Chromatin Accessibility Landscapes of Acute Lymphoblastic Leukemia

Abstract Acute lymphoblastic leukemia (ALL) is the most common malignancy in pediatric patients spanning both B- and T-cell lineages. ALL also occurs less commonly in adults but with cure rates of only around 30%. Past work has characterized ALL into molecular subtypes spanning a range of aberrant chromosomal rearrangements and oncogene chimeric fusions driving malignancy. While transcriptional profiling of these subtypes has been extensively examined, the accompanying chromatin accessibility landscape and corresponding gene regulatory repertoire is not well characterized for many subtypes. To better profile the ALL epigenomic and gene regulatory repertoire we examined chromatin accessibility of 12 distinct molecular subtypes (BCR-ABL1, ETV6-RUNX1, Hyperdiploid, Hypodiploid, KMT2A rearranged, Ph-Like, PAX5, DUX4/ERG, TCF3-PBX1, T-ALL, Early T Precursor and B-other) across 189 primary patient samples of pediatric ALL (n = 106) and adult ALL (n = 83) origin using ATAC-seq. To our knowledge, this represents the largest collection of chromatin accessibility data in primary ALL samples spanning multiple molecular subtypes to date. Collectively, we identified over 600,000 accessible chromatin sites in the ALL genome with over 50,000 regions of differentially accessible chromatin encompassing both common and subtype-specific modalities. Further, transcription factor (TF) footprint profiling of ATAC-seq yielded tens of thousands of candidate TF binding events and identified key TF drivers within distinct molecular subtypes. We additionally performed H3K27ac ChIP-seq in a subset of 12 primary ALL patient samples, with integration of these histone data for select patient samples allowing inferences about candidate super-enhancer drivers of ALL molecular subtypes. Overall, these analyses and data offer a window into the gene regulatory and epigenetic landscape of ALL, and further highlight the complexity and heterogeneity of accessible chromatin landscapes among distinct molecular subtypes of ALL. Disclosures Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Pui: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Data Monitoring Committee. Evans: Princess Máxima Center for Pediatric Oncology, Scientific Advisory Board, Chair: Membership on an entity's Board of Directors or advisory committees; St. Jude Children's Research Hospital, Emeritus Member (began Jan 2021): Ended employment in the past 24 months; BioSkryb, Inc.: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Mapping the Glucocorticoid Gene Regulatory Network and Alterations That Contribute to Steroid Resistance in Childhood Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2021-153002 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 674-674

Author(s):

Brennan P. Bergeron ◽

Jonathan Diedrich ◽

Yang Zhang ◽

Qian Dong ◽

Daniel Ferguson ◽

...

Keyword(s):

