scholarly journals Newly Diagnosed Childhood AML Patients Treated with Bortezomib Show Superior Survival If CD74 Is Expressed: A Report of 991 Patients from the Children's Oncology Group AAML1031 Protocol

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-39
Author(s):  
Lisa Eidenschink Brodersen ◽  
Chad A. Hudson ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Laura Pardo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
B Cell ◽  
Clinical Characteristics ◽  
De Novo ◽  
Newly Diagnosed ◽  
Oncology Group ◽  
Standard Chemotherapy ◽  
Childhood Aml ◽  
De Novo Aml

Introduction: CD74 is a type II transmembrane protein expressed on antigen-presenting cells and an MHC class II chaperone. It has been associated with tumor progression and metastasis in solid tumors, and its expression has been suggested to serve as a prognostic factor in many cancers, with higher relative expression associated with oncogenesis. As the expression of CD74 has been associated with response to bortezomib in multiple myeloma, we inquired whether such correlation might be seen in pediatric AML. We prospectively evaluated CD74 expression by difference from normal (ΔN) flow cytometry and correlated expression with clinical characteristics and outcome as part of Children's Oncology Group protocol AAML1031 that randomized patients younger than 30 years of age with de novo AML to standard treatment with (Arm B) or without (Arm A) bortezomib. The addition of bortezomib to standard chemotherapy increased toxicity but did not improve survival. Given the association of CD74 with B-lymphoid neoplasms and bortezomib's known efficacy in B-cell neoplasms and multiple myeloma, we hypothesized that within Arm B, the patients with CD74 expression would have a more favorable outcome. Methods: In total, 1,139 newly diagnosed pediatric patients with de novo AML were randomized to standard chemotherapy (n=561, Arm A) or standard chemotherapy with bortezomib (n=578, Arm B). All patients received the identical chemotherapy backbone with either four intensive chemotherapy courses or three courses followed by allogeneic hematopoietic stem cell transplantation for high-risk patients. To qualify for this correlative study, 991 patients satisfied 2 criteria: (1) submitting a bone marrow aspirate for ΔN at diagnosis and (2) providing consent for correlative biology studies. All diagnostic specimens were centrally and prospectively evaluated for the expression of CD74 by ΔN. AML was considered to be CD74-positive if the MFI was more than two times above background autofluorescence and more than 40% of the leukemia was above background autofluorescence. Results: Among 991 patients, 263 were CD74-positive (26.5%) by ΔN, with similar prevalence in Arm A (27.9%) and Arm B (25.2%). Correlation of CD74 expression with clinical characteristics showed that those with CD74 expression had higher median age (p<0.001), lower median WBC (p<0.001), higher prevalence of low risk protocol status (p=0.039), lower frequency of CEBPA mutation (p=0.039), inv(16) (p=0.001), and KMT2A rearrangements (p=0.002), and were enriched for t(8;21) (p<0.001) and t(6;9) (p=0.014) fusions. All these features retained significance when patients were sub analyzed by respective treatment arms. CD74-positive patients had a higher morphologic CR rate (p=0.016), however, measurable residual disease by flow cytometry was not significant in the entire cohort or in the sub analysis of treatment arms (p=0.155). CD74-positive patients showed superior 5-year OS (70.6% vs 61.8%, p=0.003) and EFS survival (51.2% vs 43.1%, p=0.007) compared to those who were CD74-negative. For patients in Arm A (no bortezomib), the differences in OS (66.1% vs 61.0%, p=0.138) and EFS (48.9% vs 41.7% p=0.088) were not significant between those that were CD74-positive and those that were CD74-negative (Figure 1). However, patients in Arm B receiving bortezomib that were CD74-positive showed a significant improvement in OS (75.3% vs 62.5%, p=0.006) and EFS (53.6% vs 44.3%, p=0.028) compared to those who were CD74-negative (Figure 1). Comparison of the outcomes for CD74-positive patients with and without bortezomib exposure showed a difference in OS of 66.1% vs. 75.3% for those in Arm A vs. Arm B but did not reach significance (p=0.155). Multivariable analysis for OS yielded a hazard ratio of 0.67 (95% CI: 0.44 - 1.02) and p=0.061, approaching, but not reaching, statistical significance. Conclusions: These data demonstrate that CD74 expression is associated with more favorable disease characteristics and survival. Patients receiving bortezomib that were CD74-positive showed a superior response to therapy compared to patients who did not express CD74, by both OS and EFS, suggesting that CD74-positive childhood AML patients stand to benefit from bortezomib therapy. Bortezomib may induce a mechanistic response in CD74-positive AMLs similar to that in bortezomib-treated B-cell neoplasms and/or multiple myeloma, where bortezomib has proven to be beneficial. Disclosures Cooper: Celgene: Other: Spouse was an employee of Celgene (through August 2019). Pollard:Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Efficacy and safety of aspacytarabine (BST-236) as a single-agent, first-line therapy for patients with acute myeloid leukemia unfit for standard chemotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7007-7007
Author(s):  
Jessica K. Altman ◽  
Jamie Koprivnikar ◽  
James K. McCloskey ◽  
Vamsi Kota ◽  
Olga Frankfurt ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
Single Agent ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
First Line ◽  
Standard Chemotherapy ◽  
First Line Therapy ◽  
Line Therapy ◽  
De Novo Aml

