Outcome for Adolescents and Young Adults (AYA) with the Hyper-CVAD (with or without Rituximab) Regimens for De Novo Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3084-3084 ◽  
Author(s):  
Deborah A. Thomas ◽  
Michael Rytting ◽  
Susan O'Brien ◽  
Stefan Faderl ◽  
William G. Wierda ◽  
...  
Keyword(s):  
B Cell ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Dose Intensity ◽  
Cd20 Expression ◽  
Adolescents And Adults ◽  
Pediatric All ◽  
Adverse Influence

Abstract Abstract 3084 Poster Board III-21 AYAs aged 16–20 yrs with de novo ALL or LL have superior outcomes when treated with intensive pediatric regimens; event-free survival rates range from 60–70% compared to 30–40% after conventional adult chemotherapy [Stock W, Blood 112:1646, 2008]. This is in part attributed to higher dose intensity (and cumulative dose) of the anthracycline, vincristine [VCR], corticosteroid and asparaginase components. The intensive hyper-CVAD regimen (fractionated cyclophosphamide, VCR, doxorubicin, dexamethasone alternating with methotrexate and cytarabine) was originally modeled after childhood therapy for Burkitt lymphoma, and had been applied as frontline adult ALL therapy without age restriction since 1992. In contrast to conventional adult or pediatric ALL regimens, asparaginase is not administered during induction or consolidation phases. Modifications to the regimen have included the addition of rituximab for CD20 positive precursor B-cell ALL owing to adverse influence of CD20 expression, particularly in the younger subgroup [Thomas D, Blood 113:6330, 2009]. An adapted augmented Berlin-Frankfurt-Munster (BFM) regimen modeled after the CCG experience was developed specifically as frontline therapy for adolescents and adults up to age 30 in lieu of the hyper-CVAD regimen at our institution; accrual is ongoing. We updated the previous comparative hyper-CVAD experience in this young adult subset. One hundred seventy-six pts aged 13 to 30 yrs (median 22 yrs) with de novo ALL (n=149) or LL (n=27) were treated with hyper-CVAD (n=96) or modified hyper-CVAD (25 with anthracycline intensification, 55 without; 32 overall with rituximab). Eighty-three (47%) were less than 21 years of age (median 19 yrs). Forty-nine (29%) were CD20 positive. Overall complete remission (CR) rate was 97%; overall 3-yr CR duration (CRD) and survival (OS) rates were 65% and 70%, respectively. Rates for 3-yr CRD and OS were 68% and 75% if age 21 yrs or less, compared with 60% and 66%, respectively, if age 22 to 30 yrs (p=NS). The addition of rituximab improved the 3-yr CRD rates from 26% to 65% (p=.001) and 3-yr OS rates from 47% to 75% (p=.05) for the CD20 positive precursor B-cell ALL subsets, partly accounting for the improvement in outcomes. There were no significant differences in outcome by regimen for the CD20 negative subsets (all 3-yr rates > 70%). Outcomes with the hyper-CVAD regimens in AYAs appear to more closely resemble those of the pediatric approaches than the conventional regimens; incorporation of pegylated asparaginase and intensification of vincristine/corticosteroids (e.g., augmented hyper-CVAD) may further improve the efficacy of this regimen in the frontline setting. Incorporation of rituximab or the novel CD20 antibodies such as ofatumumab into the pediatric regimens warrants consideration. Disclosures No relevant conflicts of interest to declare.

Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LL) after Frontline Therapy with Hyper-CVAD Regimens.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1930-1930 ◽  
Author(s):  
Deborah A. Thomas ◽  
Susan O’Brien ◽  
Michael Rytting ◽  
Stefan Faderl ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Dose Intensity ◽  
Entire Cohort ◽  
Cd20 Expression ◽  
Adolescents And Adults ◽  
Frontline Therapy ◽  
Adverse Influence ◽  
Optimal Approach

