-HSCT patients, including 92 and 62 patients with MRD >=10-4, respectively). Mantel-Byar RFS estimations showed that HSCT did not benefit to patients with MRD <10-4 (HR, 1.2; p=0.67) as opposed to those with MRD >=10-4 (HR, 0.6; p=0.02), with a positive HSCT-by-MRD interaction (p=0.04) (Figure 1). Conclusion In adult patients with high-risk ALL in first CR treated in the GRAALL-2003/2005 trials, myeloablative allogeneic HSCT from sibling and unrelated donors was associated with a 64% RFS at 3 years. The 26% NRM observed at 3 years in patients aged 45 years or more suggests considering RIC-HSCT in these patients. MRD response appears to be a powerful tool to select patients who might benefit from HSCT. This selection tool will be prospectively evaluated in the next GRAALL-2013 trial. ND and AH contributed equally to the work. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Prognostic impact of kinase-activating fusions and IKZF1 deletions in pediatric high-risk B-lineage acute lymphoblastic leukemia

2018 ◽  
Vol 2 (5) ◽  
pp. 529-533 ◽  
Author(s):  
Thai Hoa Tran ◽  
Marian H. Harris ◽  
Jonathan V. Nguyen ◽  
Traci M. Blonquist ◽  
Kristen E. Stevenson ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Prognostic Factor ◽  
Lymphoblastic Leukemia ◽  
Independent Prognostic Factor ◽  
Prognostic Impact ◽  
Key Points ◽  
B Lineage ◽  
Poor Outcomes

Key Points Fifteen percent of NCI high-risk, Ph-negative, B-ALL patients harbored a kinase-activating fusion, and often associated with IKZF1 deletion. IKZF1 deletion represents an independent prognostic factor of poor outcomes, regardless of fusion-positivity.

scholarly journals Interleukin-4 induces programmed cell death (apoptosis) in cases of high-risk acute lymphoblastic leukemia

Blood ◽  
1994 ◽  
Vol 83 (7) ◽  
pp. 1731-1737 ◽  
Author(s):  
A Manabe ◽  
E Coustan-Smith ◽  
M Kumagai ◽  
FG Behm ◽  
SC Raimondi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Programmed Cell Death ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Fatal Outcome ◽  
Interleukin 4 ◽  
B Lineage

Abstract We investigated the effects of interleukin-4 (IL-4) on the survival of leukemic and normal B-cell progenitors cultured on bone marrow stroma. IL-4 (at 100 U/mL) was cytotoxic in 16 of 21 cases of B-lineage acute lymphoblastic leukemia, causing reductions in CD19+ cell numbers that ranged from 50% to greater than 99% (median 83.5%) of those in parallel cultures not exposed to the cytokine. All nine cases with the t(9;22)(q34;q11) or the t(4;11)(q21;q23), chromosomal features that are often associated with multidrug resistance and a fatal outcome, were susceptible to IL-4 toxicity. IL-4 cytotoxicity resulted from induction of programmed cell death (apoptosis); there was no evidence of cell killing mediated by T, natural killer, or stromal cells. IL-4 cytotoxicity extended to a proportion of normal B-cell progenitors. After 7 days of culture with IL-4 at 100 U/mL, fewer CD19+, CD34+ normal lymphoblasts (the most immature subset) survived: in five experiments the mean (+/- SEM) reduction in cell recoveries caused by IL-4 was 60.0% +/- 6.0%. By contrast, reductions in recovery of more differentiated bone marrow B cells (CD19+, CD34-, surface Ig+) were low (6.6% +/- 2.2%; P < .001 by t-test). Our findings indicate that IL-4 is cytotoxic for human B-cell precursors and support clinical testing of IL-4 in cases of high-risk lymphoblastic leukemia resistant to conventional therapy.

scholarly journals Neurocognitive Functioning of Children Treated for High-Risk B-Acute Lymphoblastic Leukemia Randomly Assigned to Different Methotrexate and Corticosteroid Treatment Strategies: A Report From the Children’s Oncology Group

2017 ◽  
Vol 35 (23) ◽  
pp. 2700-2707 ◽  
Author(s):  
Kristina K. Hardy ◽  
Leanne Embry ◽  
John A. Kairalla ◽  
Shanjun Helian ◽  
Meenakshi Devidas ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Treatment Strategies ◽  
Corticosteroid Treatment ◽  
Neurocognitive Functioning ◽  
Neurocognitive Outcomes ◽  
Leucovorin Rescue ◽  
B Lineage ◽  
The Impact

