scholarly journals Exome Array Analyses Identify Low-Frequency Germline Variants Associated with Increased Risk of AML in a HLA-Matched Unrelated Donor Blood and Marrow Transplant Population

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 42-42
Author(s):  
Alyssa I. Clay ◽  
Theresa Hahn ◽  
Qianqian Zhu ◽  
Li Yan ◽  
Leah Preus ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
De Novo ◽  
Association Studies ◽  
Low Frequency ◽  
Hematologic Malignancies ◽  
Unrelated Donor ◽  
Advisory Committees ◽  
De Novo Aml ◽  
Normal Cytogenetics

Abstract Both genome wide association studies (GWAS) of common variation and exome wide association studies (EXWAS) of rare variation have successfully identified disease susceptibility variants for a variety of diseases. One GWAS of inherited susceptibility to Acute Myeloid Leukemia (AML) has been conducted, but no EXWAS have been performed to measure risk of AML attributable to low-frequency constitutional genetic variation. We performed the first EXWAS of risk of AML as a nested case-control study in the DISCOVeRY-BMT (Determining the Influence of Susceptibility Conveying Variants Related to one-Year mortality after BMT) cohorts. The DISCOVeRY-BMT parent study examined transplant-related mortality in leukemia patients undergoing unrelated donor allogeneic BMT. To identify low frequency variants and genes contributing to increased susceptibility to AML we used genotype data from the Illumina HumanExome BeadChip typed in the DISCOVeRY-BMT cohorts; the HumanExome BeadChip contains 242,901 variants, which are mainly protein-coding variants. The optimal sequence kernel association test (SKAT-O) was used to analyze gene-level associations with risk of AML. These gene-based tests evaluate the cumulative effects of multiple single gene variants on risk of AML. Analyses were performed in all European American AML cases and two subtypes: 1) de novo AML, 2) de novo AML with normal cytogenetics. Models were adjusted for age at transplant and principal components to control for population stratification. For gene-based tests at least 2 variants with minor allele frequency (MAF) ≤ 5%, were required to be present in the gene. This yielded a total of 13,687 genes tested, and a Bonferroni corrected significance level of P<3.65 x 10-6. Association tests were performed in 1,189 AML cases reported to CIBMTR 2000-08 (Cohort 1) and 327 AML cases reported to CIBMTR from 2009-11 (Cohort 2). Controls in Cohorts 1 (n=1,986) and 2 (n= 515) were 10/10 HLA-matched unrelated donors who passed a comprehensive medical exam and deemed healthy. We used metaSKAT to combine Cohorts 1 and 2 and obtain p-values of association with AML. We present the results of gene-level tests significant in both cohorts. The likely pathogenicity of these variants was determined in silico using SIFT, PolyPhen and MutationTaster. Patient characteristics are in Table 1. DNMT3A, on chromosome 2, was associated in the gene-based test with risk of AML (Pmeta=1.70x10-9, Table 2). Three missense variants at MAF <1% comprise both overall AML and de novo AML gene-based association: exm177559 (Asn->Ser), exm177507 (Arg->His), and exm177543 (Arg->Trp). Normal cytogenetics de novo AML gene-based assocations consisted of only 2 of these variants: exm177559 and exm177507 (Table 2). While prevalence of exm177507 is <1% for all AML cases, in de novo AML with normal cytogenetics the MAF was higher at 3%. The other 2 variants had a MAF<1% irrespective of subtype. Somatically, DNMT3A is most frequently mutated in hematologic malignancies, with >30% of de novo AML cases with a normal karyotype and >10% of MDS patients having DNMT3A mutations. Although these are germline gene associations all three of the variants found have been reported somatically in hematologic malignancies. In 200 AML cases from The Cancer Genome Atlas (TCGA) p.R882H (represented as exm177507 on the exome chip) was a frequent somatic mutation (25%). Exm177543 (p.R635W) and exm177559 (p.N501S) are reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) as somatic mutations involved in hematopoietic and lymphoid tissue in both cell lines and humans. Exm177507 and exm177543 show evidence of pathogenicity in all three in silico tools, while exm177559 was reported as deleterious and disease causing by Sift and MutationTaster, respectively. Our results show that multiple potentially pathogenic missense germline variants in DNMT3A comprise the gene-based association with AML, specifically de novo AML with normal cytogenetics. Given the functional nature of these variants it is possible germline risk stratification could be informative in determining AML risk, and subsequently development of AML harboring DNMT3A mutations. Confirmation of these findings in additional cohorts could have implications for individualized risk screening, prediction and prognosis. Additional cytogenetic subgroup analyses, including treatment-related AML, are underway. Disclosures Hahn: Novartis: Equity Ownership; NIH: Research Funding. McCarthy:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; The Binding Site: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sucheston-Campbell:NIH/NCI: Research Funding.

