Comorbidities Reduce Response to Induction Treatment and Survival in Adults with Philadelphia-Negative Acute Lymphoblastic Leukemia

Background. Comorbidities have a well-established prognostic value in the majority of hematologic neoplasms. However, the impact of comorbidities on adult patients with acute lymphoblastic leukemia (ALL) has been poorly investigated to date. Aims. In this retrospective study of a monocentric cohort of 112 adults with Philadelphia-negative (Ph-neg) ALL consecutively diagnosed between 1990 and 2018 we aimed to assess the association between comorbidities at diagnosis and remission rate, the frequency and severity of adverse events (AE) during frontline treatment, and long-term outcome. Patients and methods. Patients were included, regardless of age, if treated within or according to clinical protocols aimed at curing. Patients initially treated with low-intensity/palliative care were not considered. Ph-positive patients were excluded, as their treatment modalities markedly changed over years due to the availability of tyrosine kinase inhibitors. Patients were defined as high risk if one or more of the following features were present: WBC >30x109/L for B-cell precursor (BCP) or >100x109/L for T-cell precursor (TCP), pro-B, early or mature T ALL phenotype, high risk cytogenetics (according to the ESMO 2016 guidelines), or central nervous system involvement. Comorbidities recorded at diagnosis were classified according to the Charlson Comorbidity Index (CCI). Classification and grading of AE was performed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Responses were defined according to the ESMO 2016 guidelines. Minimal residual disease (MRD) was assessed by 6- or 8-colour flow cytometry with a 10-4 sensitivity. Variables tested for association with complete remission (CR) and MRD-negative status were: age group (stratified into quartiles), gender, phenotype (BCP or TCP), WBC, karyotype, risk class, and CCI score. Event-free survival (EFS) was calculated from the first CR to relapse or death. Overall survival (OS) was calculated from diagnosis until death. EFS and OS were estimated using the Kaplan-Meier method. Results. Median age at diagnosis was 43 years (range 14-75). BCP and TCP were 78% and 22%, respectively. Overall, 51 patients (46%) were considered as standard risk, 46 (41%) as high risk, and 15 (13%) were unclassifiable due to the lack of cytogenetics. CCI score distribution was as follows: 0 (n=66; 59%), 1 (n=18; 16%), 2 (n=9; 8%), and ≥3 (n=19; 17%). CR after induction therapy was obtained by 95/112 patients (85%). CCI was the only variable significantly associated to CR achievement (0-1 vs ≥2: 91% vs 68%; p=0.012). MRD status at the end of induction was evaluable in 64 out of 95 patients in CR and was negative in 28 (44%). No pretreatment variable predicted for the achievement of MRD complete response. Eight patients (7%) died before the first response evaluation; early death rate was significantly higher in patients with CCI ≥2 than in patients with CCI 0-1 (21% vs 2%; p=0.003). Conversely no differences in AE frequency and severity were observed according to CCI (p=0.847) or age group (p=0.881). After a median follow-up of 35 months, 46 patients (41%) were alive. OS was significantly longer in patients with CCI 0-1 as compared to CCI ≥2 (median 87 months, 95%CI: 31 to not reached vs 13 months, 95%CI: 5-36; p<0.001). Notably, pre-treatment risk stratification lost prognostic value in predicting OS and EFS in CCI 0-1 patients, while in CCI ≥2 patients retained its significance (Figure). Overall, 58 patients (52%) were primary refractory or relapsed. Relapse rate was similar according to age groups, phenotype, risk class, and CCI score. CR rate after salvage treatment (CR2) was higher in younger patients (≤43 vs >43 years: 81% vs 44%; p=0.014) and tended to be higher in patients treated with blinatumomab or inotuzumab rather than with standard chemotherapy (82% vs 55%, p=0.17). While there were no differences in CR2 according to CCI group, median survival after first relapse was 12.1 months (95%CI: 7.83-15.24) for CCI 0-1 vs 6.92 months (95%CI: 2.49-12.59) for CCI≥2(p=0.021). Conclusions. Comorbidities have a significant prognostic impact in intensively-treated adults with Ph-neg ALL. Patients with low comorbidities (CCI 0-1) had superior CR rates and less incidence of toxic death after induction, and pre-treatment high risk features did not have a detrimental impact in this group. Figure Disclosures Krampera: Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Bonifacio:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria.

Download Full-text

Blinatumomab Is Well Tolerated Maintenance Therapy Following Allogeneic Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2019-125931 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1298-1298 ◽

Cited By ~ 4

Author(s):

Partow Kebriaei ◽

Pinaki P Banerjee ◽

Christina Ganesh ◽

Mecit Kaplan ◽

Vandana Nandivada ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Checkpoint Inhibitors ◽