Purpose Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for neurocognitive deficits that are associated with treatment, individual, and environmental factors. This study examined the impact of different methotrexate (MTX) and corticosteroid treatment strategies on neurocognitive functioning in children with high-risk B-lineage ALL. Methods Participants were randomly assigned to receive high-dose MTX with leucovorin rescue or escalating dose MTX with PEG asparaginase without leucovorin rescue. Patients were also randomly assigned to corticosteroid therapy that included either dexamethasone or prednisone. A neurocognitive evaluation of intellectual functioning (IQ), working memory, and processing speed (PS) was conducted 8 to 24 months after treatment completion (n = 192). Results The method of MTX delivery and corticosteroid assignment were unrelated to differences in neurocognitive outcomes after controlling for ethnicity, race, age, gender, insurance status, and time off treatment; however, survivors who were age < 10 years at diagnosis (n = 89) had significantly lower estimated IQ ( P < .001) and PS scores ( P = .02) compared with participants age ≥ 10 years. In addition, participants who were covered by US public health insurance had estimated IQs that were significantly lower ( P < .001) than those with US private or military insurance. Conclusion Children with high-risk B-lineage ALL who were age < 10 years at diagnosis are at risk for deficits in IQ and PS in the absence of cranial radiation, regardless of MTX delivery or corticosteroid type. These data may serve as a basis for developing screening protocols to identify children who are at high risk for deficits so that early intervention can be initiated to mitigate the impact of therapy on neurocognitive outcomes.

scholarly journals Leukemic cell growth in SCID mice as a predictor of relapse in high- risk B-lineage acute lymphoblastic leukemia

Blood ◽  
1995 ◽  
Vol 85 (4) ◽  
pp. 873-878 ◽  
Author(s):  
FM Uckun ◽  
H Sather ◽  
G Reaman ◽  
J Shuster ◽  
V Land ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Scid Mice ◽  
Leukemic Cells ◽  
Newly Diagnosed ◽  
B Lineage ◽  
Human Leukemic Cells ◽  
Overt Leukemia

Mice with severe combined immunodeficiency (SCID) provide a model system to examine the in vivo homing, engraftment, and growth patterns of normal and malignant human hematopoietic cells. The relation between leukemic cell growth in this model and the treatment outcome in patients from whom cells were derived has not been established. Leukemic cells from 42 children with newly diagnosed high-risk B- lineage acute lymphoblastic leukemia were inoculated intravenously into CB.17 SCID mice. Mice were killed at 12 weeks or when they became moribund as a result of disseminated leukemia. All mice were necropsied and subjected to a series of laboratory studies to assess their burden of human leukemic cells. Twenty-three patients whose leukemic cells caused histopathologically detectable leukemia in SCID mice had a significantly higher relapse rate than the 19 patients whose leukemic cells did not (estimated 5-year event-free survival: 29.5% v 94.7%; 95% confidence intervals, 11.2% to 50.7% v 68.1% to 99.2%; P < .0001 by log- rank test). The occurrence of overt leukemia in SCID mice was was a highly significant predictor of patient relapse. The estimated instantaneous risk of relapse for patients whose leukemic cells caused overt leukemia in SCID mice was 21.5-fold greater than that for the remaining patients. Thus, growth of human leukemic cells in SCID mice is a strong and independent predictor of relapse in patients with newly diagnosed high-risk B-lineage acute lymphoblastic leukemia.

Prognostic Impact of Different High Risk Features in Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in First Complete Remission.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2303-2303
Author(s):  
Theis Terwey ◽  
Philipp Hemmati ◽  
Gero Massenkeil ◽  
Bernd Dörken ◽  
Renate Arnold
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Prognostic Impact ◽  
Very High ◽  
First Complete Remission