Efficacy of Single-Agent Decitabine in Relapsed and Primary Refractory (rel/ref) Acute Myeloid Leukemia (AML)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2518-2518
Author(s):  
Andrew Hantel ◽  
Niloufer Khan ◽  
Richard A. Larson ◽  
Lucy A. Godley ◽  
Michael J. Thirman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Genetic Risk ◽  
Research Funding ◽  
De Novo ◽  
Median Number ◽  
Advisory Committees ◽  
Secondary Aml ◽  
Induction Regimen ◽  
De Novo Aml ◽  
Wbc Count

Abstract Introduction Improving therapy for rel/ref AML remains a challenge. Decitabine, a DNA methyl-transferase inhibitor, initially showed promise in AML as a 5-day, first-line induction regimen and more recently as a 10-day regimen in older and unfit patients (1). However, little is known about the activity of decitabine in the rel/ref patient population despite increased use. Therefore, we sought to analyze the outcomes of these pts treated at our institution. Methods To obtain data regarding decitabine efficacy in rel/ref AML, we performed a retrospective analysis of outcomes following decitabine treatment in 34 adult pts treated at The University of Chicago from January 2009 to June 2014. Permission to access patient charts was granted by the medical centerÕs Institutional Review Board. AML was defined by WHO criteria, genetic risk grouping and complete remission (CR) was according to ELN classification; PR was defined as >50% decrease in bone marrow blasts and normalization of blood counts. Rel/ref AML was defined as either having had a prior CR with recurrence of disease or having received a prior induction regimen (1-2 cycles) without CR. Results Median pt age was 62 yrs (range, 18-81) and 60% were male. Median Charlson comorbidity index (CCI) was 5 (range, 0-8); 29% had ECOG performance status 0-1 and 71% had >2. 21 pts (62%) had de novo AML (7 with myelodysplasia-related changes), 3 (9%) had therapy-related myeloid neoplasm (t-MN), and 10 (29%) had secondary AML after myelodysplastic syndrome. 6% were in the ELN favorable genetic group, 3% intermediate-I, 18% intermediate-II, and 67% adverse; 2 cases were unevaluable. The median number of prior treatment regimens was three. 9% had received prior azacitidine, 85% had received prior HiDAC, and 38% had a prior allogeneic stem cell transplant (SCT). 34 pts received a total of 71 cycles of decitabine, 20 mg/m2 daily, in 5 or 10-day cycles every 28 days. All patients received 10-day courses, 91% had an initial 10-day course, and 74% had only 10-day courses. The median number of cycles per pt was 2; 59% received >1 cycle. 7 (21%) achieved CR and 4 (12%) had a partial response (PR), for an overall response rate (OR) of 33%. Responses occurred in 24% of pts with de novo AML, 66% with t-MN, and 50% with secondary AML. Intermediate and adverse group pts had OR of 14% and 39%, respectively. All pts achieving CR did so after 1 cycle; PR required a median of 3 cycles. Pts who achieved CR or PR had a significantly lower pretreatment WBC count (median, 9.5 vs 49.5 x 103/µL in non-responders; p=0.015) and blast percentage (44 vs 59.4; p=0.035) than those who did not. Pts with secondary AML or t-MN had a higher probability of OR compared to those with de novo AML (54 vs 23%; p=0.042). Median overall survival (OS) of all pts was 256 days; prior SCT was associated with reduced OS (p=0.017). When comparing de novo to secondary AML & t-MN, 1-year OS was not significantly different (Figure 1). Responders had a significantly longer OS (median, 622 days vs 278 days for non-responders; p=0.012). Age, race, CCI, ECOG PS, genetic risk group, prior HiDAC, dysplasia, azacitidine, and number of prior treatments did not impact OR or OS. 16 (47%) pts proceeded to SCT. During treatment, 70% had a grade 3-4 non-hematologic toxicity (based on NCI CTACE v4.0); the most common was fatigue. The median number of hospitalizations for complications per patient was 2 (range, 0-7). Causes of hospitalization were febrile neutropenia (40%), infection (22%), cytopenias (18%), rash (6%), acute kidney injury (6%), and 8% were for other causes. Conclusion Decitabine treatment of 34 adults with rel/ref AML resulted in an OR of 33% (21% CR) and allowed nearly one-half of these pts to proceed to SCT. All pts achieving CR did so after 1 cycle. Responding pts had improved OS over those without response (p=0.012). Interestingly, secondary AML or t-MN were 7.8 times more likely to achieve a response compared to de novo AML (p=0.046); lower WBC count and marrow blast percentage also correlated with higher OR. Further delineation of molecular subsets associated with response to decitabine should be evaluated in a larger prospective trial in this high-risk AML population. Citation 1. Blum KA, et al. Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence of DNA hypomethylation. Br J of Haem. Jul 2010;150(2):189-195. Figure 1. Figure 1. Disclosures Off Label Use: Decitabine is indicated for treatment of MDS but is often used to treat newly diagnosed or relapsed/refractory AML. In this study we analyzed results of patients with AML who were treated with decitabine in the relapsed/refractory setting.. Thirman:AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Gilead: Research Funding; Merck: Research Funding. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liu:Astra Zeneca/Medimmune: Consultancy; Pfizer: Consultancy; Astra Zeneca/Medimmune: Consultancy; Pfizer: Consultancy. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees.