Board Of Directors ◽

Cell Lines ◽

Regulatory Network ◽

Ex Vivo ◽

Lymphoblastic Leukemia ◽

Regulatory Elements ◽

Steroid Resistance ◽

Advisory Committees ◽

Gene Regulatory ◽

Accessible Chromatin

Abstract Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer and despite improved survival rates, relapsed ALL is still among the most common causes of cancer death in children. Although changes in the expression of specific genes have been linked to chemotherapeutic resistance, relatively little is understood of the pharmacogenomic impact of the noncoding, cis-regulatory landscape governing gene regulation. Glucocorticoids (GCs; i.e. steroids) are a mainstay of contemporary, multi-drug chemotherapy in ALL, and GC resistance is predictive of both relapse and poor clinical outcome in ALL. Because GCs function through activation of glucocorticoid receptor (GR), a nuclear receptor transcription factor that interacts directly with cis-regulatory elements, unveiling the glucocorticoid gene regulatory network (GC-GRN) in leukemia cells is crucial to understanding not only the biological mechanism of apoptosis, but also illuminating gene regulatory mechanisms contributing to GC resistance. To test the hypothesis that alterations to the GC-GRN are important contributors to steroid resistance in ALL, we comprehensively mapped cellular responses to GCs in human ALL cell lines using >100 independent functional genomic datasets. This comprehensive approach uncovered thousands of genes and cis-regulatory elements that were responsive to GCs, and further identified >38,000 high-confidence glucocorticoid response elements (GREs) in the ALL genome. A closer examination of these data revealed GR binding profiles that were consistent with the long-range flexible billboard model of gene regulation. By further integrating our results with genetic and epigenetic data in primary ALL cells from patients enrolled on St. Jude clinical trials, we identified 45 DNA sequence variants associated with ex vivo GC resistance that map to GREs and functionally validated an associated variant within the TLE1 gene locus. We also uncovered 1929 accessible chromatin sites (FDR<0.1) in primary ALL cells that were associated with ex vivo GC resistance, and these GC-resistance accessible chromatin sites were highly enriched at GREs determined from ALL cell lines (p<2.2x10 -16). High-throughput pharmacogenomic CRISPRi screening in human ALL cell lines with a library of >10,000 sgRNAs targeting >1000 GR binding events at putative GC-resistance accessible chromatin sites identified a subset of GR binding sites implicated in GC resistance. Overall, these data indicate that GCs initiate pervasive, genome-wide effects on the leukemia epigenome and transcriptome, and that genetic and epigenetic alterations to GREs are mechanisms contributing to GC resistance in childhood ALL. Disclosures Pui: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Data Monitoring Committee. Evans: Princess Máxima Center for Pediatric Oncology, Scientific Advisory Board, Chair: Membership on an entity's Board of Directors or advisory committees; BioSkryb, Inc.: Membership on an entity's Board of Directors or advisory committees; St. Jude Children's Research Hospital, Emeritus Member (began Jan 2021): Ended employment in the past 24 months.

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

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

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

Clinical, Cytogenetic and Immunophenotype Distribution of Adult Acute Lymphoblastic Leukemia Among Latinos — a Report from a Large Single Institution Cohort in Southern California

Blood ◽

10.1182/blood-2018-99-119962 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2816-2816

Author(s):

Elisa Quiroz ◽

Rebecca Nelson ◽

Vinod A. Pullarkat ◽

Ibrahim Aldoss ◽

Thomas Slavin ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Los Angeles ◽

Board Of Directors ◽

Latin American ◽

Lymphoblastic Leukemia ◽

Hazard Ratio ◽

Latino Population ◽

Cns Involvement ◽

Advisory Committees ◽