Abstract Abstract 2303 Poster Board II-280 Introduction: In acute lymphoblastic leukemia (ALL) specific clinical and biological features confer high relapse risk and inferior overall survival (OS) after treatment with conventional chemotherapy alone. The differential prognostic impact of these high risk features after treatment with allogeneic hematopoietic stem cell transplantation (HCT) has not been well studied. Patients and Methods: 79 adult ALL patients in first complete remission (CR) received allogeneic HCT at our center between 1995 and 2008. All patients were high or very high risk according to German Multicenter Study Group for Adult ALL (GMALL) criteria. Median age was 36 years (range: 17-68). Patients received high-dose conditioning consisting of 12 Gy total body irradiation ± etoposide ± cyclophosphamide (n=69, 87%) or reduced intensity conditioning (RIC) consisting of fludarabine/busulfan/ATG (n=10, 13%) and HSCT from related (n=34, 43%) or unrelated (n=45, 57%) donors. Bone marrow (n=17, 22%) or peripheral blood stem cells (n=62, 78%) were given. Graft-versus-host-disease prophylaxis was CSA/MTX for high-dose conditioning or CSA/MMF for RIC. Results: Patients were classified as high risk or very high risk due to Philadelphia chromosome-positive disease (Ph+) (n=30, 38%), leukocytosis>30/nl at diagnosis in B-ALL (n=25, 23%), late response to induction therapy in B-ALL (>week 4) (n=13, 16%), early or mature T-ALL (n=13, 16%), pro-B-ALL/t(4;11) (n=8, 10%), persistence of minimal residual disease (MRD) (>week 16) (n=8, 10%) or complex aberrant karyotype (n=6, 8%). 57 patients (72%) presented with one high risk feature, whereas 20 patients (25%) and 2 patients (3%) presented with two or three features, respectively. Currently, after a median follow-up of 56 months (7-169) 49 patients (62%) remain alive. Projected OS of the whole cohort at 1, 2 and 5 years was 78%, 70% and 55% and leukemia-free survival was 77%, 66% and 55%. Cumulative incidence of non-relapse mortality (NRM) and relapse mortality (RM) at 5 years was 23% and 18%, respectively. In multivariate Cox regression analysis, a non-significant trend for inferior OS was seen for patients with early or mature T-ALL (hazard ratio (HR): 2.03 (95%CI: 0.92-4.52), p=0.082), whereas no differential effect on OS, NRM or RM was seen for any other high risk feature (Table 1). In additional analyses, inferior OS (HR 1.81 (95%CI: 1.02-3.29), p=0.043) and increased RM (HR 2.17 (95%CI 1.16-4.05), p=0.015) was observed for patients with more than one high risk feature. Conclusions: In summary, this single center study on allogeneic HCT in high risk ALL found a negative prognostic trend for early or mature T cell immunophenotype. No differential prognostic impact on OS, NRM and RM was seen for other high risk features as defined by GMALL criteria, however this conclusion is limited by the low patient number in some of the subgroups. Overall survival for the whole cohort was 55% at 5 years, with inferior OS and higher RM being observed in patients with more than one high risk feature. Disclosures: No relevant conflicts of interest to declare.

Outcome by Treatment Including An Intensified Consolidation Program with Dose-Escalated Doxorubicin for Newly Diagnosed Acute Lymphoblastic Leukemia (ALL): A Study by the Japan Adult Leukemia Study Group (JALSG ALL97 study).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4334-4334
Author(s):  
Itsuro Jinnai ◽  
Tohru Sakura ◽  
Motohiro Tsuzuki ◽  
Yasuhiro Maeda ◽  
Noriko Usui ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Long Term Outcome ◽  
Allogeneic Hsct ◽  
Wbc Count ◽  
Standard Risk ◽  
Group 1