Lymphoblastic Leukemia ◽

Advisory Committees ◽

Active Disease

Background: Patients with high-risk or multiply relapsed B-lineage acute lymphoblastic leukemia (ALL) have a very high rate of relapse, even after allogeneic hematopoietic cell transplantation (HCT). In an effort to reduce the risk for relapse, we investigated the role of blinatumomab (Blin), a bi-specific T cell immunotherapy targeting CD19, as maintenance therapy following allogeneic HCT for adult patients with advanced B ALL. We rationalized that this is an ideal agent with little cytotoxicity, and the potential to provide immune protection against disease relapse during the first year post HCT when graft versus leukemia (GVL) is still maturing. Methods: Adult patients with B-ALL deemed high risk for relapse defined as disease stage beyond CR1, any active disease including MRD, or presence of high risk molecular mutations or karyotype at time of HCT, or patients with evidence of MRD immediately following HCT, were eligible for study enrollment; prior Blin treatment was allowed. Patients with active disease defined as >5% malignant blasts or active GVHD requiring steroid therapy post HCT were excluded. Patients were scheduled to receive 4 cycles of Blin as a continuous intravenous infusion at the dose of 28 microgram/24 hours over 4 weeks, with the first cycle to be administered within the first 3 months post HCT after count recovery; the subsequent cycles were administered at 6, 9, and 12 months following HCT (day of hematopoietic progenitor cell infusion). Dose escalation for cycle 1 and hospitalization for observation during cycles 1 and 2 followed standard FDA issued guidelines. Results: 14 patients enrolled to date with 12 patients treated with median age 30 years (range, 21-65 years); two patients did not proceed with treatment due to graft versus host disease (GVHD). Patient characteristics and outcomes are listed in Table 1. The median days to start of therapy post HCT was 84 (range, 38-105 days). The treatment was well tolerated with no reported cytokine release syndrome, GVHD, graft failure, or grade 5 adverse events (AE). A cumulative 26 cycles of Blin were administered with 7 Blin-related grade 3 or 4 AEs reported (leukopenia n=4, transaminitis n=2, rash n=1). Grade 2 neurotoxicity manifesting as confusion and dysphagia requiring temporary suspension of therapy and short course steroids noted in 1 patient. Median follow up was 8.5 months post HCT (range 2-35 months). All 4 patients who were MRD positive prior to start of Blin have progressed and 2 have died. None of the 8 patients who were MRD negative post transplant has relapsed. We performed multiparametric flow cytometry studies on serial peripheral blood patient samples collected prospectively at multiple time points to measure T cell subsets, T-cell function and cell surface expression of various checkpoint inhibitors including PD1, TIGIT, Tim3, 2B4 and CD160. Samples were studied on an X-20 Fortessa, and the data analyzed using Kaluza software. Interestingly, the 4 patients who progressed on Blin maintenance had lower CD8 to CD4 ratio compared to non-progressors (17:60 vs. 46:42) (Figure 1). Furthermore, compared to healthy controls, we observed higher levels of checkpoint molecules as multiple checkpoints per cell. PD1 and TIGIT upregulation and co-expression were more common in progressing patients compared to non-progressors (Figure 2). Conclusion: We observed that Blin maintenance following allogeneic HCT for B ALL is well tolerated. More patients need to be treated to confirm the efficacy of this approach. This approach is encouraging for high risk ALL patients who are MRD negative post transplant. Strategies to increase CD8 levels and blockade against checkpoint inhibitors may overcome resistance to therapy. Disclosures Kebriaei: Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria; Kite: Honoraria. Ravandi:Xencor: Consultancy, Research Funding; Selvita: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding. Jabbour:Adaptive: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian:AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Agios: Honoraria, Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Astex: Research Funding; Ariad: Research Funding. Champlin:Sanofi-Genzyme: Research Funding; Johnson and Johnson: Consultancy; Actinium: Consultancy.

Download Full-text

Leukemia Cells with a BCR-ABL1-Like signature and/or IKZF1 deletions, but Not High CRLF2 Expression, Are Predictive of an Unfavorable Prognosis in Childhood B Cell Precursor Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v120.21.880.880 ◽

2012 ◽

Vol 120 (21) ◽

pp. 880-880

Author(s):

Arian Van Der Veer ◽

Esmee Waanders ◽

Rob Pieters ◽

Marieke E. Willemse ◽

Simon Reijmersdaal ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

High Risk ◽

B Cell ◽

Minimal Residual Disease ◽

Prognostic Value ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Cell Precursor ◽