scholarly journals BRCA1/2 Containing Complex 3 (BRCC36) Is Recurrently Mutated in AML with t(8;21) and Associated with Increased Sensitivity to Chemotherapy through Impairment of the DNA Damage Repair Pathway

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1487-1487
Author(s):  
Tatjana Meyer ◽  
Nikolaus Jahn ◽  
Anna Dolnik ◽  
Peter Paschka ◽  
Verena I. Gaidzik ◽  
...  
Keyword(s):  
Dna Damage ◽  
Board Of Directors ◽  
Cell Lines ◽  
Research Funding ◽  
De Novo ◽  
Dna Damage Repair ◽  
Advisory Committees ◽  
Data Set ◽  
Damage Repair ◽  
De Novo Aml

Abstract Introduction BRCA1/BRCA2-containing complex 3 (BRCC36) is a Lys63-specific deubiquitinating enzyme (DUB) involved in DNA damage repair. Mutations in BRCC36 have been identified in 2-3% of patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). The role of BRCC36 mutations in de novo AML and their impact on DNA damage-inducing cytotoxic chemotherapy sensitivity is not clear. Aim We aimed to determine the incidence of BRCC36 mutations in AML and their impact on outcome and drug sensitivity in vitro. Methods We analyzed the entire coding region of BRCC36 for mutations in 191 AML cases with t(8;21) (q22;q22.1) and 95 cases with inv(16) (p13.1q22) using a customized targeted sequencing panel. Data for de novo AML was derived from The Cancer Genome Atlas Research Network (TCGA) data set (NEJM 2013). Lentiviral CRISPR/Cas9 was used to inactivate BRCC36 in t(8;21)-positive AML cell lines - Kasumi-1 and SKNO-1 - and murine hematopoietic stem and progenitor cells (LSKs). Knockout was confirmed by a cleavage assay as well as Western blot. AML1-ETO-9a was expressed by a retroviral vector. Cell lines and LSK cells were treated with different concentrations of doxorubicin or cytarabine and their viability was assessed seven days post treatment. DNA damage was assessed through phospho-γH2AX staining using flow-cytometry. Results BRCC36 mutations were identified in 7 out of 191 patients (3.7%) with t(8;21) AML and none of 95 patients with inv(16). In the TCGA data set one out of 200 patients (0.5%) with de novo AML had a BRCC36 mutation. This patient had a complex karyotype and would be considered as secondary AML with myelodysplastic-associated changes according to the 2016 WHO classification. Six of the 7 mutations were missense or nonsense mutations that were predicted to be deleterious to BRCC36 function. One mutation affected a splice site at exon 6, resulting in an impaired splicing capability. With intensive standard chemotherapy all patients with BRCC36 mutations achieved a complete remission and had an estimated relapse-free and overall survival of 100% after a median follow up of 4.2 years. Given its role in DNA damage repair, we hypothesized that BRCC36 inactivation sensitizes AML cells to DNA-damage inducing drugs. In order to test this, we generated BRCC36 knockout Kasumi-1 and SKNO-1 cell lines using CRISPR-Cas9. BRCC36 inactivation had no impact on cell growth on either of the cell lines. However, we found that BRCC36 knockout cells were significantly more sensitive to doxorubicin as compared to the parental cells with normal BRCC36. This was accompanied by a significant increase in DNA damage as assessed by phospho-γH2AX in BRCC36 knockout vs control cells after doxorubicin treatment. In contrast, BRCC36 inactivation had no impact on cytarabine sensitivity. We next assessed drug sensitivity in primary murine leukemic cells expressing AML1-ETO-9a. Again, inactivation of BRCC36 resulted in a significant higher sensitivity to doxorubicin but not cytarabine. Conclusion We found BRCC36 to be recurrently mutated in t(8;21)-positive AML Inactivation of BRCC36 was associated with impairment of the DNA damage repair pathway and thus higher sensitivity to DNA damage-inducing chemotherapy. This might be also reflected by the favorable clinical outcome of patients with BRCC36 mutated t(8;21)-positive AML, a finding which has to be confirmed in a large patient cohort. Disclosures Paschka: Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Amgen: Other: Travel support; Janssen: Other: Travel support; Bristol-Meyers Squibb: Other: Travel support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Travel support; Astex: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Bullinger:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau; Bayer Oncology: Research Funding; Sanofi: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Döhner:Novartis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Janssen: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Pfizer: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Agios: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding.