Abstract Abstract 4334 BACKGROUD We designed a multicenter study (JALSG ALL 97) including an intensified consolidation program with dose-escalated doxorubicin (DOX) in order to improve outcome in adults with acute lymphoblastic leukemia (ALL) in pre-imatinib era. We reported here the efficacy and prognostic factors of mainly Philadelphia chromosome (Ph)-negative patients. METHODS From May 1997 to December 2001, patients (age ranges 15 - 64 years) with previously untreated ALL (excluding mature B-cell ALL) were consecutively registered in this study. We modified the standard induction program with five drugs; vincristine (VCR), daunorubicin, cyclophosphamide, prednisolone (PSL) and L-asparaginase and the maintenance program with daily 6-mercaptopurine, weekly methotrexate (MTX) and monthly pulses of VCR and PSL used in CALGB 8811 study. Consolidation therapy included eight courses featuring dose-intensified DOX and intermediate-dose MTX. The total dose of DOX in consolidation phase was 330 mg/m2. For patients with Ph or t(4;11), allogeneic stem cell transplantation (HSCT) was recommended during their first complete remission (CR), if donors were available; whereas for patients without Ph or t(4;11) there was no criteria for choosing HSCT. The 5-year overall survival (OS), the 5-year disease-free survival (DFS), and the prognostic factors were evaluated. RESULTS There were 404 eligible patients (median age, 38 years), of whom 256 were Ph-negative and 116 were Ph-positive. Of the eligible patients, 298 patients (74%) achieved CR. With a median follow-up time of 5.8 years, the estimated 5-year OS rate was 32% (95%CI: 27.1-36.9), and the 5-year DFS was 33% (95%CI: 26.8 - 38.2). The CR rates in Ph-negative and Ph-positive patients were 81% (n=208) and 56% (n=65), respectively. The 5-year OS in Ph-negative and Ph-positive patients were 39% and 15%, respectively. In Ph-negative patients, multivariate Cox analysis showed that older age, PS and WBC count were the independent prognostic factors for OS. The 5-year OS rates for patients younger than 35 years and a WBC count less than 30 × 109/L (risk group 1), for patients younger than 35 years and a WBC count above 30 × 109/L (risk group 2), for patients older than 35 years and a WBC count less than 30 × 109/L (risk group 3), and for patients older than 35 years and a WBC count above 30 × 109/L (risk group 4), were 51%, 29%, 33%, and 27%, respectively (P=0.0005). Of the 208 Ph-negative patients who achieved CR, 60 patients (29%) were underwent allogeneic-HSCT during their first CR (37 from a related donor and 23 from an unrelated donor), resulting that 8 (13%) died in remission, 16 (27%) relapsed, and 36 (60%) remained in continuous CR. The 5-year OS rate for the 60 patients was 63 %. Among them, the 5-year OS rates for the 31 patients of the risk group 1 (standard risk group) and for other 29 patients (high risk group) were 73% and 54%, respectively. Among 148 patients who did not receive allogeneic-HSCT during first CR, six (4 %) died in remission, 105 (71%) relapsed, and 37 (25%) remained in continuous CR. The 5-year OS rates for the 148 patients, for patients with standard risk, and for patients with high risk were 37%, 44% and 33%, respectively. CONCLUSION Result of this study was in the range of those reported by most large cooperative groups, but showed little improvement of adult Ph-negative ALL therapy. The prognostic factors for long term outcome of Ph-negative patients were similar to those in previous reported. This study also suggested that allogeneic-HSCT for Ph-negative patients in first CR might have contributed to the improvement of the outcome. Disclosures: No relevant conflicts of interest to declare.

Outcome of Relapse After Allogeneic Transplantation for Childhood Acute Lymphoblastic Leukemia In Complete Remission. A Study of the Pediatric Diseases and Acute Leukemia Working Parties of the EBMT Group

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1291-1291
Author(s):  
Adriana Balduzzi ◽  
Myriam Labopin ◽  
Vanderson Rocha ◽  
Nabila Elarouci ◽  
Giorgio Dini ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Pediatric Population ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Prognostic Impact ◽  
Dismal Prognosis ◽  
B Lineage ◽  
Donor Lymphocyte Infusions

Abstract Abstract 1291 Introduction. Childhood acute lymphoblastic leukemia (ALL) relapse occurring after hematopoietic cell transplantation (HCT) has a very dismal prognosis. Its treatment is still controversial and ranges from palliative treatment or chemotherapy to donor lymphocyte infusions, second transplant or experimental approaches. Objectives. The aim of this study is to assess the actual outcome in a pediatric population. The primary endpoint of this study is the 2-year probability of survival of children with ALL relapsing after allogeneic HCT; the secondary endpoint is the relationship between outcome and time of relapse after transplant, for which the following categories were considered: <3, 3–6, 6–12, > 12 months. Patients. Patients younger than 18 years of age undergoing first HCT from any allogeneic donor for ALL in first (CR1) or second (CR2) remission between January 1st 1998 and December 31st 2007 reported to the EBMT were eligible for the study. Results. Out of 3628 transplanted children with ALL reported to the EBMT, 836 (median age 9 years, male 66%) relapsed at a median of 6 months (range 1–67; 25th, 75th 4, 12 months) after HCT. The HCT was performed in CR1 (60%) or CR2 (40%) for a B-lineage (60%) or T- (13%) or unknown (27%) immunophenotype ALL, from an HLA-matched related (44%), unrelated (59%) or mismatched related (7%) donor, with marrow (61%), peripheral (28%) or umbilical (11%) stem cells. Out of 836, 81% died at a median of 2 months (25th,75th centiles:1,7) and 19% were reported as alive at last follow-up at a median of 22 months after relapse (range: 1–130). The 3-year probability of overall survival (3y-OS) was 14% (SE 1). As to immunophenotype, disease phase and donor type, 3y-OS was 15% (SE 2) in B-lineage and 8% (SE 3) in T-ALL, 18% (SE 2) in patients transplanted in CR1 and 11% (SE 6) in CR2 and 17% (SE 2) in patients transplanted from an HLA-identical sibling and 12% (SE 2) from any other donor. According to time of relapse after transplant, 3-year OS was 6% (SE 2), 10% (SE 2), 15% (SE 2) and 27% (SE 4) in those who relapsed in the first quarter, second quarter, second semester or after the first year, respectively. Donor lymphocyte infusions were reported for 7% and a second HCT for 16% of the 836 relapsed children. The probability of undergoing a second HCT within 1 year after relapse was 17% (SE 1); this probability was 6% for relapses occurring <6 months and 25% for later relapses. 3y-OS of those who underwent a second HCT was 32% (SE 5). Conclusions. The multivariate analyses confirmed the prognostic role of disease phase and immunophenotype, but not of the type of donor, assessed the strong prognostic impact of the time elapsed in CR after HCT before relapse, being earlier relapses at worse outcome compared with later relapses, possibly due to the chance of undergoing a second HCT, which role per se was not statistically significant. Disclosures: No relevant conflicts of interest to declare.