American Ethnicity

Abstract Introduction: Acute Lymphoblastic Leukemia (ALL) is divided into Pre-B and T phenotypes depending on the progenitor cell giving rise to the malignant clone. This disease is the most common cancer in children while rare in adults. Interestingly, higher incidence rates and poorer outcomes have been reported in patients of Latin American ethnicity. This has been attributed to higher rates of Philadelphia-Like (Ph-like) ALL and increased incidence of high risk features such as absence of hyperdiploidy and absence of t(12;21). The current data among Latinos either exclusively looks at B cell precursor (BCP) ALL or does not distinguish between subtypes. Our study sets out to better define the phenotype of this subset of patients with traditionally poor outcomes. Methods: Our database consisted of 825 adult patients (ages 18-85 years) diagnosed with ALL from the City of Hope Comprehensive Cancer Center in Los Angeles, California. The population in Southern California has a particularly high number of Latinos due to its proximity to Mexico and Central America. According to the 2017 United States Census, 48.6% of the Los Angeles population is of Hispanic or Latino origin. Age at diagnosis, initial WBC count, CNS involvement, imumnophenotype, cytogenetics and rate of hematopoietic cell transplantation during therapy were assessed between ethnic groups. Multivariable Logistic Regression was done to determine the features that distinguish Latino patients for Non-Hispanic Whites. Results: 57.4% of the patients were Latinos and 42.6% were Non-Hispanic Whites (NHWs), a distribution unique to the Los Angeles area and consistent with US census population data. BCP ALL was more common in Latinos when compared to NHWs with a Hazard Ratio of 5.13 (95% CI between 2.97-8.87). The presence of the t(9;22) or Philadelphia chromosome (Ph+) was more common in NHW patients. The Hazard Ratio for Ph+ ALL in NHWs was 0.53 (95% CI between 0.37-0.77) CNS involvement was more common in Latino patients and MLL was the only cytogenetic abnormality less common in NHWs. Normal Karyotype (NK), Complex and Others were all more common in Latino patients. No difference was found between WBC counts of Latinos and NHW. (Fig. 1). Discussion: ALL has been shown to have higher rates in the Latino population. Our results among adults ages 18-85 years old, demonstrated that this difference can be attributed to higher incidence of BCP ALL and not T-cell among Latinos. This is consistent with the previously reported higher rate of Ph-Like ALL and distinct molecular aberrations among Latinos. Our data shows that the rate of Ph+ ALL is higher in NHWs when compared to Latinos. This is a very interesting finding as the presence of Ph+ ALL and Ph-like ALL are mutually exclusive. Associations have been previously reported between Ph-like ALL and Latin American ethnicity. Although there are types of ALL that are neither Ph+ nor Ph-like this finding suggests a higher incidence of Ph-like ALL in Latinos. At the present time, standard cytogenetics do not include CRLF2, IKZF1 and other mutations found in Ph-like ALL. Complex cytogenetics and CNS involvement, both factors associated with poor prognosis, are most likely to present in a Latino patient. While the precise mechanism is unknown, our findings further support the hypothesis that a unique genetic fingerprint has led to development and outcomes of Ph-like ALL in Latinos. It is evident that this subset of unfavorable BCP ALL population needs special attention. More studies are imperative to further elucidate the mechanism behind Ph-like ALL and pinpoint the risk factors in the Latino population. Disclosures Douer: Spectrum: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Jazz Pharmaceuticals: Consultancy; Gilled Sciences, Inc: Consultancy; Shire: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Prognostic Impact of t(4;11)(q21;q23)/KMT2A-AFF1-Positivity in 926 BCR-ABL1-Negative B-Lineage Acute Lymphoblastic Leukemia Patients Treated in Gimema Clinical Trials Since 1996