scholarly journals TP73 Isoforms (TAp73 and ΔNp73) Are Overexpressed in Acute Myeloid Leukemias and Potential Therapeutic Targets to Enhance Anti-Leukemia Activities of Bcl-2 and MDM2 Inhibitors

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2629-2629
Author(s):  
Yuki Nishida ◽  
Jo Ishizawa ◽  
Vivian Ruvolo ◽  
Michael Andreeff
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
De Novo ◽  
Hematopoietic Cells ◽  
Mrna Levels ◽  
Advisory Committees ◽  
Myeloid Leukemias ◽  
Equity Ownership ◽  
De Novo Aml ◽  
Mdm2 Inhibitor

Abstract Background TP73 is one of the TP53 family transcription factors and generates two isoforms, the transactivation p73 (TAp73) and the N-terminally truncated ΔNp73. TAp73 shares a homologous N-terminal activation domain with p53 and has similar pro-apoptotic function to p53. ΔNp73 lacks an activation domain and has activities distinct from TAp73. ΔNp73 has a dominant negative effect on the DNA binding of TAp73 and more importantly, of p53, since the DNA binding domain is homologous with that of TAp73 and highly similar to that of p53. In acute myeloid leukemias (AML), TP73 has been reported to be expressed except in acute promyelocytic leukemias. However, the association of TP73 isoforms with clinical and genetic characteristics and the regulation of the isoforms in AML have not been explored. Results We determined copy numbers of ΔNp73 and TAp73 mRNA levels in 78 AML samples including 31 de novo AML using droplet digital PCR (ddPCR), which allows to determine the absolute quantity of the isoforms expressed, and investigated their clinical and biological relevance. ΔNp73 and TAp73 expression was detected in 93.6% and 98.7% of AML samples at variable levels (mean ± SEM, 10.6 ± 5.0, and 106.6 ± 33.7 copies/µL, for ΔNp73 and TAp73, respectively). ΔNp73 and TAp73 mRNA levels were highly correlated (R2 = 0.72, P < 0.0001). Normal peripheral blood mononuclear cells and CD34+ hematopoietic cells showed little or no ΔNp73 and TAp73 expression (0.09 ± 0.09 and 0.42 ± 0.35 copies/µL, respectively), demonstrating that expression of ΔNp73 and TAp73 is 100 - 1,000 fold higher in AML as compared to normal hematopoietic cells. These data collectively suggests that transcriptional systems of both isoforms in AML cells are abnormally activated. Disease status (de novo or relapsed/refractory) and cytogenetic abnormalities did not correlate with ΔNp73 and TAp73 levels. However, AML with IDH1/2 mutations had 8.5-fold lower ΔNp73 expression than those with wild-type IDH1/2 (1.8 ± 0.8 vs 15.4 ± 7.7 copies/µL, P = 0.0069), with a similar trend for TAp73 (49.0 ± 20.3 vs 138.6 ± 51.4 copies/µL, P = 0.056). For de novo AML samples, those with DNMT3a and NRAS mutations had significantly higher ΔNp73, but not TAp73, than those without these mutations (21.6 ± 18.2 vs 2.5 ± 1.2 copies/µL, P = 0.017 and 5.6 ± 2.5 vs 9.7 ± 8.0 copies/µL, P = 0.047, respectively). These findings suggest that ΔNp73 and TAp73 can be differentially regulated in AML based on mutation status. To further explore the regulation of TP73 isoforms, we used MDM2 inhibitor Nutlin-3a to induce p53 which is a transcriptional inducer of ΔNp73. Indeed, MDM2 inhibition increased p73 protein levels, and knockdown of both TAp73 and ΔNp73 in AML cells enhanced apoptosis induction by Nutlin-3a (specific annexin V induction by 5 uM Nutlin-3a, 21.9 ± 1.3% vs 61.3 ± 5.2%, P = 0.0084 in OCI-AML3 cells with vector control vs Shp73, respectively), possibly due to the silencing of ΔNp73. AML cells with IDH1/2 mutations are more dependent on Bcl-2 than those without (Chan, Nat Med 2015). Intriguingly, (R)-2HG, the oncometabolite of mutant IDH1/2, reduced both TAp73 and ΔNp73 in AML cells and increased susceptibility to the Bcl-2 inhibitor ABT-199. These results imply a potential mechanism that regulates p73 isoforms by histone methylation or other epigenetic modifications in AML. Conclusion Absolute quantitation of TP73 isoforms by ddPCR revealed high expression in AML cells compared to normal hematopoietic cells. The repressed expression of TP73 isoforms in AML cells with IDH1/2 mutations or by the oncometabolite (R)-2HG suggests that epigenetic modifications through (R)-2HG can regulate TP73 transcription and enhance the anti-leukemia effect by Bcl-2 inhibition. Finally, downregulation of TP73 isoforms enhances the efficacy of MDM2 inhibitor in AML, suggesting a potential therapeutic strategy to enhance MDM2 inhibitor-mediated p53 activation. Disclosures Andreeff: Amgen: Consultancy, Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Astra Zeneca: Research Funding; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; SentiBio: Equity Ownership; Reata: Equity Ownership; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding.