7007 Background: Aspacytarabine (BST-236) is a prodrug of cytarabine, the backbone of acute myeloid leukemia (AML) standard of care chemotherapy, associated with toxicity which precludes its administration in older patients and patients with comorbidities. Aspacytarabine is inactive in its intact prodrug form until cytarabine is gradually released at pharmacokinetics which decrease the systemic exposure to peak toxic cytarabine levels, resulting in reduced systemic toxicity and relative sparing of normal tissues, enabling therapy with high cytarabine doses to patients otherwise unfit to receive it. Methods: A phase 2b open-label, single-arm study to evaluate the efficacy and safety of aspacytarabine as a first-line single-agent therapy in newly-diagnosed AML patients unfit for standard chemotherapy (NCT03435848). Aspacytarabine is administrated at 4.5 g/m2/d (containing 3 g/m2/d cytarabine) in 1-2 induction and 1-3 consolidation courses, each consisting of 6 daily 1-hour infusions. Patients with secondary AML, prior hypomethylating agent (HMA) therapy, and therapy-related AML, are eligible. Results: To date, in the ongoing study, 46 newly-diagnosed AML patients unfit for standard chemotherapy (median age 75 years) were treated with aspacytarabine and completed 1-4 courses of 4.5 g/m2/d aspacytarabine, including 26 patients (63%) with de novo AML and 17 (37%) with secondary AML. Six patients (13%) were previously treated with HMA (median 12 courses). The baseline median bone marrow blasts was 52%, and 54% and 29% of patients had adverse or intermediate European LeukemiaNet (ELN) score, respectively. Twenty (43%) patients had ECOG 2. Aspacytarabine is safe and well-tolerated in repeated-course administration. Grade > 2 drug-related adverse events include mainly hematological events and infections. The 30-day mortality rate is 11%. Of 43 patients evaluable for efficacy analysis to date, 15 patients (35%) reached a complete remission (CR) following 1 (13 patients) or 2 (2 patients) induction courses, all with complete hematological recovery (median 27.5 days, range 22-39 days). The CR rates in de novo AML patients and patients with adverse ELN score are 46% and 33%, respectively. Of the 11 patients evaluable to date for minimal residual disease (MRD) flow cytometry test, 8 are MRD negative (73%). While aspacytarabine treatment consists of a limited number of courses, median duration of response and median overall survival for responders are not reached at 12 and 24 months, respectively (end of follow up). Updated results will be presented at the meeting. Conclusions: The cumulative clinical data suggest that aspacytarabine, a time-limited single-agent treatment, is safe and efficacious as a first-line therapy for patients who are unfit for intensive chemotherapy, which may establish it as a new tolerable AML chemotherapy backbone. Clinical trial information: NCT03435848.