Novel Chromosomal Rearrangements and Sequence Mutations in High-Risk Ph-Like Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 67-67
Author(s):  
Kathryn G. Roberts ◽  
Ryan D Morin ◽  
Jinghui Zhang ◽  
Martin Hirst ◽  
Richard C. Harvey ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Cytokine Receptor ◽  
Negative Regulator ◽  
Rna Seq ◽  
Kinase Signaling ◽  
Rt Pcr ◽  
B Lineage

Abstract Abstract 67 Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, and relapsed B-lineage ALL remains a leading cause of cancer death in young people. Recent genomic analyses by our group and others identified a unique subtype of BCR-ABL-negative, high-risk B-ALL, with deletion or mutation of IKZF1 and a gene expression profile similar to BCR-ABL1-positive ALL (Ph-like ALL). Up to 50% of Ph-like patients harbor rearrangements of the cytokine receptor gene, CRLF2, with concomitant JAK mutations detected in ∼30%. However, the nature of genetic alterations activating kinase signaling in the remaining cases is unknown. To identify novel genetic alterations in Ph-like ALL, we performed transcriptome sequencing (RNA-seq) on 11 cases of Ph-like B-ALL (10 from the P9906 Children's Oncology Group trial and 1 from the St Jude Total XV study), and whole genome sequencing (WGS) on two of these. Using multiple complementary analysis pipelines including deFuse, Mosaik, CREST and CONSERTING, we identified novel rearrangements, structural variations and sequence mutations dysregulating cytokine receptor and kinase signaling in 10 cases. Putative rearrangements and sequence mutations were validated using RT-PCR, genomic PCR and Sanger sequencing. The spectrum of alterations included 3 cases with known IGH@CRLF2 rearrangement, 2 cases with the NUP214-ABL1 rearrangement, 1 case each with the in-frame fusions EBF1-PDGFRB, BCR-JAK2 or STRN3-JAK2, and 1 case with a cryptic IGH@-EPOR rearrangement. Detailed analysis of RNA-seq data revealed a 7.5 kb insertion of EPOR downstream of the enhancer domain in the IGH@ locus, which was not detected by fluorescence in situ hybridization. WGS identified an in-frame activating insertion in the transmembrane domain of IL7R (L242>FPGVC) in 1 index case, and recurrence screening identified similar IL7R sequence mutations in 8 cases from the P9906 cohort (N=188). This patient also harbored a focal homozygous deletion removing the first two exons of SH2B3 that was not evident by SNP array analysis. SH2B3 encodes LNK, a negative regulator of JAK2 signaling. Notably, all patients harbor genetic lesions affecting B-lymphoid development (e.g IKZF1), suggesting these events cooperate to drive B-lineage ALL. To determine the frequency of each fusion, candidate RT-PCR was performed on 231 cases from the COG AALL0232 trial of high-risk B-ALL, 40 (17%) of which were identified as Ph-like using Predictor Analysis of Microarrays (PAM). The EBF1-PDGFRB fusion was detected in 3 additional patients, each containing an intact PDGFRB kinase domain. No additional cases of NUP214-ABL1, BCR-JAK2, or STRN3-JAK2 were identified. Phosphoflow analysis on 3 primary ALL samples demonstrated increased CKRL phosphorylation in the NUP214-ABL1 case and tyrosine phosphorylation in the cases with BCR-JAK2 and STRN3-JAK2 fusions. Importantly, this activation was reduced with the tyrosine kinase inhibitors (TKI) imatinib, dasatinib and the T315I inhibitor XL228 in cells harboring the ABL1 fusion, and the JAK2 inhibitor, XL019, in the JAK2-rearranged samples. Furthermore, the novel EBF1-PDGFRB fusion transformed Ba/F3 cells to growth factor independence, induced constitutive activation of pSTAT5, pAkt, pERK1/2, and responded with low IC50 values to imatinib, dasatinib and the specific PDGFRB/FGFR inhibitor, dovitinib. Using complementary genomic approaches we show that rearrangements, sequence mutations and DNA copy number alterations dysregulating cytokine receptor and kinase signaling are a hallmark of Ph-like ALL. These data support the screening of patients at diagnosis to identify those with Ph-like ALL, characterize the genomic lesions driving this phenotype, and to determine those that may benefit from TKI treatment. Disclosures: Hunger: Bristol-Myers Squibb: Author's children own stock in BMS, Membership on an entity's Board of Directors or advisory committees.