Molecular Features ◽

Minimal Residual

Abstract Abstract 880 Background The prognosis of childhood B cell precursor acute lymphoblastic leukemia (BCP-ALL) has improved enormously due to risk-adapted therapeutic stratification of patients. Still, most relapses occur in the group that is supposed to have an intermediate relapse risk. To overcome this problem, new prognostic markers are needed. Recently, new high-risk molecular features were identified in BCP-ALL: the BCR-ABL1-like signature, IKZF1 deletions and high CRLF2 expression (CRLF2-high). These features can occur together; however, whether they confer independent prognostic value is currently unknown. In this study we determined the frequency, co-occurrence and prognostic relevance of these new molecular features in four independent cohorts of children with ALL. Methods BCR-ABL1-like gene signature (110-gene probe classifier), IKZF1 deletions (Multiplex Ligation-dependent Probe Amplification) and CRLF2 expression levels (Affymetrix U133 plus 2.0) were determined in leukemic cells (>90% blasts) from 1128 children with newly diagnosed ALL enrolled in three consecutive Dutch Childhood Oncology Group trials (DCOG ALL-8/-9/-10) and in the German COALL-97/03 trial. The cumulative incidence of relapse (CIR) was calculated using death as a competing event. Results BCR-ABL1-like, IKZF1-deleted and CRLF2-high cases were found in 16%, 17% and 10% of the BCP-ALL cases, respectively. Collectively, these three features constitute 34% of BCP-ALL cases for which 4% of those had all three, 29% had any two and 67% had only one these features. The BCR-ABL1-like signature and IKZF1-deletions co-occurred the most frequent of these three features (22%). The BCR-ABL1-like signature was only found in B-other cases negative for the genetic abnormalities ETV6-RUNX1, BCR-ABL1, hyperdiploid, TCF3- and MLL-rearrangement, whereas IKZF1-deleted and CRLF2-high cases were also found in other subtypes of BCP-ALL. The frequency of IKZF1- deletions was highest in BCR-ABL1- positive (70%) and BCR-ABL1-like (40%) cases. The BCR-ABL1-like signature, IKZF1 deletions and CLRF2-high were associated with prognosis in four, three and one out of 4 studied treatment protocols, respectively. Protocol-stratified analysis revealed that five-year CIR was higher in BCR-ABL1-like (32%, p<0.001) and IKZF1- deleted (34%, p<0.001) compared to other BCP-ALL cases (11% and 13%, respectively), whereas no unfavorable CIR was associated with the CRLF2-high feature. IKZF1- deleted cases also were at higher risk of relapse in the hyperdipoid (5-year CIR 34%, p=0.04) and non-BCR-ABL1- like B-other group (5-year CIR 40%, p=0.02) compared to 9% for non-deleted BCP-ALL cases whereas IKZF1-deletions had no (additive) prognostic value in ETV6-RUNX1- positive or BCR-ABL1-like cases. Cases with only the BCR-ABL1-like signature (HR 5.3) or only an IKZF1 deletion (HR 4.4) as well as those cases positive for both features (HR 3.7) were at higher risk to develop an adverse event than those cases negative for both features (p<0.001). Together these two features accounted for 62.9% of all relapses in BCP-ALL whereas no relapse occurred in the cases with high CRLF2 expression as single feature. The adverse prognosis associated with BCR-ABL1-like signature and/or IKZF1-deletions was independent of other risk factors including age and white blood cell count. Moreover, the BCR-ABL1-like signature (HR=3.7 p=0.026) and IKZF1- deletions (HR 2.7, p=0.043) were predictive of an unfavorable prognosis in the group of BCP-ALL cases with intermediate minimal residual disease levels at day 79 of treatment. Conclusions High CRLF2 expression is the least predictive, whereas the BCR-ABL1-like signature and IKZF1- deletions –both individually and combined- are strong independent prognostic factors and have additional prognostic value on top of intermediate minimal residual disease levels in children with BCP-ALL. These findings demonstrate that these two molecular features are important clinically for identifying high-risk patients who may require more intensive therapy. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Genetic Characteristics and Clinical Outcomes of T-Cell Acute Lymphoblastic Leukemia; Myeloid-Suppressive Therapeutic Approach Based on Allogeneic Hematopoietic Cell Transplantation May Benefit in Early T-Cell Precursor Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2019-129870 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1470-1470

Author(s):

Jae-Ho Yoon ◽

Han Bi Lee ◽

Gi June Min ◽

Sung-Soo Park ◽

Silvia Park ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Board Of Directors ◽

Clinical Outcomes ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Lymphoblastic Leukemia ◽

Cell Precursor ◽

Advisory Committees

Background: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a recently recognized high-risk subgroup of T-cell ALL. T-cell ALL is characterized by poorer survival outcomes compared to B-cell ALL, but the optimal treatment strategies are not well elucidated yet. Aim: We performed integrative genetic analyses and tried to find important genetic events in T-cell ALL. We also identified clinical outcomes of T-cell ALL including ETP-ALL subgroup, which were treated with myeloid-suppressive chemotherapy followed by allogeneic hematopoietic cell transplantation (allo-HCT) for post-remission therapy. Methods: We enrolled 40 adult patients with T-cell ALL for analyses of gene mutations and treatment outcomes. Integrative genetic analyses were performed with massive parallel sequencing for NOTCH1, FBXW7, DNMT3A, PHF6, RUNX1, KRAS, NRAS, PTEN, GATA3, EZH2 and SH2B3, and multiplex ligation-dependent probe amplification (MLPA) for copy number alterations of several genes. Among them, quantification of CDKN2A and CDKN2B mRNA expression was performed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). All were treated with myeloid-suppressive chemotherapy which consisted of hyper-fractionated cyclophosphamide (300 mg/BSA, every 12 h, days 1-3), vincristine (1.4 mg/BSA, maximum dose 2 mg, days 4 and 11), daunorubicin (45 mg/m2, days 4 and 11), and dexamethasone (40 mg, days 1-4 and days 11-14) for remission induction, followed by consolidation with high-dose cytarabine (2 g/BSA, every 12 h, days 1-5) and mitoxantrone (12 mg/BSA, days 1-2). Above two anthracycline-intensified regimens were alternatively used for further consolidation. For patients not in complete remission (CR), mitoxantrone (12 mg/BSA, d 1-4), cytarabine (2 g/BSA, every 12 h, d 1-4) and etoposide (100 mg/BSA, d 5-7) were used for reinduction. Our strategy for T-cell ALL in CR was to offer allo-HCT according to the donor availability. Results: We identified 16 patients with ETP-ALL presenting 1 or more stem cell or myeloid marker with absence of CD1a, CD5, and CD8 expression, and 24 patients with non-ETP-ALL. For genetic mutation profiles between ETP-ALL and non-ETP-ALL, we found DNMT3A was more frequently observed in ETP-ALL (25% vs. 12.5%), while FBXW7 (33.3% vs. 6.2%) and RUNX1 (25.0% vs. 0.0%) were more frequently observed in non-ETP-ALL. We also observed that CDKN2A expression was significantly higher in ETP-ALL (0.053 vs. 0.001, p=0.017). In total, 33 (82.5%) patients achieved CR (24 after induction, 9 after reinduction) and their estimated 5-year overall survival (OS) was 31.3% with median survival of 18.9 months. All 16 (100%) patients with ETP-ALL achieved CR (13 after induction, 3 after reinduction), while non-ETP-ALL in 17 (70.8%, 11 after induction, 6 after reinduction) patients. Estimated 5-year OS of ETP-ALL was 41.7% and non-ETP-ALL was 24.3% (p=0.135). Finally, 12 (75.0%) out of 16 ETP-ALL and 11 (45.8%) out of 24 non-ETP-ALL underwent allo-HCT in CR and their 5-year OS was 55.6% and 45.5%, respectively. Conclusion: Our data suggested different genetic predisposition between ETP-ALL and non-ETP-ALL and myeloid-suppressive chemotherapy showed a good CR rate in ETP-ALL. Myeloid-suppressive chemotherapy induced CR followed by post-remission allo-HCT can be a good solution for improving poor survival outcome of ETP-ALL. Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