Assessment Of Human Equilibrative Nucleoside Transporter 1 (hENT1) – Expression By Flow Cytometry In Acute Myeloid Leukemia and Myelodysplastic Syndromes and Correlation To Clinical Outcome In Acute Myeloid Leukemia Patients Treated With Intensive Chemotherapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2582-2582 ◽  
Author(s):  
Frauke Bellos ◽  
Bruce H. Davis ◽  
Naomi B. Culp ◽  
Birgitte Booij ◽  
Susanne Schnittger ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Molecular Genetic ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Equity Ownership ◽  
De Novo Aml ◽  
Very High ◽  
Acute Myeloid

Abstract Background Nucleoside analogs depend on cellular hENT1 expression for entry into cells and cytotoxic activity. Studies suggest low cellular hENT1 levels correlate with poor response to such chemotherapies in solid tumors, data on AML and MDS is scarce. Aim To examine hENT1 expression by multiparameter flow cytometry (MFC) in newly diagnosed AML and MDS and correlate results to morphologic, cytogenetic (CG) and molecular genetic (MG) findings. To examine hENT1 expression with respect to clinical outcome in AML patients (pts) treated with intensive cytarabine-based chemotherapy (CHT). Methods We studied pts with newly diagnosed AML (n=145) and MDS (n=96), 133/108 male/female, median age 67.3 (AML) and 73.3 years (MDS). CG was done in 130 AML and 86 MDS. Pts included 107 de novo AML, 9 t-AML, 29 s-AML; FAB: 9 M0, 27 M1, 50 M2, 9 M3, 21 M4, 8 M4eo, 7 M5, 14 not classified; by CG (MRC): 21 favorable, 75 intermediate, 34 adverse. 91 were de novo MDS, 5 t-MDS; 1 RARS, 17 RCMD-RS, 37 RCMD, 3 5q- syndrome, 3 RAEB-1, 5 RAEB-2, 1 CMML, 24 not classified; 2 IPSS-R very low, 55 IPSS-R low, 8 IPSS-R intermediate, 8 IPSS-R high, 13 IPSS-R very high. hENT1 expression was quantified by a novel four color intracellular staining assay using monoclonal antibodies against hENT1, CD45, CD64 and myeloperoxidase. Median fluorescence intensities (MFI) of hENT1 were determined in myeloid progenitors (MP), granulocytes (G) and monocytic cells (Mo) and correlated to hENT1 MFI in lymphocytes to derive hENT1 index (index). Results No correlation of index to age, gender, hemoglobin level or counts for blasts, WBC or platelets was detected. In AML, we generally saw higher index by trend in the more favorable prognostic subgroups. M3/t(15;17)/PML-RARA+ displayed higher index in MP than non-M3 AML (4.24 vs 2.56, p<0.001). G index was lower in M0 (3.01) vs M1, M2, M4 and M4eo (5.66, 4.34, 5.35, 4.77; p=0.01, 0.028, 0.004, 0.043, respectively) and in M2 compared to M1 and M4 (4.34. vs 5.66 and 5.35, p=0.01 and 0.033, respectively). M2 showed lower MP index than M5 (2.42 vs 2.99, p=0.016). Considering CG, index in MP was higher in favorable vs