Abstract AYAs aged 16–20 with de novo ALL or LL have superior outcomes when treated with intensive pediatric regimens; event-free survival (EFS) rates range from 60–70% compared to 30–40% after conventional adult chemotherapy [Stock W, Blood 2008, e-pub]. This is in part attributed to higher dose intensity (and cumulative dose) of the anthracycline, vincristine [VCR], corticosteroid and asparaginase components. Of note, the intensive hyper-CVAD regimen (cyclophosphamide, VCR, doxorubicin, dexamethasone alternating with methotrexate/cytarabine) was originally modeled after childhood therapy for Burkitt lymphoma. It has been applied as frontline adult ALL therapy without age restriction since 1992. In contrast to conventional adult or pediatric ALL regimens, asparaginase is not administered during the induction or consolidation phases. Modifications to the regimen have included the addition of rituximab for CD20 positive precursor B-cell ALL and LL owing to adverse influence of CD20 expression, particularly in the younger subgroup [Thomas D, Blood 2008, e-pub]. An adapted augmented Berlin-Frankfurt- Munster (BFM) regimen modeled after the CCG experience was developed specifically as frontline therapy for adolescents and adults up to age 30 in lieu of the hyper-CVAD regimen at our institution; accrual is ongoing. We reviewed the previous hyper-CVAD experience in the AYA subset. One hundred two pts aged 13 to 21 yrs (median 19 yrs) with de novo ALL (n=92) or LL (n=10) were treated with hyper-CVAD (15 with rituximab). Complete remission (CR) rate was 97%; 3-yr EFS and OS rates were 65% and 70%, respectively. Preliminary reports from other investigators suggest that an intensified pediatric approach may be feasible even up to age 60. The GRAALL-2003 study reported 42-mos EFS and OS rates of 55% and 58%, respectively, in 225 de novo ALL pts aged 15– 60 (median 31 yrs) [Huget F, ASCO 2008, abstr 7005]. Median follow-up was 37 mos. A similar cohort of pts treated with the hyper-CVAD regimens included 385 pts with a slightly older median age of 35 yrs. Median follow-up was 62 mos (range, 1–180 mos). EFS and OS rates for the entire cohort were 50% and 55%, respectively. For pts below the age of 35, these rates improved to 55% and 67%. Clearly age remains a prognostic factor even with intensive chemotherapy approaches. Outcomes with the hyper-CVAD regimens appear to more closely resemble those of the pediatric approaches than the conventional regimens. Continued monitoring of ongoing prospective clinical trials using pediatric regimens in adults is paramount to delineating the optimal approach.

Chemoimmunotherapy with a Modified Hyper-CVAD and Rituximab Regimen Improves Outcome for Patients with De Novo Philadelphia Negative Precursor B-Cell Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 836-836
Author(s):  
Deborah A. Thomas ◽  
Hagop M. Kantarjian ◽  
Stefan Faderl ◽  
William G. Wierda ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
B Cell ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
High Dose ◽  
Induction Phase ◽  
Liposomal Daunorubicin ◽  
Cd20 Expression

Abstract Abstract 836 The hyper-CVAD regimen is an effective frontline program for de novo adult ALL and LL [Kantarjian, JCO 18:547, 2000; Kantarjian, Cancer 101:2788, 2004, Thomas, Blood 104:1624, 2004]. Intensive chemotherapy with hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternates with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone). Historical CR rate was 92% with 3-year disease-free survival (DFS) rate of 38%. The regimen was modified in 1999. Induction chemotherapy was given in a protective environment owing to higher mortality in patients (pts) aged 60 years or older (17% vs 3%). Course 2 of liposomal daunorubicin and cytarabine was incorporated owing to reports suggesting benefit of early anthracycline intensification. Rituximab 375 mg/m2 (days 1 & 11 of hyper-CVAD, days 1 & 8 of methotrexate-cytarabine) was given if CD20 expression was 20% or greater due to its association with disease recurrence [Thomas, Blood 113:6330, 2009]. The maintenance phase was extended to 30 months with additional intensifications owing to late relapses after completion of POMP therapy. Newly diagnosed or primary refractory (1 course only) pts with ALL (n=204) or LL (n=27) were treated on the two sequential studies. Burkitt-type leukemia/lymphoma (BLL) and Philadelphia positive ALL were treated on alternative protocols. From May 2000 to December 2001, 69 pts were treated with modified hyper-CVAD with anthracycline intensification (9 induction-consolidation courses). Course 2 was then eliminated from the regimen (8 courses), with an additional 162 pts treated to date (pts age 30 years or less are now treated with augmented BFM). Median age was 43 yrs (range, 15–83). CD20 expression was noted in 49%. Overall CR rate of the evaluable group (n=225) was 93%; 7 pts achieved PR (LL with residual disease), five failed to respond, and 4 died during the induction phase. Three-yr CRD and OS rates were 70% and 62%, respectively after a median follow-up of 50 months (range, 2–106+). In the younger CD20 positive precursor B-cell ALL subset (n=99), rituximab improved outcome compared to historical experience with hyper-CVAD alone (n=127), with 3-yr CRD rates (75% vs 45%, p<.001) and OS rates (65% vs 38%, p<.001) approaching those of their CD20 negative counterparts. In contrast to the Burkitt experience, rituximab was not beneficial for the elderly subgroup (OS rates 28% vs 34%, p NS). Anthracycline intensification did not improve outcome. The addition of rituximab to the hyper-CVAD regimen appears to benefit the younger pts (age less than 60 yrs) with CD20 positive precursor B-cell ALL. Incorporation of rituximab and other monoclonal antibodies (e.g., ofatumumab, epratuzumab) into frontline chemotherapy regimens for ALL should be investigated systematically. Disclosures: No relevant conflicts of interest to declare.