Download Full-text

Outcome of Infants Younger Than 1 Year with Acute Lymphoblastic Leukemia Treated with the Interfant-06 Protocol; Results from an International Randomised Study

Blood ◽

10.1182/blood-2018-99-112854 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 655-655 ◽

Cited By ~ 1

Author(s):

Rob Pieters ◽

Paola De Lorenzo ◽

Philip Ancliffe ◽

Luis Alberto Aversa ◽

Benoit Brethon ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Board Of Directors ◽

Lymphoblastic Leukemia ◽

Survival Rates ◽

Risk Groups ◽

Advisory Board ◽

Advisory Committees ◽

Randomised Study ◽

European North

Abstract INTRODUCTION Infant acute lymphoblastic leukemia is a high-risk subtype characterized by a very high incidence of KMT2A (MLL) gene rearrangements. In 1999, a large international consortium (Interfant) commenced; the first Interfant-99 protocol (Pieters et al, Lancet 2007) was used as baseline for the current Interfant-06 study, which run in 18 groups worldwide. AIMS To determine:In a randomised study whether two AML-type courses ADE (araC, daunorubicin, etoposide) and MAE (mitoxantrone, araC, etoposide) after induction improved outcome compared to the consolidation IB course in KMT2A-rearranged cases (MR and HR risk group). With a target of 320 randomised cases, the study had 80% power to detect a DFS difference of 16% at 3 years (41% DFS in the control arm, α=0.05).The prognostic relevance of clinical and biological parameters.The outcome of Interfant-06 versus Interfant-99.The role of SCT in HR patients and in MR patients with MRD ≥ 10e-4 at the start of OCTADAD. As Interfant-99 showed outcome differences between the West-European/North-American groups who started Interfant (original countries) versus other countries that joined later, analyses were also performed separately in these groups. RISK GROUPS AND TREATMENT Three risk groups were defined: low risk (LR) - KMT2A germline; high risk (HR) - KMT2A rearrangement plus age < 6 months plus white blood cell count (WBC) >300 x 10e9/L or a poor prednisone response; medium risk (MR) - comprised all other KMT2A-rearranged cases. Treatment consisted of induction (prednisone prephase, dexamethasone, VCR, asparaginase, DNR), consolidation phase, either IB (araC, 6-MP, cyclofosfamide) or ADE/MAE in the experimental arm, MARMA (HD-araC, HD-MTX, 6-MP, asparaginase), OCTADAD (VCR, dexamethasone, asparaginase, DNR, 6-TG, araC, cyclofosfamide) and maintenance (6-MP, MTX) with intrathecal therapy in all courses. All HR patients were allocated to receive allogeneic stem cell transplantation (SCT). After June 2009, SCT was also undertaken in MR cases with MRD ≥ 10 e-4 at start of OCTADAD as the Interfant-99 update showed a very poor outcome for these patients. RESULTS 651 infants were included (167 LR, 320 MR, 164 HR). In the original countries, 6-yr EFS (SE) and survival rates were 49.4 (2.5) and 62.1 (2.4) respectively, which were each 6% (not significantly) higher than in Interfant-99 study. In the other countries, the 6-yr EFS and survival rates were 39.0 (3.6) and 49.7 (3.7). The outcome of patients treated in the original countries was significantly better than in other countries due to lower rates of toxic death and resistant disease. The 6-year EFS and survival of all 651 cases were 46.1 (2.1) and 58.2 (2.0) respectively. 330/407 eligible cases (81%) were randomised. The 6-yr cumulative incidence (CI) of relapse with ADE/MAE was 47.5 (4.0) which was not significantly (p = 0.11) lower than the 54.9 (4.1) with IB. The 6-yr CI of death in remission was 10.2 (2.4) with ADE/MAE versus 8.3 (2.2) with IB (p = 0.51). This resulted in no significant differences in 6-yr DFS rates of 39.3 (4.0) and 36.8 (3.9) respectively (the 3-yr DFS were 45.3 [3.9] versus 38.6 [3.9]). The 6-yr EFS rate of 164 HR patients was 20.9 (3.4) with the intention to use SCT in all HR patients; 76 of them received SCT as many HR patients had very early events. Out of 23 MR patients with MRD ≥ 10e-4 before OCTADAD, 16 received SCT; 4/23 are in CCR. In total, 14.4% of MR/HR patients receiving SCT died of transplant-related mortality. T(4;11) and t(11;19) translocated cases had a significantly lower EFS than other KMT2A-rearranged cases (p = 0.005). Multivariate analyses identified KMT2A rearrangement, age < 6 months, WBC ≥ 300 x 10e9/L, and poor prednisone response but not CD10, type of MLL translocation and sex as significant predictors of adverse DFS. CONCLUSIONS The Interfant-06 study is by far the largest study performed in infant ALL. The 6-yr survival in West-European/North-American countries is 62%, which is 12% higher than in other participating countries. Two postinduction AML-type chemotherapy courses versus course IB did not lead to a significant better DFS. 6-yr survival rates are 6% higher than on Interfant-99, which is not a statistically significant improvement. Pilot studies by COG and Interfant are currently exploring the feasibility of adding azacytidine and blinatumomab to the Interfant backbone, which may lead to a worldwide randomised trial with these drugs in infant ALL. Disclosures Locatelli: Miltenyi: Honoraria; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vora:Jazz: Other: Advisory board; Medac: Other: Advisory board; Pfizer: Other: Advisory board; Amgen: Other: Advisory board; Novartis: Other: Advisory board.