intermediate and adverse pts (3.05 vs 2.58 and 2.53, p=0.034 and 0.023, respectively), Mo index was higher ín favorable vs adverse pts (3.17 vs 2.71, p=0.044). By MG, higher index in Mo and G was observed in RUNX1-RUNX1T1+ AML (4/83, 4.32 vs 3.04, p=0.01; 8.16 vs 4.60, p=0.002, respectively). Higher index for MP was found in FLT3-ITD mutated (mut) (18/111; 3.19 vs 2.62, p=0.012), CEPBA mut (4/26, 3.15 vs 2.35, p=0.004) and for Mo in NPM1 mut AML (23/104; 3.72 vs 2.84, p=0.02), whereas lower index for MP was found in RUNX1mut pts (13/65; 2.17 vs 2.59, p=0.031). De novo AML displayed higher MP index than s-AML (2.7 vs 2.28, p=0.008). Using lowest quartile of index for MP (2.1185) as cut-off, AML pts in the MRC intermediate group treated with CHT (n=38) had inferior OS if MP index was below vs above this cut-off (OS at 6 months 63% vs. 95%, p=0.017, median follow up 4.6 months). MDS showed lower Mo and MP index than AML (2.68 vs 2.96, p=0.021, 1.84 vs 2.65, p<0.001, respectively). By IPSS-R, significance was reached for higher index in Mo and MP in very low risk compared to low risk pts (3.39 vs 2.54, p=0.013 and 4.07 vs 1.78, p<0.001, respectively), MP in very low compared to intermediate and high risk pts (4.07 vs 1.95, p=0.004; 4.07 vs 1.76, p=0.002), and MP and G in very low vs very high risk pts (4.07 vs 1.71, p=0.005; 5.86 vs 3.85, p=0.001, respectively). IPSS-R intermediate vs poor and very poor showed lower G index (5.47 vs 3.59, p=0.018 and vs 3.85, p=0.034 respectively). Conclusion AML with genetic and molecular genetic good risk profile had higher hENT1 expression in MP, G and Mo, suggesting a causal mechanism for better response to CHT and better outcome. Consequently, AML with poor risk molecular genetics (RUNX1 mut) showed lower levels of hENT1 in MP. The detection of higher levels in FLT3-ITD mut pts is in line with reportedly good response to CHT, overall worse outcome being mostly due to early relapses. Strikingly, we saw differences in outcome in pts treated with CHT according to hENT1 expression with shorter OS in pts with low index for MP. Higher index in de novo AML than s-AML and MDS may be causal for better response to nucleoside-based CHT in de novo AML. Data for MDS may be interpreted accordingly, lower risk cases showing higher index in MP, G and Mo. Further analyses are needed to explore hENT1 expression in AML and MDS more comprehensively. Disclosures: Bellos: MLL Munich Leukemia Laboratory: Employment. Davis:Trillium Diagnostics, LLC: Equity Ownership. Culp:Trillium Diagnostics, LLC: Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Comprehensive Genomic and Transcript Profiling of CBL Gene in Childhood AML: A Report from Children's Oncology Group Studies AAML03P1, AAML0531 and COG/NCI Target AML Initiative