scholarly journals IKZF1deletions Coupled with CD20 Expression Represents a Novel High-Risk Subtype in Adult B-Cell Progenitor Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4474-4474
Author(s):  
Bingqing Tang ◽  
Zhixiang Wang ◽  
Dainan Lin ◽  
Xianjun He ◽  
Zihong Cai ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
Validation Cohort ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Poor Outcome ◽  
Cd20 Expression ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Genetic deletions of IKZF1 are associated with poor prognosis in B-cell acute lymphoblastic leukemia (B-ALL). Here we investigated the effect of IKZF1 deletions (IKZF1 del) plus with immunotype in adult B-ALL in PDT-ALL-2016 cohort. This cohort study involved 161 patients with B-ALL from 2016 to 2019, with detailed information about IKZF1 del and CD20 expression. Validation cohort consists N= patients from TARGET cohort. IKZF1 del was detected in 36.0% of patients with 3-year event-free survival (EFS) of 37.2±6.7% and overall survival (OS) of 51.1±7.3%, compared to IKZF1 wild-type (IKZF1 wt) with EFS 55.4±5.1% (P&lt;0.01) and OS 74.6±4.5% (P&lt;0.05), respectively. CD20 expression was also associated with inferior EFS than CD20-negative group (P&lt;0.05). Furthermore, IKZF1 del coupled with CD20 expression, termed as IKZF1 del/CD20+, comprised 12.4% of patients with 3-year EFS of 25.0±9.7% compared with IKZF1 wt (P&lt;0.05 ) and IKZF1 del/CD20- (P&lt;0.05 ) groups, respectively. Multivariable analyses demonstrated independence of IKZF1 del/CD20+ with highest hazard ratio for EFS and OS. Furthermore, the prognostic strength of IKZF1 del/CD20+ was confirmed in TARGET validation cohort. Eighty-one patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT). Notably, neither IKZF1 del(P=0.6288), CD20 (P=0.0705) or IKZF1 del/CD20 (P=0.3410) groups were identified as poor outcome in allo-HSCT cohort. Collectively, our data demonstrate that IKZF1 del/CD20+ represents a very high-risk subtype in adult B-ALL; and particularly, allo-HSCT could overcome the poor outcome of IKZF1 del and IKZF1 del/CD20+. Disclosures No relevant conflicts of interest to declare.

Significance of Minimal Residual Disease (MRD) by Multiparameter Flow Cytometry (MFC) In Adults with De Novo Acute Lymphoblastic Leukemia (ALL) After Therapy with the Modified Hyper-CVAD Regimen

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2145-2145
Author(s):  
Deborah A. Thomas ◽  
Susan O'Brien ◽  
Jeffrey Jorgensen ◽  
Sa A. Wang ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
De Novo ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Philadelphia Chromosome ◽  
Multiparameter Flow Cytometry ◽  
High Dose ◽  
Increased Risk ◽  
Cd20 Expression

Abstract Abstract 2145 The hyper-CVAD regimen is an effective frontline program for de novo adult ALL [Kantarjian, JCO 18:547, 2000; Kantarjian, Cancer 101:2788, 2004]. Intensive cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternate with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone) interrupted with early and late intensifications. The regimen was modified in 1999 in order to improve on the results. Induction chemotherapy was administered in a laminar air flow room for pts aged 60 years or older owing to high induction mortality rate (17%). Rituximab 375 mg/m2 (days 1 & 11 of hyper-CVAD, days 1 & 8 of MTX-cytarabine for 8 total doses) was given if CD20 expression was > 20% owing to association with increased propensity for relapse [Thomas D, Blood 113:6330, 2009]. CNS prophylaxis alternated intrathecal MTX day 2 with cytarabine day 7 of the first 3 courses for low CNS risk and first 4 courses for high CNS risk (in the absence of CNS disease). The maintenance phase was extended from 24 to 30 mos with modifications of the early and late intensifications (hyper-CVAD followed by MTX-L-asparaginase mos 6 & 7 and 18 & 19) in order to reduce incidence of late relapses. Newly diagnosed or primary refractory (1 course only) pts with Philadelphia chromosome negative B-lymphoblastic leukemia (n=126) were treated with this modified hyper-CVAD regimen without anthracycline intensification (pts age 30 years or less have been allocated to treatment with the pediatric-inspired augmented Berlin-Frankfurt-Muenster regimen since 2006). Median age was 43 yrs (range, 15–83). CD20 expression was noted in 49%. Overall CR rate of the group was 93%; the rate of MRD negativity by 4- or 6-color MFC (sensitivity of 0.01%) at the time of CR in 95 evaluable pts was 72%. Overall, MRD positivity by MFC at the time of CR was associated with a higher relapse rate (52% versus 21%, p=.01) and lower 3-yr CR duration rates (45% versus 78%, p=.01). The CD20 positive pts (n=57) who were treated with rituximab had a higher rate of MRD negativity by MFC at CR than their CD20 negative counterparts (81% versus 58%, p=.02). MRD positivity by MFC after hyper-CVAD and rituximab was associated with a significantly lower 3-yr CR duration rate (24% versus 82%, p=.002), but survival rates were not statistically different (27% versus 70%) likely due in part to deaths in CR in the older subset of the MRD-negative group. In contrast, for the CD20 negative subset, presence of detectable MRD by MFC at the time of CR was not associated a with lower 3-yr CR duration rate (58% versus 63%). Dectectable MRD by MFC at the time of CR, despite subsequent eradication with consolidation chemotherapy in the majority of patients, predicts for increased risk of disease recurrence. Strategies to improve the MRD negativity rate at the time of CR (e.g., addition of monoclonal antibodies directed at other lymphoblast antigens such as CD22 for the CD20 negative subset and use of the newer anti-CD20 monoclonal antibodies for the CD20 positive subset) may further improve outcome after frontline therapy with the modified hyper-CVAD regimens. Disclosures: Thomas: Novartis: Honoraria; Bristol-Meyer-Squibb: Honoraria; Pfizer:; Amgen: Research Funding. Off Label Use: Imatinib for de novo Philadelphia positive ALL. Dasatinib for de novo Philadelphia positive ALL. Rituximab for CD20 positive ALL and Burkitt leukemia/lymphoma. Nelarabine for de novo T-lymphoblastic leukemia/lymphoma.