Download Full-text

Phase I Study of Ixazomib Added to Chemotherapy in the Treatment of Acute Lymphoblastic Leukemia in Older Adults

Blood ◽

10.1182/blood-2020-139661 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 41-42

Author(s):

Philip C. Amrein ◽

Karen K. Ballen ◽

Kristen E. Stevenson ◽

Traci M. Blonquist ◽

Andrew M. Brunner ◽

...

Keyword(s):

Overall Survival ◽

Acute Lymphoblastic Leukemia ◽

Complete Remission ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Advisory Committees ◽

Survival Estimate ◽

Grade 3 ◽

Experienced Grade

Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients >60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates (CR) of approximately 60% and 3-year survivals (OS) of less than 15%. Intensified treatment in a later CALGB trial showed little improvement with a CR=61% and 5-year OS=6% (Stock, Cancer 2013). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as early efficacy of adding ixazomib to a current MGH-DFCI/HCC multi-agent regimen for older adults with ALL. Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Patients with mature ALL (including Burkitt's) were excluded. Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible, and dasatinib was added to the chemotherapy on Day 10 for these patients. The chemotherapy treatment schedule from induction through maintenance is outlined in Table 1. A standard 3 + 3 patient cohort dose escalation design was used to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients, the primary objective of the trial. After consolidation I, patients in complete remission (CR) with a suitable donor were offered a hematopoietic stem cell transplantation (HSCT) as per institutional guidelines. Those not going to HSCT continued therapy as noted in the table. Results: There were 19 patients with B-ALL enrolled, none with T-ALL. Among these patients, 7 harbored BCR-ABL1 rearrangements. The median age was 65 years, 74% were male, and 90% had a performance status 0 or 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT's: a grade 3 peripheral neuropathy and a grade 5 acute kidney injury (Table 2). Grade 3 and 4 toxicities encountered at any time consisted mainly of grade 4 neutropenia in 13 patients and grade 4 thrombocytopenia in 12 patients. One patient experienced grade 3 neutropenia and 5 patients experienced grade 3 thrombocytopenia. Two patients with grade 2 neuropathy did not meet the definition of DLT. Among the 19 patients, 15 (79%, [95% confidence interval (CI), 54-94%]) achieved CR (14) or CRi (1), and 5 patients went on to HSCT. The median follow-up time was 2 years (range, 1-5) for 8 patients remaining alive. The 1-year overall survival estimate was 53% [95% CI, 29-72%], while the 2-year overall survival estimate was 47% [95% CI, 24-67%]. Conclusions: A dose of 2.3 mg of ixazomib in combination with induction chemotherapy among older patients with ALL was well-tolerated and associated with a promising rate of complete remission. Disclosures Amrein: Takeda: Research Funding; AstraZeneca: Consultancy, Research Funding; Amgen: Research Funding. Brunner:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Hobbs:Novartis: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding. Neuberg:Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company. Fathi:Takeda: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Blueprint: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy. OffLabel Disclosure: MLN 9708, ixazomib is FDA approved for multiple myeloma. In this trial it is used to treat acute lymphoblastic leukemia.

Download Full-text

Pegaspargase Can Safely be Administered in Adults Age 40 and Older with Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2019-124727 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3816-3816 ◽

Cited By ~ 2

Author(s):

Ryan J. Daley ◽

Sridevi Rajeeve ◽

Charlene C. Kabel ◽

Jeremy J. Pappacena ◽

Sarah E. Stump ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Hypersensitivity Reactions ◽

Newly Diagnosed ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Frontline Treatment