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 170-170
Author(s):  
Diana Chin ◽  
Matthew A. Kutny ◽  
Jonathan Grim ◽  
Robert B. Gerbing ◽  
Kristen Miller ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Somatic Mutations ◽  
De Novo ◽  
Transcript Variant ◽  
Oncology Group ◽  
Core Binding Factor ◽  
Transcript Variants ◽  
Binding Factor ◽  
De Novo Aml ◽  
Pediatric Aml

Abstract The Casitas B-Lineage Lymphoma (CBL) gene encodes for an E3 ubiquitin ligase that targets activated receptor tyrosine kinases for degradation. Mutations of the CBL gene have been described in juvenile myelomonocytic leukemia (JMML) but less is known about mutations and variants of CBL in de novo AML. We previously reported that somatic mutations of CBL are rare in pediatric AML. In this report we present a comprehensive evaluation of genomic and transcript variants of CBL including novel deletion events as well as transcript variants which, in combination with somatic mutations, account for over 6% of pediatric AML with extreme association with inv(16) and favorable outcome. Initial assessment of CBL transcript in a cohort of 100 patients identified previously reported deletion of exon 8 (CBL ΔE8, N=2) associated with CBL splice mutations as well as a novel whole exon 8 and 9 deletion variant (CBL ΔE8+9, N=3) without identifiable underlying somatic alterations. Long distance PCR, as well as custom Nanostring CNV array evaluation revealed a genomic deletion underlying this transcript variant. Subsequent whole genome sequencing as part of COG/NCI TARGET AML initiative, identified discrete genomic deletions of 1998, 3588 and 6189 bp across exon 8 and 9, leading to the generation of this novel variant. We evaluated the functional consequence of the novel CBL ΔE8+9 deletion variant by expressing it in IL3-dependent Ba/F3 cell line. Compared to control cells, Ba/F3 cells expressing CBL ΔE8+9 demonstrated cytokine independent growth. A comprehensive profiling of CBL variants was conducted in 796 pediatric de novo AML patients by transcript profiling (transcript variants) or by exome capture sequencing (somatic mutations including point mutations and smaller indels). All patients were treated on Children's Oncology Group studies AAML03P1 (N=167) and AAML0531 (N=629) and presence of CBL variants was correlated with disease characteristics and clinical outcome. Of the 796 patient specimens tested, 50 patients (6.3%) had one of 3 distinct CBL variants; transcript variant (N=28), somatic mutation (N=14), or dual transcript variant and somatic mutation (N=8). All cases of CBL ΔE8+9 were associated with a corresponding genomic deletion. Out of 14 cases of CBL ΔE8 and 1 case of CBL ΔE9, only 4 cases (27%) had a splice site mutation identified as the underlying mechanism of splice variant. Presence of CBL variants was correlated with clinical characteristics and outcome. Those with CBL variants had a significantly higher prevalence of inv(16) compared with CBL wild type (WT) (37% vs. 13%, p<0.001). This association differed by CBL variant type; 44% transcript variants and 50% dual variants had inv(16) compared to 14% somatic mutations and 13% CBL WT (p<0.001). NPMc+ was more prevalent in those with CBL somatic mutations (29%) than transcript variant (4%), dual variant (0%) or CBL WT (8%) (p=0.035). Similarly, genetic risk groups differed between CBL variants vs. WT (Low risk 70% vs 39%, p=<0.001; Standard risk 22% vs. 46%, p=0.001; High risk 8% vs. 15%, p=0.196). Clinical characteristics including gender, age, race and ethnicity were not significantly different. FAB morphologic assessment revealed an enrichment for the M4 subtype in CBL variant vs. WT (53% vs. 23%, P<.001) which is likely accounted for by the association of inv(16) with this morphologic group. Patients with CBL variants had a 100% clinical remission rate by end of induction II compared to 89% for CBL WT patients (p=0.014). Survival from study entry was similar between CBL mutant vs. WT patients (5 year OS 72% vs. 66%, p=0.24; 5 year EFS 61% vs. 50%, p=0.11). Due to the strong association of CBL mutation with core binding factor leukemia, we assessed whether CBL variant was prognostic of outcome within this favorable risk group, but there was no significant difference in outcomes. Variants of the CBL gene in pediatric AML include genetic mutations with and without whole exon deletions. These CBL variants are highly associated with low risk AML but do not provide independent risk prognosis. The cooperating events of CBL variants in core binding factor leukemia deserve greater study. Our initial analysis of the transcript variants in a cell line model suggest that these large exon 8+9 deletions represent important oncogenic events. The authors would like to gratefully acknowledge the important contributions of the late Dr. Robert Arceci to the AML TARGET initiative. Disclosures No relevant conflicts of interest to declare.

Evaluation of Immune Profile in Patients with Multiple Myeloma Using Cytof Technology

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3404-3404
Author(s):  
Jana Jakubikova ◽  
Efstathios Kastritis ◽  
Danka Cholujova ◽  
Teru Hideshima ◽  
Ludmila M Flores ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
B Cells ◽  
B Cell ◽  
Natural Killer ◽  
Plasma Cells ◽  
Memory B Cells ◽  
High Dimensional ◽  
Newly Diagnosed ◽  
D Cells