CD20 up-Regulation In Induction Therapy for Childhood B Lymphoblastic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2124-2124 ◽  
Author(s):  
Tanya C. Watt ◽  
Sunita Park ◽  
Todd Cooper
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Prognostic Significance ◽  
Cell Precursor ◽  
Cd20 Expression ◽  
Anti Cd20

Abstract Abstract 2124 Background: Despite improvement in survival rates for B lymphoblastic leukemia (B-ALL), children who relapse have dismal outcomes. Antibody-directed therapies represent a novel strategy to improve survival rates. Approximately 50% of children diagnosed with B-ALL express CD20 on the blast surface, providing a potential therapeutic target.1 A recent study in Europe suggested one week pretreatment with corticosteroids resulted in an increase in CD20 expression, even in samples that were initially CD20 negative.2 This increased expression potentiated cytotoxicity by rituximab, an anti-CD20 monoclonal antibody. Demonstration of CD20 up-regulation on lymphoblasts in children treated with combination cytotoxic chemotherapy and corticosteroids would provide an important rationale for the inclusion of CD20 monoclonal antibody therapy in childhood B-ALL. Methods: A retrospective review was performed on 84 consecutive children diagnosed with B-ALL between June 2008 and March 2010 at Children's Healthcare of Atlanta. Flow cytometry records were reviewed for expression of CD20 on the surface of leukemic blasts at various time points during induction (day 1, 8, 15, and 29). Samples were considered positive for CD20 if greater than 20% of blasts expressed the antigen. To quantify the exact percentage of CD20 expression, lymphoblasts were gated on the CD19 surface antigen, and the percentage of blasts with surface CD20 was recorded. The Wilcoxon signed-rank test (2-tailed) was used to assess the significance of the differences between data in paired samples. Comparisons between the following paired bone marrow samples were performed: day 1 and 8, day 1 and 15, day 1 and 29, day 8 and 15, and day 15 and 29. For each analysis, only samples with both data points were included. Results: Sixty-eight percent of patients had positive CD20 expression on the diagnostic bone marrow specimen. At day 8, 22% of the initially negative samples expressed CD20. As demonstrated in Table, the mean percentage of lymphoblasts that expressed CD20 increased from day 1 through the remainder of therapy. The difference in the percentage of blasts that expressed CD20 between days 1 and 8 and days 1 and 15 was statistically significant. Comparisons between other days were limited by a small sample size, obviating any difference in the data. There was no difference in up-regulation between patients treated with dexamethasone or prednisone during induction. Conclusions: Adult studies suggest that CD20 expression in B-ALL confers a worse prognosis. 3 A recent clinical trial demonstrated an improved 3 year EFS (68 vs. 28%, p<0.001) in CD20 positive B-ALL adults with the addition of rituximab.4 In vitro work by Dworzak et al suggests one week of corticosteroid monotherapy increases CD20 expression, leading to increased rituximab cytotoxicity.2 Our data demonstrates statistically significant up-regulation in children, even in the setting of multi-agent chemotherapy such as that used in pediatric clinical trials. This data provides rationale for the addition of CD20 monoclonal antibodies to induction therapy in childhood B-ALL. References: 1. Jeha S, Behm F, Pei D, et al. Prognostic significance of CD20 expression in childhood B-cell precursor acute lymphoblastic leukemia. Blood 2006;108:3302-4. 2. Dworzak MN, Schumich A, Printz D, et al. CD20 up-regulation in pediatric B-cell precursor acute lymphoblastic leukemia during induction treatment: setting the stage for anti-CD20 directed immunotherapy. Blood 2008;112:3982-8. 3. Thomas DA, O'Brien S, Jorgensen JL, et al. Prognostic significance of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia. Blood 2008. 4. Thomas D CJ, et al. Update of the modified hyper-CVAD regimen with or without rituximab in newly diagnosed adult acute lymphoblastic leukemia (ALL). ASH Abstract 2008. Disclosures: No relevant conflicts of interest to declare.