Introduction: Asparaginase (ASP) has demonstrated a survival benefit in pediatric patients (pts) with acute lymphoblastic leukemia (ALL) and is now part of standard-of-care frontline treatment. As a result, asparaginase preparations have been incorporated into the treatment of adult ALL to improve outcomes. Pegaspargase (PEG-ASP), a modified version of asparaginase with prolonged asparagine depletion, appears to be safe in adults up to age 40 (Stock, et al., Blood, 2019), but is associated with a unique spectrum of toxicities, the risks of which appear to increase with age. Therefore, the safety of PEG-ASP remains a significant concern in older adults w/ ALL. Methods: We conducted a single center retrospective chart review of pts age ≥40 years who received PEG-ASP as part of frontline induction/consolidation or reinduction, between March 2008 and June 2018 at Memorial Sloan Kettering Cancer Center. The primary objective was to evaluate the tolerability and toxicity of PEG-ASP based on the incidence and severity of ASP-related toxicities (hypersensitivity reactions, hypertriglyceridemia, hyperbilirubinemia, transaminitis, pancreatitis, hypofibrinogenemia, etc) according to the Common Terminology Criteria for Adverse Events, version 4.03. Laboratory values recorded were either the peak or the nadir, the more appropriate for toxicity assessment, within a 4-week period following PEG-ASP administration. Secondary objectives were to determine the total number of doses of PEG-ASP administered in comparison to the number of doses intended, and to characterize the rationale for PEG-ASP discontinuation when applicable. Fisher's exact test was used to compare the incidence of PEG-ASP toxicities with respect to pt and treatment characteristics (regimen, age, BMI, gender, Philadelphia chromosome positive (Ph+) vs. Ph-, presence of extramedullary disease, PEG-ASP dose). P values were not adjusted for multiple comparisons. Results: We identified 60 pts with ALL (40 B-ALL and 20 T-ALL) who received at least one dose of PEG-ASP. Nine pts were Ph+. The median pt age at initiation of the treatment was 53, (range, 40 to 80), and 19 pts had a BMI ≥30 kg/m2. Forty-four pts received treatment for newly diagnosed ALL, and 16 pts for relapsed disease. Table 1 lists pt baseline characteristics. Among the 44 pts with newly diagnosed ALL, 27 pts received PEG-ASP as part of pediatric or pediatric-inspired regimens at doses of 2000 - 2500 units/m2, and 1 pt received a modified dose of 1000 units/m2 due to age. The remaining 16 pts received PEG-ASP at doses of 1000 - 2000 units/m2 for consolidation, per established adult regimens (ALL-2 and L-20; Lamanna, et al., Cancer, 2013). Grade 3/4 ASP-related toxicities with a >10% incidence included: hyperbilirubinemia, transaminitis, hypoalbuminemia, hyperglycemia, hypofibrinogenemia, and hypertriglyceridemia. Frontline treatment regimens in which PEG-ASP was used in consolidation cycles only (ALL-2, L-20) were associated w/ a lower incidence of hyperbilirubinemia (p=0.009) and hypertriglyceridemia (p<0.001) compared to those regimens that included PEG-ASP during induction (pediatric/pediatric-inspired regimens) (Table 2). Younger age (40-59 vs. ≥60 years) was associated with a greater risk of hypertriglyceridemia (p<0.001) and higher PEG-ASP dose (≥2000 vs. <2000 units/m2) was associated with a greater risk of hypertriglyceridemia and hypofibrinogenemia (p=0.002 and p=0.025, respectively). Thirty-eight pts (63%) received all intended doses of PEG-ASP. Six pts stopped PEG-ASP to proceed to allogeneic hematopoietic stem cell transplantation (5 in CR1, 1 in CR2), and 7 pts stopped for hypersensitivity reactions. Hepatotoxicity was the only ASP-related toxicity that led to PEG-ASP discontinuation occurring in 5 pts (hyperbilirubinemia, N=4; transaminitis, N=1). The total number of intended doses of PEG-ASP based on regimens used was 186, and 112 were administered. Conclusion: PEG-ASP was incorporated into the treatment of 60 adult ALL pts age ≥40, with manageable toxicity. Seven pts discontinued PEG-ASP due to hypersensitivity reactions and 5 discontinued due to hepatotoxicity, but other reported toxicities did not lead to PEG-ASP discontinuation and the majority of the pts completed all intended doses of PEG-ASP. This study suggests that with careful monitoring, PEG-ASP can safely be administered in adults ≥40 years of age. Disclosures Rajeeve: ASH-HONORS Grant: Research Funding. Tallman:UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Biosight: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees. Geyer:Dava Oncology: Honoraria; Amgen: Research Funding. Park:Takeda: Consultancy; Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy.

Download Full-text

BCR/ABL1-Like Acute Lymphoblastic Leukemia: From Diagnostic Approaches to Molecularly Targeted Therapy

Acta Haematologica ◽

10.1159/000519782 ◽

2021 ◽

pp. 1-9

Author(s):

Anna Płotka ◽

Krzysztof Lewandowski

Keyword(s):

Flow Cytometry ◽

Targeted Therapy ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Lymphoblastic Leukemia ◽

Genetic Alterations ◽

Diagnostic Analysis ◽

Cell Precursor ◽

Molecularly Targeted Therapy ◽

Diagnostic Approaches

Background: BCR/ABL1-like acute lymphoblastic leukemia is a newly recognized high-risk subtype of ALL, characterized by the presence of genetic alterations activating kinase and cytokine receptor signaling. This subtype is associated with inferior outcomes, compared to other B-cell precursor ALL. Summary: The recognition of BCR/ABL1-like ALL is challenging due to the complexity of underlying genetic alterations. Rearrangements of CRLF2 are the most frequent alteration in BCR/ABL1-like ALL and can be identified by flow cytometry. The identification of BCR/ABL1-like ALL can be achieved with stepwise algorithms or broad-based testing. The main goal of the diagnostic analysis is to detect the underlying genetic alterations, which are critical for the diagnosis and targeted therapy. Key Messages: The aim of the manuscript is to review the available data on BCR/ABL1-like ALL characteristics, diagnostic algorithms, and novel, molecularly targeted therapeutic options.