Blood ◽

10.1182/blood-2019-121977 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1469-1469

Author(s):

Alfonso Piciocchi ◽

Monica Messina ◽

Loredana Elia ◽

Antonella Vitale ◽

Stefano Soddu ◽

...

Keyword(s):

Clinical Trials ◽

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Clinical Features ◽

Lymphoblastic Leukemia ◽

Educational Training ◽

Advisory Committees ◽

Survival Analyses ◽

B Lineage ◽

Wbc Count

Background and aims. B-lineage acute lymphoblastic leukemia (B-ALL) carrying t(4;11)(q21;q23)/KMT2A-AFF1 accounts for roughly 10% of adult B-ALL, it is associated to pro-B immunophenotype and aggressive clinical features. However, the role of KMT2A-AFF1 in pediatric-like, minimal residual disease (MRD)-driven clinical trials and the impact of transplant in this poor prognostic subgroup are still debated. To address these issues we investigated the incidence, clinical features and outcome of KMT2A-AFF1-positive ALL treated in 6 consecutive GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) clinical trials. Materials and methods. Between November 1996 and September 2016, 926 BCR-ABL1-negative B-ALL patients were enrolled in the GIMEMA clinical trials LAL0496, LAL2000, LAL0904, LAL1104, LAL1308, LAL1913. The median follow-up is 25.4 months (range: 0.1-146.9). Starting from LAL2000, KMT2A-AFF1-positive patients were classified as high-risk and managed more intensively. LAL1308 and LAL1913 adopted a similar pediatric-like backbone, at variance from LAL0496, LAL2000 and LAL0904. Overall, median age was 34.3 (range, 14.1 - 81.9), there were 502 males (54.2%) and 424 females (45.8%) and the median WBC count was 8.80 x 109/L (range, 0.4- 872.3). Incidence, clinical features and outcome of KMT2A-AFF1-positive were analyzed in comparison with KMT2A-AFF1-negative B-ALL. MRD evaluation after induction treatment was available in 197 patients enrolled in the more recent protocols. Results. Overall, 97/926 (10.5%) samples harbored KMT2A-AFF1 fusion gene. The comparison between KMT2A-AFF1-positive and the 829 KMT2A-AFF1-negative B-ALL patients revealed that KMT2A-AFF1-positive patients had a higher median age (42 vs 32.5 years old, p<0.001), were more likely to be female (60/97 vs 364/829, p=0.001) and had a significantly higher median WBC count (70.7 vs 7.2 x 109/L, p<0.001). The complete remission (CR) rate did not differ between KMT2A-AFF1-positive and -negative patients (87.5% vs 81.5%, p=0.188). Notwithstanding, at 24 months, KMT2A-AFF1-positive patients had a significantly shorter survival than KMT2A-AFF1-negative in terms of median overall (OS, 20.3% vs 45.5%, p=0.003, Figure 1A), disease-free (DFS, 9.2% vs 34.3%, p<0.0001) and event-free survival (EFS, 9.5% vs 21.9%, p=0.03, Figure 1B). Of the KMT2A-AFF1-positive patients, 25 underwent transplant (18 received an allograft, 7 an autograft) and - in keeping with this - survival analyses were repeated after censoring for transplant and we found that KMT2A-AFF1-positive patients maintained a significantly worse OS (p<0.0001), DFS (p<0.0001), EFS (p=0.036). Similarly, the effect of KMT2A-AFF1-positivity was adjusted for treatment received and retained statistical significance (HR: 1.3, 95%CI: 1.0-1.7, p=0.050). Moreover, when survival analyses were restricted to the only KMT2A-AFF1-positive patients, we did not observe significant differences among the median survival across the various clinical trials (p=0.581). MRD quantification, with the caveat that the number of patients evaluated for MRD is small, showed that KMT2A-AFF1-positive and negative patients did not differ in the achievement of MRD-negativity: indeed, 8/26 (30.8%) KMT2A-AFF1-positive and 71/171 (41.5%) KMT2A-AFF1-negative patients were MRD-negative post-induction. Conclusions. The present study examined a cohort of 926 BCR-ABL1-negative B-ALL treated in Italian multicenter clinical trials. Overall, though not differing in the achievement of CR and MRD negativity, the analysis of survival curves confirms that KMT2A-AFF1-positive patients have a significantly shorter survival than KMT2A-AFF1-negative patients. This result holds true also when censoring for transplant, thus suggesting that allograft does not confer a survival advantage to KMT2A-AFF1-positive patients. Moreover, KMT2A-AFF1-positive patients perform poorly also in more intensive regimen, as emerged from the analysis of the GIMEMA LAL1913 clinical trial. These findings encourage the adoption of alternative strategies: among the available targeted therapies, preclinical models of KMT2A-leukemia show sensitivity to BCL2-inhibitors, thus providing the rationale for testing this approach in upcoming clinical trials for KMT2A-AFF1-positive patients. Figure Disclosures Chiaretti: Amgen: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. 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. Di Raimondo:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy. Bassan:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Vignetti:Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Educational Training; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Educational Training.

Download Full-text

Inotuzumab Ozogamicin (Ino) May Overcome the Impact of Philadelphia Chromosome (Ph)-like Phenotype in Adult Patients (pts) with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood-2019-126940 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1641-1641 ◽

Cited By ~ 1

Author(s):

Elias Jabbour ◽

Kathryn G. Roberts ◽

Koji Sasaki ◽

Yaqi Zhao ◽

Chunxu Qu ◽

...

Keyword(s):