Abstract Introduction: CyTOF (time-of-flight mass cytometry) is a novel high-dimensional technology which permits immunophenotyping and analysis of signaling in single cells. This approach enables simultaneous evaluation of up to 40 parameters using antibodies tagged with distinct elemental isotopes, by combining flow cytometry with atomic mass spectrometry. Since multiple myeloma (MM) is characterized by immune dysfunction, we used CyTOF technology to define the complex immune profile in MM patient bone marrow (BM) samples. Methods: We used 40 different markers to define various B, T, natural killer (NK) subsets, as well as cells of monocytic, granulocytic, erythroid and platelet lineages. Our preliminary data are results from 10 patients with MGUS/ smoldering MM (SMM); 10 newly diagnosed MM; 20 relapsed/refractory MM; and 15 WM patients (5 newly diagnosed and 10 receiving treatment) in comparison with age-matched healthy donors’ BM (HD). A significantly larger cohort of MM (N=150) and WM (N=50) patients is being similarly analyzed and will be presented. To evaluate phenotypic abnormalities in various B cell subsets, we used B lineage markers CD10, CD19, CD20, CD22, CD27, CD34, CD38, CD45, IgA, IgD, IgG and IgM to define B cells maturation stages from hematopoietic stem cells (HSC) to naïve to mature B lymphocytes (pro-B; pre-B-I; pre-B-II; immature B; and mature (naïve) B cells), as well as memory non-switched and memory switched B cells, plasmablasts, normal (CD138+CD38+CD19+CD45+) and clonal plasma cells (CD138+CD38+CD19-CD45-/low), which reside in the specific BM niche. Furthermore, natural killer (NK) subsets (such as NK and NKT cells) and T cells (such as memory CD4T, naive CD4T, memory CD8T, naive CD8T, T regulatory cells and Tg/d cells) were examined. High-dimensional data was obtained using CyTOF technology and analyzed by SPADE and viSNE software. Results: Our data showed significantly decreased HSC in patients with newly diagnosed and relapsed/refractory MM compared to HD (P<0.025). A significant increase in pre-B-I cells was detected in relapsed/refractory MM vs. MGUS/SMM (P<0.028), but the opposite trend was observed in the pre-B-II subpopulation (P<0.005). No differences in immature B cell populations were observed in different stages of MM. However, a significantly higher percentage of immature B cells was present in relapsed/refractory MM compared to HD (P=0.008), and transitional B cells were significantly decreased in newly diagnosed MM compared to HD (P<0.001). Moreover, memory B cells were significant decreased in all MM stages compared to HD (P<0.003). Non-switched memory B cells were significantly increased in MGUS and SMM compared to newly diagnosed MM, while a significant increase of switched memory B cells was present in newly diagnosed MM compared to relapsed/refractory MM. A significant increase in plasmablasts was seen in relapsed/refractory MM in comparison with other MM stages (P<0.011) by CyTOF analyses. Malignant plasma cells (PC) were defined as CD19-, CD38++, CD45-/dim, CD138+ and either cyk or cyl positive. Importantly, a significant increase in clonal PC was found in all MM stages vs. HD, as well as in newly diagnosed MM compared to relapsed/refractory MM (P<0.01). The percentage of PC from CyTOF analyses correlated with % of PC obtained using flow cytometry by Bland-Altman method comparison. We also observed significant differences in T cell subsets including naïve, central memory, effector, and effector memory CD4+ and CD8+T populations between MGUS and newly diagnosed MM, but no significant changes in T regulatory and Tg/d cells. Furthermore, plasmacytoid dendritic (pDC) cells were significantly increased in newly diagnosed MM, and PD-1 expressed on pDC was significantly decreased in newly diagnosed MM compared to MGUS (P=0.007). Interestingly, PD-1 and its ligand PD-L1 were variably expressed on B cells (2-9% and 3-27%) and PC (0.5-46% and 3-41%) from MM BM samples. Other surface molecules including CD269 (4-32%), CD289 (1-8%), CD362 (0.5-1%) and CD329 (1-4%), were variably expressed in PC. Conclusion: A better understanding of the neoplastic BM milieu will provide the framework for identifying and validating novel targeted therapies directed against MM. CyTOF technology represents a novel diagnostic tool to assess the status not only of MM, but also of host immunity, and may allow for the development of rational personalized therapies. Disclosures No relevant conflicts of interest to declare.