Long-Term Outcomes after Myeloablative Allogeneic Hematopoietic Cell Transplantation for Adult Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5534-5534
Author(s):  
Moaath Mustafa Ali ◽  
Donna M Abounader ◽  
Lisa A. Rybicki ◽  
Jamie Starn ◽  
Christina Ferraro ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Long Term Outcomes ◽  
Post Transplant

Abstract Allogeneic hematopoietic cell transplantation (alloHCT) is a curative therapy for high-risk acute lymphoblastic leukemia (ALL). However, long-term outcomes after alloHCT for adult ALL have not been well described. We conducted a retrospective cohort study of 72 consecutive adult ALL patients who underwent a first myeloablative alloHCT at our institution from January 2000-December 2013. Median age at HCT was 38 yrs (range, 18-62), 40 (56%) were male, 18 (38%) had high HCT CI score, 14 (19%) had prior CNS leukemia and 35 (49%) had BCR-ABL+ disease. Donor source was HLA-matched related donor for 50% patients and 90% received PBSC as graft source. All patients were transplanted in CR (72% were in 1st or 2nd CR) and 92% received T-cell replete grafts. Median time from diagnosis to alloHCT was 5 months (range, 2-90). The incidences of grade II-IV and III-IV acute GvHD, chronic GvHD and extensive chronic GvHD were 43%, 13%, 51% and 36%, respectively. The median follow-up for our cohort is 76 months. At 6 years after HCT, probability of overall survival (OS) was 33% (95% CI, 21-44%) and relapse-free survival (RFS) was 30% (95% CI, 19-42%), and the cumulative incidence of relapse was 36% (95% CI, 25-48%) and non-relapse mortality (NRM) was 37% (95% CI, 26-49%). The most common causes of death were relapse (43%) and infection (21%); majority of relapses occurred within the first 2-years post-transplantation. There were no second cancer related deaths. In multivariable analyses, factors significantly associated with OS were HCT CI score (HR 2.69 for high vs. low/int., P=0.002) and CMV status (HR 2.62 for donor+ vs. others, P=0.05). HCT CI score was the only predictive factor for RFS (HR 2.26 for high, P=0.007). We also compared outcomes by BCR-ABL status. BCR-ABL+ patients were older (median age 42 vs. 36 yrs, p=0.02), had low HCT CI score (34% vs 22%, p=0.01), were more likely to be in CR1 (74% vs. 32%, p=0.002), and as a result, proceeded to HCT sooner after diagnosis (median 4 vs 7 months, p=<0.001). For BCR-ABL+ and BCR-ABL- patients, 6 year OS was 41% and 25%, RFS was 40% and 21%, relapse was 27% and 45% and NRM was 38% and 36% (P=NS for all comparisons). Myeloablative alloHCT can provide long-term survival for selected high-risk adult ALL patients. Relapses are relatively uncommon after 2 years post-transplant. Long-term NRM is high in this population and we did not observe a plateau in its incidence until 7.5 years post-transplant, suggesting the need for long-term follow up to prevent and manage late complications of alloHCT. Figure 1. Figure 1. Disclosures Majhail: Gamida Cell Ltd.: Consultancy; Anthem Inc.: Consultancy.

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