Gene Expression ◽

Overall Survival ◽

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Advisory Committees ◽

The Impact

Background: Ino showed significant activity in phase II trials in pts with R/R ALL, that was subsequently confirmed in Phase III trial where Ino demonstrated higher response rates and superior overall survival vs standard of care chemotherapy (SOC) in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R ALL).Ph-like or BCR-ABL1-like ALL possesses a gene expression profile similar to that of BCR-ABL1 ALL but lacks the BCR-ABL1 fusion protein. It is characterized by increased expression of hematopoietic stem-cell genes, deletion of B-cell lineage genes and kinase-activating alterations. Ph-like ALL is associated with refractoriness to standard induction/consolidation chemotherapy and poor prognosis. Aim: To evaluate the outcomes of pts with R/R Ph-like ALL treated in phase II trial with Ino monotherapy. Methods: We performed an integrated analysis of whole genome sequencing (to identify sequence mutations, structural variations and DNA copy number alterations), and transcriptome sequencing (RNAseq; to quantify gene expression, determine Ph-like gene expression profile and identify fusions) on 53 patients' samples treated with Ino between June 2010 and September 2012. Results: Fifty-three evaluable pts with R/R ALL with stored baseline samples were analyzed. Pts characteristics are summarized in Table 1. Median age was 50 years. Ino was given as Salvage 1, Salvage 2, and Salvage 3 and beyond in 20 (38%), 18 (34%), and 15 (28%) pts, respectively. Figure 1 reflects the different genomic subgroups identified among 53 evaluable pts. Ph-like gene signature was found in 12 pts (22.6%). Among these 12 pts, 6 had IGH-CRLF2, 2 IGH-EPOR, 1 SNX2-ABL1, and 3 had no fusions identified. The overall response rates (ORR) were 54% [complete remission (CR) 20%, CR with partial hematologic recovery (CRh) 32%, and marrow CR (CRi) 2%]. Among pts with morphologic remission, 46% and 82% achieved minimal residual disease (MRD) negativity at CR and at any time, respectively. The ORR for pts with Ph-like ALL, Ph-positive ALL, ALL with KMT2A, and others were 58% (CR=25%; CRh=33%), 42% (CR=8%; CRh=33%), 57% (CR=14%; CRh=29%; CRi=14%), and 56% (CR=26%; CRh=30%), respectively. The respective overall MRD negativity rates were 71%, 100%, 75%, and 83% (Table 1). The median follow-up was 60 months. The median event-free (EFS) and overall survival (OS) were 3.3 and 5.4 months, respectively. There was no difference in EFS and OS between the subgroups analyzed (P=0.464; P=0.824). The median EFS and OS were 4.5 and 4.5 months for pts with Ph-like, 3.1 and 7.2 months for those with Ph-positive ALL, 2.8 and 4.4 months for those with KMT2A, and 2.2 and 4.6 months for others (Table 1). 21 (40%) pts had subsequent allogeneic stem cell transplant; 6 (50%), 3 (25%), 4 (57%), and 8 (36%) in each subgroup, respectively. The rate of VOD was 3 (6%) with no difference among different subgroups. Conclusion: The current analysis suggest that Ino therapy may overcome the impact of Ph-like phenotype in pts with ALL. Confirmation of these findings in a larger cohort and in frontline ALL patients is needed. Disclosures Jabbour: Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Jain:Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Konopleva:Cellectis: Research Funding; Agios: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Eli Lilly: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Ablynx: Research Funding; Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding. Mullighan:Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; AbbVie: Research Funding; Loxo Oncology: Research Funding; Amgen: Honoraria, Other: speaker, sponsored travel. Kantarjian:Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria.

Download Full-text

Blinatumomab in Combination with Pembrolizumab Is Safe for Adults with Relapsed or Refractory B-Lineage Acute Lymphoblastic Leukemia: University of California Hematologic Malignancies Consortium Study 1504

Blood ◽

10.1182/blood-2019-131061 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3880-3880 ◽

Cited By ~ 3

Author(s):

Marc Schwartz ◽

Lloyd E. Damon ◽

Deepa Jeyakumar ◽

Caitlin L. Costello ◽

Dimitrios Tzachanis ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Complete Response ◽