Outcome after Frontline Therapy with the Modified Hyper-CVAD Regimen with or without Rituximab for De Novo Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LL).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1931-1931 ◽  
Author(s):  
Deborah A. Thomas ◽  
Hagop Kantarjian ◽  
Stefan Faderl ◽  
William G. Wierda ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
B Cell ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
The Elderly ◽  
High Dose ◽  
Induction Phase ◽  
Intensive Chemotherapy ◽  
Cd20 Expression ◽  
Laminar Air Flow

Abstract The hyper-CVAD regimen is an effective frontline program for de novo adult ALL and LL [Kantarjian, JCO18:547, 2000; Kantarjian, Cancer101:2788, 2004, Thomas, Blood104:1624, 2004]. Intensive chemotherapy with hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternates with high dose methotrexate and cytarabine every 21 days for 8 courses, followed by maintenance with POMP (6-mercaptopurine, methotrexate, VCR, prednisone). Historical CR rate was 92% with 3-year disease-free survival (DFS) rate of 38%. The regimen was modified in 1999 to address the following: higher induction mortality in patients (pts) aged 60 years or older (17% vs 3%); possible benefit of early anthracycline intensification; worse survival with CD20 expression [Thomas D, Blood, e-pub]; and late relapses after completion of POMP therapy. Hyper-CVAD Modified Hyper-CVAD Laminar air flow rooms No For age ≥60 yrs Dose-intensive anthracycline No C2 lipo DNR & ara-C Rituximab No For CD20 ≥20% Intrathecal CNS prophylaxis 4, 8 (16 BL) 6, 8 (16 BL) POMP maintenance 24 mos 30 months Intensifications Months 7, 11 Months 6, 7 & 18, 19 Newly diagnosed or primary refractory (1 course only) pts with ALL (n=184) or LL (n=27) were treated on two sequential studies. Burkitt-type leukemia/lymphoma (BLL) and Philadelphia positive ALL were treated on alternative protocols. From May 2000 to December 2001, 69 pts were treated with the modified regimen as detailed above (9 courses of intensive chemotherapy). Course 2 was then eliminated from the regimen (8 courses of intensive chemotherapy), with an additional 145 pts treated to date. Median age was 40 yrs (range 15–83). CD20 expression was noted in 40%. Overall CR rate of the group (n=211) was 90%; 4 pts achieved PR, five failed to respond, and 3 died during the induction phase. After a median follow-up of 42 months (range, 2–80), outcome appeared favorable for the younger group (30 yrs or less) with 3-year remission duration (CRD) and survival (OS) rates of 70% and 80%. In the CD20 positive precursor B-cell ALL subset (n=88), rituximab improved outcome compared to historical experience, with 3-yr CRD rates (68% vs 28%, p&lt;.001) and OS rates (65% vs 35%, p=.01) approaching those of the CD20 negative counterparts. In contrast to the Burkitt experience, rituximab was not beneficial for the elderly subgroup (OS rates 48% vs 35%, p NS). Anthracycline intensification appeared to worsen outcome. Rituximab appears to benefit the younger pts with CD20 positive precursor B-cell ALL. Incorporation of rituximab and other monoclonal antibodies (e.g., ofatumumab, epratuzumab) into frontline chemotherapy regimens should be investigated systematically.

scholarly journals Extensive RAG-Mediated Rearrangements and Mutations in BCR-ABL1 and BCR-ABL1-like Adult Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4067-4067
Author(s):  
Mathijs A. Sanders ◽  
Anikó Szabó ◽  
Carla Exalto ◽  
Remco Hoogenboezem ◽  
Annelieke Zeilemaker ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cells ◽  
B Cell ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Cell Development ◽  
B Cell Development ◽  
Genetic Events