The Addition of Bortezomib to Standard Chemotherapy for Pediatric Acute Myeloid Leukemia Has Increased Toxicity without Therapeutic Benefit: A Report from the Children's Oncology Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 899-899 ◽  
Author(s):  
Richard Aplenc ◽  
Soheil Meshinchi ◽  
Lillian Sung ◽  
Todd A. Alonzo ◽  
Jessica Pollard ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Oncology Group ◽  
Standard Chemotherapy ◽  
Free Survival ◽  
Risk Patients ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Introduction: Despite the very high intensity of current chemotherapy regimens for children with acute myeloid leukemia (AML), approximately 50% of patients will experience disease relapse. New therapeutic strategies to improve clinical outcomes have centered on improving the efficacy of standard chemotherapy with novel agents such as gemtuzumab and other agents designed to augment standard chemotherapy. Bortezomib, a proteasome inhibitor, is one such agent. The Children's Oncology Group (COG) Phase III clinical trial AAML1031 tested the hypothesis that the addition of bortezomib to standard chemotherapy would improve treatment outcomes in pediatric patients with newly diagnosed AML. Methods: The COG AAML1031 trial randomized patients younger than 30 years of age with de novo AML to either standard chemotherapy (Arm A) or standard chemotherapy with bortezomib (Arm B). Patients with high allelic ratio FLT3 ITD were offered enrollment on a standard chemotherapy plus sorafenib (Arm C, n = 102) and are excluded from this efficacy analysis. All patients received induction chemotherapy with cytarabine, daunorubicin, and etoposide (ADE). Risk stratification occurred at the end of ADE induction and was based on the presence of high risk cytogenetic/molecular markers and/or minimal residual disease (MRD) >0.1% determined by multidimensional flow cytometry. Low risk patients received three additional courses of chemotherapy consisting of a second course of ADE, a third course of cytarabine/etoposide and a fourth course of cytarabine/mitoxantrone. High risk patients received a second course of cytarabine/mitoxantrone, a third course of cytarabine/etoposide, and then allogeneic stem cell transplant (SCT) from the best available donor. Bortezomib 1.3 mg/m2 was given on days 1, 4 and 8 of each cycle with one dose de-escalation to 1 mg/m2 allowed for dose limiting toxicity. Results: A total of 1097 patients were randomized to either standard therapy (Arm A, n = 542) or standard chemotherapy with bortezomib (Arm B, n = 555). No statistically significant differences in sex, age, race, ethnicity, WHO classification, initial blast count, or initial CNS status was observed between arms. Remission induction rate did not differ between treatment arms 89% vs 91%, p = 0.457. MRD was negative in 75% of patients on both treatment arms at the end of Induction I and mean MRD measures did not differ significantly: 2.8% vs 1.9%, p = 0.247. For all patients, event free survival (EFS) and overall survival (OS) at 3 years were 44.4% ± 3.8% and 60.6% ± 4.4%. EFS was not significantly different between Arms A and B (44.0% ± 5.2% vs 44.6% ± 5.6%, p = 0.285) (Figure 1). Likewise, OS was similar between arms (59.0 ± 6.7 vs 62.2 ± 6.0, p = 0.732) (Figure 1). One year cumulative treatment related mortality (TRM) was 14.6 ± 9.3 and 10.8 ± 7.5, p = 0.49 for Arms A and B, respectively. No significant differences were seen in OS, disease-free survival, and TRM from the end of Induction I in low and high risk groups. Cox proportional hazards analysis demonstrated that initial WBC count at diagnosis was the only consistently identified risk factor for OS, DFS, and TRM. Targeted toxicity monitoring identified increased toxicity risks in Arm B for peripheral neuropathy (Induction I/II), dose reductions (all chemotherapy courses), and PICU admissions (Induction I/II) and Intensification I). Serial monitoring of cardiac ejection fraction/shortening fraction in all patients did not demonstrate a clinically meaningful difference in drop in ejection fraction/shortening fraction by treatment arm. No other consistent differences in targeted toxicity rates were identified. Conclusions: The addition of bortezomib to standard chemotherapy increased toxicity but did not improve EFS or OS in children with newly diagnosedAML Consequently, bortezomib should not be used in children with de novo AML in combination with standard chemotherapy. Future work will evaluate the role of intensifying Induction II therapy for patients with high risk AML, further refine risk stratification, and define a more optimal role for allogeneic donor SCT in pediatric AML. Figure 1 Figure 1. Disclosures Loken: Hematologics: Employment, Equity Ownership.

De novo CD5-positive diffuse large B-cell lymphoma: clinical characteristics and therapeutic outcome

1999 ◽  
Vol 105 (4) ◽  
pp. 1133-1139 ◽  
Author(s):  
Motoko Yamaguchi ◽  
Toshiyuki Ohno ◽  
Kouji Oka ◽  
Masanori Taniguchi ◽  
Motohiro Ito ◽  
...  
Keyword(s):  
B Cell ◽  
Clinical Characteristics ◽  
De Novo ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Therapeutic Outcome ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals Potential Relationship between Clinical Significance and Serum Exosomal miRNAs in Patients with Multiple Myeloma

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Zhi-yao Zhang ◽  
Yan-chen Li ◽  
Chuan-ying Geng ◽  
Hui-juan Wang ◽  
Wen-ming Chen
Keyword(s):  
Multiple Myeloma ◽  
Clinical Characteristics ◽  
Clinical Symptoms ◽  
Clinical Feature ◽  
Newly Diagnosed ◽  
Related Factors ◽  
Expression Levels ◽  
Potential Relationship ◽  
Exosomal Mirnas ◽  
Exosomal Mirna