Advisory Committees ◽

High Bone ◽

Grade 3 ◽

Expansion Cohort

Clinical and preclinical findings suggest that PD-L1 overexpression on lymphoblasts and in the bone marrow microenvironment may mediate resistance to blinatumomab by inhibiting T-cell activation. We report preliminary findings from an ongoing phase I/II multicenter trial to evaluate the safety and efficacy of blinatumomab with pembrolizumab in adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and a high bone marrow lymphoblast percentage (NCT 03160079). The primary objective of this Phase I/II trial is to determine overall response rate (ORR = complete response (CR) + complete response with partial hematologic recovery (CRh) rate) after 1-2 cycles of blinatumomab with pembrolizumab, with key secondary endpoints of adverse events (AEs), minimal residual disease (MRD)-negative CR/CRh rate, 2-year disease-free and overall survival, and allogeneic HCT rate. Eligible patients are 18 years of age or older with R/R B-ALL after ≥ 1 prior line of therapy (including Philadelphia chromosome positive (Ph+) B-ALL failing one second or third generation tyrosine kinase inhibitor) and >50% lymphoblasts on screening bone marrow sample. Patients receive blinatumomab by continuous IV at 9 mcg/day on days 1-7 and 28 mcg/day on days 8-28 of cycle 1, then 28 mcg/day on days 1-28 in subsequent cycles. Pembrolizumab 200 mg IV is given on days 15 and 36 of each 42-day cycle. Patients in CR/CRh after 1-2 cycles complete a maximum of 5 cycles. A safety cohort of up to 6 patients assessed safety by 3+3 design. Dose-limiting toxicities (DLTs) were defined as Grade 3 or 4 non-hematologic AEs related to the addition of pembrolizumab to blinatumomab with a DLT monitoring period of 28 days from the first pembrolizumab dose. At the time of this analysis, 5 patients have been enrolled and treated with all 5 completing the DLT monitoring period. Patients had a median age of 60 years (range 22-74) and one had Ph+ disease. Median bone marrow lymphoblast percentage at time of enrollment was 84% (range 53-90). Patients received a median of 1 cycle (range 1-3) of blinatumomab with pembrolizumab. Common AEs included fever, headache, increased bilirubin, nausea, neurotoxicity, and tachycardia. Grade 3-4 non-hematologic AEs included disseminated intravascular coagulation, hyperferritinemia, hypokalemia, subdural hematoma, encephalopathy, hyponatremia, and macrophage activation syndrome in 1 patient (all related to blinatumomab), hyperbilirubinemia and elevated AST in 1 patient, and hypertriglyceridemia in 1 patient. No grade 3 or greater immune-related AEs have occurred. No pembrolizumab-related DLTs occurred in the first 5 patients in the safety cohort and enrollment is now proceeding in the dose-expansion cohort. The ORR was 50% with 2/4 evaluable patients achieving a CR. One patient achieved an MRD-negative CR in cycle 1 and completed 3 cycles before proceeding to allogeneic HCT. One patient discontinued treatment due to subdural hemorrhage and macrophage activation syndrome during cycle 1 and achieved a CR. Both patients remain in CR for over 6 months. Two patients discontinued treatment due to refractory or progressive disease. The one patient not evaluable for response withdrew from study therapy after 1 cycle without ALL progression. Patient, disease, and treatment characteristics as well as outcomes are summarized in the Table. Blinatumomab with pembrolizumab is safe for adults with R/R B-ALL and a high bone marrow lymphoblast percentage. Enrollment continues in the dose-expansion cohort to assess efficacy. Disclosures Damon: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Costello:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Takeda: Honoraria, Research Funding. Schiller:Biomed Valley Discoveries: Research Funding; Astellas: Research Funding; Amgen: Other, Research Funding; Agios: Research Funding, Speakers Bureau; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding. Wieduwilt:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen, Leadiant, Merck, Servier: Research Funding; Reata Pharmaceuticals: Equity Ownership; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Pembrolizumab (given off label)to enhance the efficacy of blinatumomab (given on label) for relaped/refractory B-cell acute lymphoblastic leukemia

Download Full-text

Vascular and Parenchymal Alterations of the Liver and Liver Surveillance in Patients Who Received Inotuzumab Ozogamicin As the Standard of Care for Relapse/Refractory Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2019-130632 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1343-1343

Author(s):

Giovanni Marconi ◽

Federico Ravaioli ◽

Giovanni Martinelli ◽

Elton Dajti ◽

Maria Chiara Abbenante ◽

...