Abstract BCR-ABL1 and BCR-ABL1-like acute lymphoblastic leukemia (ALL) are two major pre-B cell acute leukemia subtypes characterized by genetic alterations affecting lymphoid-specific transcription factors. Studies examining the chain of genetic events necessary to develop leukemia established that the BCR-ABL1 fusion gene and kinase-activating BCR-ABL1-like lesions are initiating events, however, insufficient for leukemia development. Secondary genetic events targeting B cell development genes are therefore an essential requirement for overt ALL. A recent study (Papaemmanuil et al, Nat. Genet., 2014) revealed that illegitimate RAG-mediated recombination is the predominant mutational mechanism establishing these secondary genetic events in ETV6-RUNX1 ALL. Of note, ETV6-RUNX1ALL is mainly restricted to pediatric cases and it remains unanswered whether this mutational process also plays a prominent role in adult ALL pathogenesis. We carried out a detailed genomic characterization to determine whether aberrant RAG activity is also a prominent mutational driver in certain adult B cell ALL (B-ALL) subtypes. Diagnostic material of 53 unselected B-ALL cases and matched remission specimens were characterized using DNA mapping arrays to discern copy number alterations (CNAs). We observed multiple BCR-ABL1/BCR-ABL1-like patients with abundant genetic lesions and selected 5 cases for targeted sequencing of CNA boundaries to determine whether these lesions were driven by RAG-mediated recombination. Whole genome sequencing (WGS) for a single BCR-ABL1-like patient was used to asses this mutational mechanism genome-wide. In total 64 structural variants (SVs) could be analyzed at base-pair level. De novo motif detection on breakpoint sequences revealed the prominence of the heptamer CACAGTG (E-value=5.68x10-91), a constituent of the recombination signal sequence (RSS), present in 121 out of 128 breakpoints (94.5%). RSS detection revealed that 58 out of 64 SVs (90.6%) had a cryptic RSS (cRSS) on one or both sides of the lesion. Incorporation of non-templated sequences was observed for 54 out of the 64 (84.4%) SVs. Superimposition of breakpoints on chromatin marks revealed a strong enrichment for active promoters and enhancers (p < 2.2x10-16). WGS data revealed cRSS motifs and incorporation of non-templated sequences for 23 out of 26 SVs (88.5%). Integrative analysis of all 6 cases confirmed 125 unique SV breakpoints strongly enriched for the active chromatin marks H3K4me3 and H3K27ac. STAT5 binding, a postulated regulator of V(D)J recombination, is similarly enriched at the breakpoints. Promiscuous binding of RAG1 and RAG2 was previously noted in human thymocytes and murine pre-B cells (Teng et al, Cell, 2015). Strikingly, the breakpoints are frequently bound by RAG2 in human thymocytes. In total 66 out of 125 breakpoints could be translated to the murine genome and revealed a strong enrichment of RAG1 and RAG2 binding at homologous positions in murine pre-B cells. Exhaustive mutation detection revealed complex somatic mutations within cRSS motifs, which are rare V(D)J recombination products introduced by erroneous cleavage and error-prone repair (open-and-shut joints). Strikingly, 4 out of 6 BCR-ABL1/BCR-ABL1-like cases had mutations in the BTLA promoter-situated cRSS, frequently in combination with a RAG-mediated deletion of the other allele (Figure 1). Genomic screening in 142 B-ALL patients confirmed 8 additional cases with BTLA promoter mutations, predominantly (6 out of 8) belonging to the BCR-ABL1/BCR-ABL1-like subgroups. We provide strong evidence that aberrant RAG activity plays a pivotal role in the development of BCR-ABL1/BCR-ABL1-like adult ALL. We demonstrate that breakpoints are strongly enriched for RAG binding implying a predisposition for illegitimate V(D)J recombination. Importantly, we report on a novel mutational mechanism introducing mutations in cRSS motifs through open-and-shut joints, frequently resulting in the biallelic inactivation of BTLA. Proliferation and V(D)J recombination during pre-B cell development is orchestrated by the interplay of IL7R and pre-BCR signalling. Strikingly, most kinase-activating lesions constitutively activate these signalling cascades and could enact, in concert with BTLA inactivation, constant proliferation, pro-survival and V(D)J recombination-initiating signals with disastrous consequences. Disclosures No relevant conflicts of interest to declare.

scholarly journals Anlotinib Shows Potent Antileukemia Effects in B-Cell Acute Lymphocytic Leukemia through the Blockage of Angiogenic Related Pathways

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 49-49
Author(s):  
Qiuling Chen ◽  
Yuelong Jiang ◽  
Qinwei Chen ◽  
Long Liu ◽  
Bing Xu
Keyword(s):  
B Cell ◽  
Solid Tumors ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Unmet Need ◽  
Lymphocytic Leukemia ◽  
Advanced Lung Cancer ◽  
Antitumor Effects