Remissions after Third Induction Chemotherapy for Primary Non-Responders with Acute Myeloid Leukemia (AML) Are Uncommon and Short-Lived

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2800-2800
Author(s):  
Sara Farshchi Zarabi ◽  
Steven M. Chan ◽  
Vikas Gupta ◽  
Dina Khalaf ◽  
Andrzej Lutynski ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Palliative Care ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
De Novo ◽  
Phase 1 ◽  
Cell Transplant ◽  
Advisory Committees ◽  
De Novo Aml

Abstract The outcome of adult patients with AML who are primary non-responders to two courses of induction chemotherapy is poor. However, the utility of a 3rd induction for a select subgroup of these patients is uncertain. Here, we evaluated the rates of response and survival after a 3rd course of induction chemotherapy for primary non-responders with AML. We identified 98 patients from the Princess Margaret Cancer Centre between May 1999 and March 2015 who were non-responders to induction and reinduction chemotherapy. No-response to re-induction chemotherapy was defined according to the Revised Recommendations of the International Working Group for AML (JCO, 2003) as patients who survived > 7 days post re-induction and had persistent AML in blood or bone marrow (>5%). Median age was 58.3 years [range: 20-76.6]. 50 (51%) were male. 2% had favorable, 18% normal, 18% intermediate, and 48% adverse cytogenetics. 50% had de novo AML, 23% had AML secondary to MDS or MPN, and 17% had therapy-related AML. Induction chemotherapy consisted of "7+3" (n =88), Nove-HiDAC (n=1), Flag-Ida (n= 2), or similar variants (n=7). Reinduction chemotherapy consisted of Nove-HiDAC (n=70), Flag-Ida (n=7), "7+3" (n=1) or other similar variants (n =20). No patients received the same regimen for both induction and reinduction. Of the 98 primary non-responders, 15 received a 3rd induction regimen, while the others received supportive/palliative care ± low-dose chemotherapy (57 pts), or a non-induction clinical trial (26 pts). Average age was 56.4 (sd: 12.9) for patients who received supportive/palliative care and 47.0 (sd: 17.5) for patients who received a 3rd induction (p=0.008). Other baseline characteristics including gender, cytogenetic risk, marrow blast count post 2nd induction, and time between 1st and 2nd induction, did not differ between patients who did and did not receive a 3rd induction. Time to 3rd induction was a median of 54 days [range:36-126] from the start of the 2nd induction. Of the 15 third inductions, 7 were clinical trials evaluating novel agents in combination with induction chemotherapy, while the other 8 were combinations of standard chemotherapeutics (Flag-Ida n=1), AMSA+HiDAC (n=2), Daunorubicin+ HiDAC (n=1), Nove-HiDAC (n=4). Of the 15 patients who received a 3rd induction, 3 (20%) achieved a CR following Nove-HiDAC and Flag-Ida or AMSA+HiDAC chemotherapy, where the Ara-C was given as continuous infusion. 1 patient underwent allogeneic stem cell transplant (SCT) approximately 3.7 months after 3rd induction and remains alive 4.6 years post CR. 2 patients relapsed 2.3 and 4.7 months post CR without having received alloSCT. None of the 12 other patients responded to the 3rd induction and none had prolonged aplasia. 2 of 15 (13%) died during 3rd induction. Among the 83 patients who did not receive a 3rdinduction, 1 achieved a CR after a phase 1 clinical trial (MDM2 inhibitor) and remains in CR 3.6 years following an alloSCT. For patients who survived the immediate post induction period and were discharged from hospital median overall survival from the start of the 2nd induction did not differ between patients who did and did not receive a 3rd induction (276 days [range: 78-1304] vs 181.5 days [range: 47-1855] respectively p= 0.14). Median duration of hospital stay (including subsequent admissions) was longer for patients receiving a 3rd induction compared to those who did not (94 days following start of the 2nd induction [range: 47-169] vs 57 days [range: 51-181], respectively;(p= 0.003)). In summary, remissions after 3rd inductions for primary non-responders are uncommon, and short-lived, suggesting that 3rd inductions should be considered with caution and only when an SCT strategy is in place. Disclosures Gupta: Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Schuh:Amgen: Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schimmer:Novartis: Honoraria.