Keyword(s):

Portal Hypertension ◽

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Lymphoblastic Leukemia ◽

Monitoring Program ◽

Liver Stiffness ◽

Standard Of Care ◽

Advisory Committees ◽

Hematopoietic Stem

Rationale: Inotuzumab ozagomicin (IO) has been linked to an increased incidence of veno-occlusive disease (VOD) and liver alterations. Most VOD events occurred during hematopoietic stem cell (HSCT) transplantation after IO therapy. We have previously described that the measurement of liver stiffness can anticipate the diagnosis of VOD in the context of HSCT. The mechanisms underlying the increased risk of VOD and liver damage in patients receiving IO are not well understood; in the pathogenesis endothelial damage, ozagomicin release and on-target off-tumor effects may be involved. Here, we aimed to assess the effects of IO on the changes of liver, vascular and biochemistry parameters. Methods: Intensive monitoring of the liver was incorporated into the standard of care of patients who received IO for relapsed or refractory (R / R) acute lymphoblastic leukemia (ALL). Upper abdomen ultrasound with Doppler was performed at baseline and at the end of therapy; liver stiffness measurement (LSM) by Fibroscan® (Echosens, Paris, France) at every IO course or at every IO infusion. With the exception of ursodeoxycholic acid, the patients did not receive prophylaxis for VOD. Data was collected after anonymous aggregation, in accordance with GCP and Helsinki declaration. Results are reported as median with interquartile ranges (IQR). Results: At data cut-off, 1st Apr 2019, 16 patient received baseline assessment and at least a post-IO assessment in our monitoring program. In our patent set, median age was 44.5 (IQR 30.7 - 64.0); 12/16 (75 %) patients relapsed after the last treatment and 4/16 (25 %) patients were refractory to the last treatment; patients received a median of 3 (IQR 2 - 3.7) lines before IO; 6/16 (37.5 %) patients undergone HSCT before IO, of which a patient had 1st and 2nd HSCT before IO; 5/16 (31.25 %) undergone HSCT after IO therapy (no patients had second HSCT after IO). Patients received a median of 2 (IQR 2.0 - 3.7) IO administration according to the schedule of the phase 3 trial. The median duration of the therapy was 61.5 days (IQR 43.2 - 114.0) and median progression-free survival in our population was 278.0 days (95% C.I. 264.0 - 292.0). In our patient set, we performed 113 biochemistry determination, 30 liver ultrasounds with Doppler and 116 LSM examination. One patient received a liver biopsy. Among the biochemical exams (AST, ALT, GGT and alkaline phosphatase) only the AST values significantly increased after 1st course of IO (from the median value of 21 U/L to 53 U/L after course 3). Liver ultrasound with Doppler revealed portal hypertension signs in half of the patients during IO monitoring program. Among these patients 7/16 (44%), 3/16 (17%), 5/16 (33.3%) and 3/16 (17%) showed splenomegaly, recanalization of the paraumbilical vein, dilatation of portal vein and ascites, respectively. Median LSM significantly increased from a baseline value of 6 kPa to 7.8 kPa after last post-IO assessment (p-value<0.01). The median increase of LSM values on the baseline after course 1 of IO was 3.3% (0%- 4.9%), after course 2 was 38.3% (26.4% - 45.2%) after course 3 was 43.3% (35.4% - 48.6%) and after course 4 was 56.7 (45.8% - 60.1%), see figure. Eight of the 16 patients (50%) showed an increase in LSM with values comparable to fibrosis higher than 2 (> 7.1 kPa). With a median follow up of 387.5 days (IQR 182.8-524.5) we observed one VOD event (7%); the VOD was graded severe and occurred after HSCT post-IO. Conclusions: Our clinical experience represents the first step to better understand the IO-related liver alterations, as we described the frequency and relevance of quantitative markers. Most of the patients in our set developed ultrasound and/or elastography alteration during IO therapy. Furthermore, these alterations do not seem to correlate with biochemistry. Even if most of the patients had sub-clinical vascular and parenchymal alterations of the liver portal-hypertension related, VOD incidence in our set is comparable with literature. Long-term follow-up results are expected to test whether alterations return or evolve over time. Stratifying the tailored risk liver complications with prospective non-invasive and marker-driven strategies in term of IO dosing and HSCT timing could be a great benefit for patients. * FR and GM contributed to this manuscript equally # AC and CP contributed to this manuscript equally Figure Disclosures Martinelli: Roche: Consultancy; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy. Cavo:janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau. Papayannidis:Amgen: Honoraria; Novartis: Honoraria; Teva: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Shire: Honoraria.

Download Full-text