Download Full-text

Allogeneic HCT with Reduced Intensity Conditioning Versus Autologous HCT for >55 Years Old Patients with Acute Lymphoblastic Leukemia in First Complete Remission: An Analysis from Acute Leukemia Working Party of the EBMT

Blood ◽

10.1182/blood.v124.21.3974.3974 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3974-3974

Author(s):

Sebastian Giebel ◽

Myriam Labopin ◽

Norbert Claude Gorin ◽

Noel Milpied ◽

Eefke Petersen ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Treatment Failure ◽

Board Of Directors ◽

Lymphoblastic Leukemia ◽

Treatment Options ◽

Advisory Committees ◽

Recipient Age ◽

Reduced Risk ◽

First Complete Remission ◽

Reduced Intensity

Abstract BACKGROUND: The prognosis of patients >55 years old with acute lymphoblastic leukemia (ALL) is poor with reported 5-year survival not exceeding 20%. Disease relapse is a major cause of treatment failure. These patients are usually considered ineligible for standard myeloablative allogeneic hematopoietic cell transplantation (alloHCT) due to frequent presence of co-morbidities and higher rate of toxicities. Alternative strategies include reduced intensity(RIC)-alloHCT or autologous(auto)-HCT. However, the role of these treatment options has not been well established thus far. The aim of the current study was to retrospectively compare results of RIC-alloHCT and autoHCT in ALL >55 years old and to identify factors affecting outcome. Data were derived from the registry of the European Group for Blood and Marrow Transplantation. PATIENTS: 267 patients treated with RIC-alloHCT from either HLA-identical sibling (n=154) or matched unrelated donor (n=113) and 179 treated with autoHCT in first complete remission between 2000 and 2011 have been included in this analysis. Median age in both groups was 60 (55-74)y and 60 (55-76)y, respectively, while median interval from diagnosis to HCT was 5.9 months and 6.6 months, respectively. The proportion of Ph(+) ALL among those with reported cytogenetics was 71% and 66%, respectively. RESULTS: With a median follow-up of 33 months, the probability of OS at two years was 44% for RIC-alloHCT and 57% for autoHCT (p=0.02), while LFS rates were 34% and 41%, respectively (p=0.06). The advantage in favor of autoHCT was significant for Ph(-) ALL (OS: 61% vs. 38%, p=0.02; LFS: 54% vs. 21%, p=0.005) while not for Ph(+) ALL (OS: 55% vs. 47%, p=0.6; LFS: 42% vs. 35%, p=0.4). Relapse incidence at two years was comparable for RIC-alloHCT and autoHCT (42% vs. 48%, p=0.39) while non-relapse mortality was significantly reduced for autoHCT (23% vs. 11%, respectively, p=0.002). In a multivariate analysis adjusted for recipient age and gender as well as interval from diagnosis to transplantation the use of autoHSCT was independently associated with reduced risk of mortality (HR=0.69, p=0.01), treatment failure (HR=0.76, p=0.03) and non-relapse mortality (HR=0.39; p=0.0004) with no effect on relapse incidence (HR=0.98, p=0.88). In the RIC-alloHSCT subgroup LFS was negatively affected by female donor/male recipient combination (HR=1.64, p=0.01). LFS rates for both sibling and MUD transplants were comparable (32+/-4% vs. 35+/-5%, p=0.18). The use of peripheral blood cells compared to bone marrow was associated with reduced risk of relapse (HR=0.5, p=0.03). In the autoHSCT setting there was a tendency to higher risk of treatment failure by increasing recipient age (HR=1.05, p=0.06). Other variables including type of conditioning (TBI-based vs. chemotherapy-based) did not affect survival in any of the study cohorts. CONCLUSIONS: Considering poor overall prognosis of ALL patients >55 years old, results of both RIC-alloHCT and autoHCT appear enhancing and both types of transplantation may be considered valuable treatment options. Potential advantage of autoHCT as suggested by results of our analysis should be further explored including data on disease-related prognostic factors and the status of minimal residual disease. Prospective studies are warranted to define final recommendations. Disclosures Niederwieser: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gentium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Download Full-text

Integration of genetic and clinical risk factors improves prognostication in relapsed childhood B-cell precursor acute lymphoblastic leukemia

Blood ◽

10.1182/blood-2016-03-704973 ◽

2016 ◽

Vol 128 (7) ◽

pp. 911-922 ◽

Cited By ~ 46

Author(s):

Julie A. E. Irving ◽

Amir Enshaei ◽

Catriona A. Parker ◽

Rosemary Sutton ◽

Roland P. Kuiper ◽

...

Keyword(s):

Risk Factors ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Chromosomal Abnormalities ◽

Lymphoblastic Leukemia ◽

Clinical Risk Factors ◽

Clinical High Risk ◽

Cell Precursor ◽

Clinical Risk ◽

Key Points

Key Points Chromosomal abnormalities predict outcome after relapse in BCP-ALL, and high-risk cytogenetics takes precedence over clinical risk factors. Patients with mutations or deletions targeting TP53, NR3C1, BTG1, and NRAS were associated with clinical high risk and an inferior outcome.