Exome Array Analyses Identify New Genes Influencing Survival Outcomes after HLA-Matched Unrelated Donor Blood and Marrow Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 518-518
Author(s):  
Qianqian Zhu# ◽  
Li Yan# ◽  
Qian Liu ◽  
Qiang Hu ◽  
Leah Preus ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Low Frequency ◽  
Marrow Transplant ◽  
Survival Outcomes ◽  
Unrelated Donor ◽  
Advisory Committees ◽  
Protein Coding ◽  
Blood And Marrow Transplant ◽  
Coding Variants

Abstract #the authors contributed equally to this work While survival outcomes after HLA-matched unrelated donor (URD) blood and marrow transplant (BMT) have significantly improved over the last two decades, about 40% of patients die before 1-year post URD BMT. Previously we performed a genome-wide association study (GWAS) named DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT) to investigate the contributions of common genetic variants on survival outcomes. To address the specific contributions of low frequency (≤ 1%) exonic variants on survival outcomes, we used the DISCOVeRY-BMT cohorts typed with the Illumina HumanExome BeadChip containing 242,901 variants, which are mainly protein-coding variants. We used a gene-based test (the optimal sequence kernel association test (SKAT-O)) to evaluate the cumulative effects of multiple genetic variants within a gene on overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) 1 year after URD BMT. SKAT-O measures the overall significance of the gene and allows the variants to have different directions and magnitude of effects. We used a 2-stage study design: SKAT-O analysis was carried out in Cohort 1 consisting of 1,972 AML, ALL or MDS patients reported to the Center for International Blood and Marrow Transplant Research from 2000 to 2008 and their 2,006 10/10 HLA-matched URD. Genes with a suggestive association with each outcome (P < 1×10-3) entered the final meta-analysis including Cohort 1 and an independent cohort (Cohort 2), consisting of 503 recipients and 520 10/10 HLA-matched URD from 2009 to 2011. The analysis included recipients and URD of European descent due to the low frequency of other populations. All association models included age at BMT, diagnosis (AML, ALL, MDS), disease status at BMT, cell source (peripheral blood, marrow), year of BMT, and principal components from EIGENSTRAT to control for population stratification. Only coding variants (missense and nonsense) with minor allele frequency ≤ 1% were included in our analysis, which resulted in > 12,000 genes tested in our gene-based analysis in recipients and donors. Exome-wide significance was set at Pmeta< 4.10×10-6 after Bonferroni correction for the total number of genes tested. The likely pathogenicity of these variants was determined in silico using SIFT and PolyPhen. In recipients, we identified OR51D1, a member of the olfactory receptor gene family, as significantly associated with both OS and TRM. The OS association with ORD51D1 is driven by TRM as the same six missense variants contribute to both TRM and OS, but not to DRM. In donors, four (ALPP, EMID1, SLC44A5, LRP1), one (HHAT), and two (LYZL4, NT5E) genes were significantly associated with OS, TRM, and DRM, respectively (Table). ALPP encodes an alkaline phosphatase. SLC44A5 is a member of the solute carrier gene family. LRP1 (low density lipoprotein receptor-related protein 1) encodes an endocytic receptor involved in several cellular processes, including intracellular signaling, lipid homeostasis, and clearance of apoptotic cells. HHAT encodes an enzyme that acts within the hedgehog secretory pathway, which is involved in hematologic malignancy. LYZL4 is a member of a family of lysozyme-like genes, which have a protective role in host defense. The encoded protein of NT5E, CD270, is used as a determinant of lymphocyte differentiation. The likely pathogenicity of several of the functional variants in all significant genes identified was predicted to be both (possibly or probably) damaging and deleterious (Table), thus indicating that the amino acid substitution of the variant may not be well tolerated. One damaging variant in LRP1 has been identified as a somatic mutation in hematopoietic and lymphoid tissue. Our study is the first analysis of the low-frequency coding variant contribution to URD BMT survival outcomes. We found that the missense variants contributing to many of these significant gene associations shows evidence of pathogenicity and thus it is biologically plausible these variants are contributing to survival outcomes. Further confirmation of these findings, and studies of the functional consequences of protein-coding changes in these genes, may provide more individualized risk prediction and prognosis as well as alternative donor selection strategies. Table. Table. Disclosures McCarthy: Gamida Cell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; The Binding Site: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hahn:Novartis: Equity Ownership; NIH: Research Funding. Sucheston-Campbell:NIH/NCI: Research Funding.