Acute lymphoblastic leukemia (ALL) derives from the malignant transformation of lymphoid progenitor cells with ~85% being originated from B-cell progenitors (B-ALL). Despite fairly good prognoses for most pediatric B-ALL patients, the outcome is fatal in over 50% of adult patients who have a recurrent or progressive disease and lack of effective therapeutic approaches. Therefore, novel treatment strategies with high efficacy and low toxicity are an unmet need for B-ALL patients, especially those with relapsed or refractory status. Angiogenesis is a process of new vessel formation that requires the participation of multiple proangiogenic factors (e.g., VEGF, PDGF, and FGF) and their corresponding receptors (e.g., VEGFR, PDGFR, and FGFR). Angiogenesis, a well-established feature of solid tumors, also contributes to leukemia progression and correlates with the involvement of specific sanctuary sites in ALL, highlighting that the perturbation of angiogenesis would be an attractive approach for ALL treatment. Anlotinib is an oral tyrosine kinase (TKI) inhibitor with a broad range of antitumor effects via the suppression of VEGFR, PDGFR and FGFR. Of importance, anlotinib has been approved for the treatment of advanced lung cancer in China. Here, we evaluated the antileukemia activity of anlotinib in preclinical B-ALL models and its underlying molecular mechanisms. In this study, we observed that anlotinib significantly blunted the capability of cell proliferation and arrested cell cycle at G2 phase in B-ALL cell lines. Subsequently, we found that anlotinib resulted in remarkably enhanced apoptosis in B-ALL in vitro. To assess the in vivo antileukemia potential, we established a B-ALL patient-derived xenograft (PDX) mouse model and then treated the B-ALL PDX model with anlotinib. As a result, oral administration of anlotinib pronouncedly delayed in vivo B-ALL cell growth and reduced leukemia burden with acceptable safety profiles in this model. As for the mechanism of action, the antileukemia effect of anlotinib was associated with the disruption of the role of VEGFR2, PDGFRb, and FGFR3. Moreover, we revealed that this drug blocked the PI3K/AKT/mTOR/ signaling, a pathway that is linked with angiogenesis and its proangiogenic regulators, including VEGFR2, PDGFRb, and FGFR3. In aggregate, these results indicate that anlotinib is a potent antitumor agent for the treatment of B-ALL via the inhibition of angiogenic relevant pathways, which provide a novel potential treatment intervention for patients with B-ALL who have little effective therapy options. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Anlotinib originally designed by China is a novel orally active multitarget inhibitor that is evaluating in clinical trials against multiple solid tumors.

scholarly journals Novel CD19/CD22 Bicistronic Chimeric Antigen Receptors Outperform Single or Bivalent Cars in Eradicating CD19+CD22+, CD19-, and CD22- Pre-B Leukemia

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 810-810 ◽  
Author(s):  
Haiying Qin ◽  
Sang M Nguyen ◽  
Sneha Ramakrishna ◽  
Samiksha Tarun ◽  
Lila Yang ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Single Chain ◽  
Dual Targeting ◽  
Single Antigen ◽  
Therapeutic Function

Abstract Treatment of pre-B cell acute lymphoblastic leukemia (ALL) using chimeric antigen receptor expressing T cells (CART) targeting CD19 have demonstrated impressive clinical results in children and young adults with up to 70-90% complete remission rate in multiple clinical trials. However, about 30% of patients relapse due to loss of the targeted epitope on CD19 or CART failure. Our CD22-targeted CAR trial has generated promising results in relapsed/refractory ALL, including CD19 antigen negative ALL, but relapse associated with decreased CD22 site density has occurred. Thus, developing strategies to prevent relapses due to changes in antigen expression have the potential to increase the likelihood of durable remissions. In addition, dual targeting of both CD19 and CD22 on pre-B ALL may be synergistic compared to targeting a single antigen, a potential approach to improve efficacy in patients with heterogeneous expression of CD19 and CD22 on leukemic blasts. We describe the systematic development and comparison of the structure and therapeutic function of three different types (over 15 different constructs) of novel CARs targeting both CD19 and CD22: (1) Bivalent Tandem CAR, (2) Bivalent Loop CAR, and (3) Bicistronic CAR. These dual CARs were assembled using CD19- and CD22-binding single chain fragment variable (scFv) regions derived from clinically validated single antigen targeted CARs. They are structurally different in design: both tandem and loop CARs have the CD19 and CD22 scFv covalently linked in the same CAR in different orders, whereas, bicistronic CARs have 2 complete CAR constructs connected with a cleavable linker. The surface expression on the transduced T cell of the CD19/CD22 dual CARs was detected with CD22 Fc and anti-idiotype of CD19 and compared to single CD19 or CD22 CARs. Activities of dual CARs to either CD19 or CD22 were evaluated in vitro with cytotoxicity assays or killing assays against K562 cells expressing either CD19 or CD22 or both antigens and also tested against a leukemia CD19+/CD22+ cell line, NALM6, and NALM6 with CRISPER/CAS9 knockout of CD19 or CD22 or both antigens. Therapeutic function of the top candidates of the dual CARs was then validated in vivo against these NALM6 leukemia lines. Some of these dual CARs were also further tested against patient-derived xenografts. Finally, we tested the dual targeting CARs in an artificial relapse model in which mice were co-injected with a mix of CD19 knockout and CD22 knockout NALM6 leukemia lines. From these studies, we established that the order of the scFv, size of the linker, type of leader sequence, and co-stimulatory domain in the CAR constructs all impact the efficacy of the dual targeting CARs. Tandem, Loop, and Bicistronic CARs all demonstrate some levels of in vitro and in vivo activities, but the bicistronic CAR was most effective at clearing leukemia and preventing relapse. In the CD19+/CD22+ NALM6 model, bicistronic CAR treated mice remain disease free while CD19 CAR or CD22 CAR treated mice already died or relapsed on day 27. In the relapse model, as expected, CD19 or CD22 single CAR T cell treatment resulted in progression of the corresponding antigen-negative NALM6. Treatment with dual targeted bicistronic CARs resulted in clearance of both CD19 and CD22 negative ALL with durable remission. In summary, we described novel CD19/CD22 dual targeting CARs with robust pre-clinical activity against pre-B cell ALL, and validated this approach in the prevention of resistance to single-antigen targeted CARs in preclinical models. Disclosures No relevant conflicts of interest to declare.