Download Full-text

Pediatric-Inspired Chemotherapy Incorporating Pegaspargase Is Safe and Results in High Rates of MRD Negativity in Adults Ages 18-60 with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Blood ◽

10.1182/blood-2018-99-115486 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4013-4013 ◽

Cited By ~ 2

Author(s):

Mark Blaine Geyer ◽

Ellen K. Ritchie ◽

Arati V. Rao ◽

M. Isabella Cazacu ◽

Shreya Vemuri ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Advisory Board ◽

Lymphoblastic Lymphoma ◽

Advisory Committees ◽

Grade 3

Abstract Introduction: Among adolescents and young adults with (w/) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL), treatment using a pediatric (vs. adult) regimen appears to achieve superior event-free (EFS) and overall survival (OS); this observation has driven increased interest in adapting pediatric regimens for middle-aged adults w/ ALL/LBL. However, greater risk of toxicities associated w/ asparaginase complicates administration of pediatric-inspired regimens in adults. We therefore designed a pediatric-inspired chemotherapy regimen w/ doses of pegaspargase (PEG) rationally synchronized to limit overlapping toxicities w/ other chemotherapeutic agents. Methods: We conducted a phase II multi-center trial in adults ages 18-60 w/ newly-diagnosed Philadelphia chromosome-negative (Ph-) ALL/LBL (NCT01920737). Pts w/ Ph+ ALL or Burkitt-type ALL were ineligible. The treatment regimen consisted of 2-phase induction (I-1, I-2), followed by consolidation w/ 2 courses of alternating high-dose methotrexate-based intensification and reinduction, followed by 3 years of maintenance (Figure 1). PEG 2000 IU/m2 was administered in each of the 6 intensive courses of induction/consolidation at intervals of ≥4 weeks. Minimal residual disease (MRD) was assessed in bone marrow (BM) by multiparameter flow cytometry (FACS) on day (d) 15 of I1 and following I-1 and I-2. Any detectable MRD (even <0.01% of BM WBCs) was considered positive. Toxicities were assessed by CTCAE v4.0. Results: 39 pts were enrolled (30M, 9F), w/ B-ALL (n=28), T-ALL (n=7), B-LBL (n=3), and T-LBL (n=5). Median age at start of treatment was 38.3 years (range 20.2-60.4), w/ 18 pts age 40-60. Grade 3-4 toxicities associated w/ PEG are summarized in Table 1. Grade 3-4 hyperbilirubinemia was observed post-PEG in I-1 in 9 pts, but only recurred thereafter in 1/8 pts resuming PEG. Pts completing consolidation on protocol (n=16) received median of 6 doses of PEG (range, 2-6). Four pts developed hypersensitivity to PEG and subsequently received Erwinia asparaginase. PEG was discontinued in 4 additional pts due to hepatotoxicity (n=2), pancreatitis (n=1), and physician preference (n=1). Of pts w/ available response assessments, 35/36 (97%) achieved morphologic complete response (CR) or CR w/ incomplete hematologic recovery (CRi) following I-1 (n=34) or I-2 (n=1). Both pts not achieving CR/CRi after I-I had early T-precursor ALL; one of these pts was withdrawn from study, and the other (w/ M2 marrow after I-1) achieved CR after I-2. Of the pts w/ ALL (excluding LBL) w/ available BM MRD assessments, 11/28 (39%) achieved undetectable MRD by FACS following I-1; 18/22 (82%) achieved undetectable MRD by FACS following I-2. Of the pts w/ LBL w/ available BM MRD assessments, 7/7 (100%) achieved or maintained undetectable MRD by FACS following I-1 and I-2. Ten pts underwent allogeneic hematopoietic cell transplantation (alloHCT) in CR1. Seven pts experienced relapse at median 15.2 months from start of treatment (range, 5.4-30.4), of whom 6 subsequently underwent 1st (n=5) or 2nd (n=1) alloHCT. Of the 11 pts w/ ALL w/ undetectable MRD following I-1, only one has relapsed. Five patients have died, including 2 pts in CR1 (from sepsis and multi-organ system failure), and 3 pts in relapse. At median follow-up of 22.3 months among surviving pts (range, 1.0-48.1), median EFS and OS (Figure 2A&B) have not been reached (EFS not censored at alloHCT). 3-year EFS was 62.1% (95% CI: 38.4-78.9%) and 3-year OS was 80.0% (95% CI: 57.5-91.4%). Conclusions: PEG can be incorporated into pediatric-inspired chemotherapy regimens w/ manageable toxicity for appropriately selected adults up to age 60 w/ Ph- ALL/LBL. While PEG-related AEs are common, few pts require permanent discontinuation of asparaginase. Grade 3-4 hyperbilirubinemia was common, particularly post-I-1, but recurred infrequently when PEG was continued. Two induction courses resulted in a high rate of MRD negativity post-I-2 and translated to a low rate of relapse. Though further follow-up is required, 3-year EFS is encouraging. Data regarding asparaginase enzyme activity and silent inactivation w/ neutralizing anti-PEG antibody will be presented. Ongoing and future studies will additionally investigate whether incorporating novel therapies (e.g. blinatumomab, nelarabine) into frontline consolidation therapy may reduce risk of relapse among adults receiving PEG-containing regimens. Disclosures Geyer: Dava Oncology: Honoraria. Ritchie:Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; NS Pharma: Research Funding; Incyte: Consultancy, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding. Rao:Kite, a Gilead Company: Employment. Tallman:Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Cellerant: Research Funding; AbbVie: Research Funding; BioSight: Other: Advisory board; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding. Douer:Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Pfizer: Honoraria; Spectrum: Consultancy. Park:Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Novartis: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Adaptive Biotechnologies: Consultancy.

Download Full-text