scholarly journals DNA Repair Genes' Expression Abnormalities in De Novo Acute Myelogenous Leukemia (AML): Implications for Targeted Treatment

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5176-5176
Author(s):  
Frieda Kontsioti ◽  
Eirini Maratou ◽  
Anthi Bouhla ◽  
Vassiliki Mpakou ◽  
Konstantinos Gkodopoulos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Board Of Directors ◽  
Research Funding ◽  
De Novo ◽  
Cytotoxic Agents ◽  
Advisory Committees ◽  
Dna Damage And Repair ◽  
Relative Expression ◽  
De Novo Aml

INTRODUCTION AML is the most common malignant myeloid disorder in adults. Relapses are initiated by chemoresistant leukemic cells. DNA damage and repair mechanisms influence not only the genetic predisposition to leukemia but are also very important for refractoriness to treatment. The aim of this study was to investigate the possible alterations in the gene expression profile in DNA damage signaling pathways in two leukemic cell lines following their exposure to chemotherapeutic agents and verify the findings in AML patients. METHODS Kasumi-1 and MV4-11 AML cells were treated with either idarubicin (0.1μΜ) for 6h or cytarabine (1μΜ) for 48h. Dead cells were eliminated from drug-treated cells using the appropriate commercial kit. Gene expression profiling through PCR arrays analysis (RT2Profiler, Qiagen) was performed after RNA extraction from untreated, drug-treated and chemoresistant (live) cells following their exposure to cytotoxic agents. Human DNA Damage Signaling pathway related genes' expression was evaluated and analyzed through RT2Profiler PCR Array data analysis tool. Following our initial results, two genes were selected for further analysis: PPP1R15A and HUS-1 genes' relative expression was evaluated by qRT-PCR analysis with QuantiTect Primer Assays kit (Qiagen) using the 2^-∆∆Ct method. The analysis included 28 de novo AML patients before the onset of the 7+3 combination chemotherapy and 16 healthy donors. Eighteen cases had normal karyotype including 7 with flt3 mutation, 1 case had inv(16) and 9 cases intermediate risk karyotype. Statistics were performed through One Way Anova analysis. RESULTS PCR Array analysis after idarubicin and cytarabine treatment of Kasumi-1 cells revealed a significant up-regulation of genes involved in apoptosis, cell cycle, DNA damage and repair, and ATM/ATR signaling. Significant differences in their gene expression patterns were observed between cytarabine-treated Kasumi-1 cells and chemoresistant ones. HUS-1 gene (DSB) was 3x fold up-regulated in cytarabine-treated cells and 0.7x fold down-regulated in chemoresistant cells compared to untreated cells. Cytarabine and idarubicin treatment of MV4-11 cells led to an up-regulation of genes involved in cell cycle, DNA damage repair, including DSB repair and NER mechanisms. Most importantly, PPP1R15A gene's expression in both cytarabine and idarubicin chemoresistant MV4-11 cells was significantly 4.2x and 2.7x fold up-regulated compared to drug treated cells. Following these results the expression level of genes PPP1R15A and HUS1 was examined in the bone marrow cells of AML patients in order to verify their association with chemoresistance. PPP1R15A gene's relative expression was significantly up-regulated in non-responding to induction chemotherapy AML patients compared to responding (median: 2.705 vs. 0.73, p<0.05) and in non-responding to chemotherapy AML patients compared to controls (median: 2.705 vs. 0.577, p<0.01). HUS1 gene's relative expression was remarkably down-regulated in AML patients compared to controls (median: 1.585 vs. 7.74, p<0.001). This was also observed comparing responding and refractory to chemotherapy AML patients to controls (median: 1.09 vs. 7.74, p<0.001 and 1.585 vs. 7.74, p<0.05, respectively). CONCLUSIONS The up-regulation of PPP1R15A gene in chemoresistant MV4-11 cells after treatment with cytotoxic agents is justified since this gene participates in growth arrest and apoptosis in response to DNA damage, negative growth signals and protein malfolding by binding to protein phosphatase PP1, and attenuating the translational elongation of key transcription factors through dephoshorylation of eukaryotic initiation factor 2a(eIF2a). Most importantly the significant increased baseline expression of PPP1R15A in AML chemoresistant patients indicates its involvement in chemoresistance mechanisms and paves the way for targeted treatment. HUS1 gene's expression was remarkably depressed in de novo AML samples. This gene is required for the optimal ATM/ATR signaling response to DSBs and replication stress forming part of the RAD9A-RAD1-HUS1 (9-1-1) complex functioning as a damage sensor in checkpoint pathway. Therefore the described above reduced expression in AML samples indicates reduced ATM-ATR response to DSBs associated with genetic instability and offers new options for synthetic lethality treatment strategies Disclosures Symeonidis: Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Pappa:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Clinical Characteristics and Outcomes of Patients with Newly Diagnosed De Novo Acute Myeloid Leukemia (AML) during the COVID-19 Pandemic