scholarly journals IKZF1 Deletion Is An Independent Predictor of Outcome In Pediatric Acute Lymphoblastic Leukemia Treated According to the ALL-BFM 2000 Protocol

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 409-409
Author(s):  
Petra Breithaupt ◽  
Barbara Meissner ◽  
Martin Zimmermann ◽  
Anja Möricke ◽  
André Schrauder ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
High Risk ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Risk Group ◽  
Independent Predictor ◽  
Lymphoblastic Leukemia ◽  
Time Points ◽  
Pediatric All

Abstract Abstract 409 Alteration of the IKZF1 gene – encoding the transcription factor IKAROS, a key player in lymphoid development and tumor suppression – has been reported to be associated with a poor outcome in pediatric precursor B-cell ALL, especially in cases positive for the BCR-ABL1 fusion gene. In order to assess the prognostic value of IKZF1 deletions in a representative cohort of pediatric ALL patients treated on the German ALL-BFM 2000 study protocol, we screened 409 patients by applying a multiplex ligation-dependent probe amplification (MLPA) assay covering all eight IKZF1 exons (P335-A3 ALL-IKZF1 probemix; MRC-Holland, Amsterdam, The Netherlands). In ALL-BFM 2000, risk group stratification (standard, SR; intermediate, MR; high, HR) was based on minimal residual disease (MRD) analysis at two different time points (TP) and required two MRD targets with sensitivities of ≤10−4 (Flohr et al. Leukemia 2008). SR patients were MRD-negative on treatment days 33 (TP1) and 78 (TP2). HR patients had residual disease (≥10−3) at TP2. MRD MR patients had positive MRD detection at either one and or both time points but at a level of <10−3 at TP2. Although MRD-based stratification criteria were introduced in ALL-BFM 2000, established high-risk parameters were also retained: patients with prednisone poor-response or ≥5% leukemic blasts in the bone marrow on day 33 or positivity for a t(9;22) or t(4;11) or their molecular equivalents (BCR/ABL1 or MLL/AF4 fusion RNA) were stratified into the high-risk group independent of their MRD results. First results on MRD and outcome were published earlier (Conter et al. Blood 2010). Out of the 409 patients analyzed in our study, 46 (11%) displayed a deletion in at least one of the eight IKZF1 exons. Forty-three out of the 46 cases showed heterozygous deletions, while 3 patients displayed homozygous loss of IKZF1 exons. MLPA results of 11 patients were validated with results derived from copy number/LOH analyses using Affymetrix SNP 6.0 arrays. IKZF1 deletion was significantly more common in precursor B compared to T cell ALL (13% vs. 4%, P = 0.03) and less frequent in TEL/AML1-positive ALL (3% vs. 13%, P = 0.004). Out of 11 BCR/ABL1-positive samples, only two were characterized by an IKZF1 deletion. Forty-four patients with IKZF1-deleted ALL had results of MRD analyses available for both informative time points (day 33 after induction and day 78 after consolidation). Despite a trend towards increasing incidence of IKZF1 deletion in patients with slow response, the distribution of IKZF1-deleted ALL patients over the risk groups was not significantly different from non-deleted ALL (SR: 40.9 vs. 41.9; MR: 45.5 vs. 52.3; HR: 13.6 vs. 5.7%; P = 0.153). Regarding treatment outcome, patients with an IKZF1 deletion had a significantly lower 5-year event-free survival (EFS) compared to non-deleted patients (0.78±0.06 vs. 0.86±0.02; P = 0.015). This result was due to a higher cumulative incidence of relapses in IKZF1-deleted patients (0.16±0.05 vs. 0.10±0.02; P = 0.031). In multivariate Cox regression analyses including known prognostic variables (gender, immunophenotype, WBC count at diagnosis, TEL/AML1 status, risk group criteria of ALL-BFM 2000), IKZF1 deletion conferred a risk of 2.16 (95% confidence interval 1.14 – 4.10; P = 0.018) for an event when compared to non-deleted patients. We conclude that IKZF1 deletion is an independent predictor of treatment outcome for patients enrolled on the ALL-BFM 2000 protocol and represents a candidate marker to be integrated in future algorithms for early risk stratification in pediatric ALL. Disclosures: No relevant conflicts of interest to declare.

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