This study evaluated the potential relationship between exosomal miRNAs and clinical symptoms in patients with multiple myeloma (MM). Forty-eight newly diagnosed myeloma patients and sixteen normal donors were enrolled in the study. The results showed that the relative expression levels of let-7c-5p, let-7d-5p, miR-140-3p, miR-185-5p, and miR-425-5p in the exosomes of MM patients were significantly lower than those of healthy controls. Furthermore, there were significant differences in the clinical characteristics of myeloma, such as kidney damage, while the expression levels of the same miRNA in exosomes and serum are not correlated. The expression of exosomal miRNA is related to the expression levels of clinical feature-related factors, such as creatinine, β2-microglobulin, β-CTX, and IL-6 in serum. Establishing this relationship could contribute to understanding the pathogenesis of MM.

High Expression Levels of Long Noncoding RNA Small Nucleolar RNA Host Gene 18 and Semaphorin 5A Indicate Poor Prognosis in Multiple Myeloma

2019 ◽  
Vol 143 (3) ◽  
pp. 279-288 ◽  
Author(s):  
Ling-Juan Huang ◽  
Ying Shen ◽  
Ju Bai ◽  
Fang-Xia Wang ◽  
Yuan-Dong Feng ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Noncoding Rna ◽  
Poor Prognosis ◽  
Clinical Characteristics ◽  
Staging System ◽  
High Expression ◽  
Newly Diagnosed ◽  
High Expression Group ◽  
International Staging System ◽  
Nucleolar Rna

Background: The aim of this study was to detect the expression of long noncoding RNA small nucleolar RNA host gene 18 (SNHG18) andsemaphorin 5A (SEMA5A) genes in multiple myeloma (MM) patients and to explore the correlation of the expression of these genes with the clinical characteristics and prognosis of MM patients. Methods: Forty-seven newly diagnosed MM, 18 complete remission MM, 13 refractory/relapse MM, and 22 iron deficiency anemia (serving as control) samples were extracted at the Department of Hematology, Second Affiliated Hospital of Xian Jiaotong University between January 2015 and December 2016. The clinical features of the MM patients are summarized. Real-time quantitative PCR was performed to analyze the relative expression levels of the SNHG18 and SEMA5Agenes. The clinical characteristics and overall survival (OS) of the MM patients were statistically analyzed while measuring different levels of SNHG18 and SEMA5Agene expression. At the same time, the correlation between the expression of SNHG18 and SEMA5A was also analyzed. Results: The analysis confirmed that SNHG18 and its possible target gene SEMA5A were both highly expressed in newly diagnosed MM patients. After analyzing the clinical significance of SNHG18 and SEMA5A in MM patients, we found that the expression of SNHG18 and SEMA5A was related to the Durie-Salmon (DS), International Staging System (ISS), and Revised International Staging System (R-ISS) classification systems, and the Mayo Clinic Risk Stratification for Multiple Myeloma (mSMART; p < 0.05). Moreover, we observed a significant difference in OS between the SNHG18/SEMA5A high expression group and the low expression group. We found a positive correlation between SNHG18 and SEMA5A expression (r = 0.709, p < 0.01). Surprisingly, the expected median OS times of both the SNHG18 and SEMA5Ahigh expression groups were significantly decreased, which was in contrast to those of both the SNHG18 and SEMA5Alow expression groups and the single-gene high expression group (p < 0.05). Conclusion: High expression of both SNHG18 and SEMA5A is associated with poor prognosis in patients with MM.

Critical role of multidimensional flow cytometry in detecting occult leptomeningeal disease in newly diagnosed aggressive B-cell lymphomas

2008 ◽  
Vol 32 (8) ◽  
pp. 1196-1199 ◽  
Author(s):  
R. Di Noto ◽  
G. Scalia ◽  
G. Abate ◽  
M. Gorrese ◽  
C. Pascariello ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
B Cell ◽  
Critical Role ◽  
Leptomeningeal Disease ◽  
Newly Diagnosed ◽  
B Cell Lymphomas
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