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2291-2291
Author(s):  
Hari S. Raman ◽  
Yael Flamand ◽  
Marlise R. Luskin ◽  
Daniel J. DeAngelo ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Disease Burden ◽  
De Novo ◽  
Molecular Characteristics ◽  
Advisory Committees ◽  
Flt3 Mutations ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Introduction The COVID-19 pandemic disrupted non-urgent and preventive medical care. During the early peak of the pandemic, an estimated 41% of US adults delayed or avoided medical care (Czeisler et al, CDC, 2020). While there were documented declines in the number of emergency department visits for myocardial infarction, stroke and hyperglycemia, similar data is not available related to acute myeloid leukemia (AML) (Lange et al, CDC, 2020). A delay in the diagnosis of AML could lead to presentation when patients are less able to withstand chemotherapy or have a higher disease burden which could compromise overall survival (OS). In this retrospective analysis, we aim to elucidate if there was a difference in clinical, cytogenetic, or molecular presentations and if there was an effect on early mortality as determined by overall survival at 1 and 6 months. Methods We compared the clinical, cytogenetic, and baseline molecular genetics of consecutive adult patients diagnosed with de novo AML at Dana-Farber Cancer Institute/Brigham and Women's (DFCI/BWH) Hospital from March 23, 2020, the date of the Massachusetts COVID State of Emergency, to August 23, 2020 to a historical cohort of similar patients between presenting between March 23, 2017 and August 23, 2020. Data was obtained from the Hematological Malignancy Data Repository and via review of the medical record. Patients were excluded from this cohort if they were diagnosed with acute promyelocytic leukemia, had known antecedent myeloid malignancy, or if they did not have DFCI/BWH 96-gene next-generation sequencing panel (RHP) performed at the time of diagnosis. Baseline clinical, laboratory, cytogenetic, and molecular characteristics and outcomes were compared between the pre-pandemic and pandemic cohorts using chi-squared, Fisher's exact, and Wilcoxon rank sum analyses (where appropriate) at a significance of p&lt;0.05. Results Thirty-eight AML patients presented during the COVID-19 pandemic (PAN) and 308 in the pre-pandemic (PREPAN) period. There was no statistically significant difference in the monthly rate of new patients presenting in PREPAN and PAN cohorts (8 vs. 6 new patients/month, p=0.73). The median age at presentation (64 PREPAN vs. 65 PAN, p=0.77), sex, and therapeutic approach (intensive, non-intensive, supportive care, other) were not statistically different between cohorts. Presenting white blood cell count, platelet count, and fibrinogen were not different between cohorts, while hematocrit was significantly lower in the PAN cohort (23.8% vs. 26.0%, p=0.001). There was a trend for a higher median blast percentage (28.5% vs. 13%, p=0.09) in the PAN cohort. There were no differences between the cohorts in the median number of cytogenetic abnormalities, nor in the incidence of complex karyotype, (25.3% vs. 23.7%) across PREPAN and PAN respectively. There were also no significant differences in the European LeukemiaNet (ELN) risk classification scores across the PREPAN and PAN time periods, with 57.8% vs. 52.6% of total patients presenting with adverse risk disease respectively. When specific mutations of TP53, NPM1, and FLT3 were evaluated, only FLT3 demonstrated a statistical difference with a higher proportion in the pandemic group (p=0.04). OS at 1-month (97.4% and 93.2%, p=0.15) and 6-months (71.1% and 75.0%, p-0.87) were not statistically different in the PREPAN and PAN cohorts, respectively. Conclusion These data represent a novel analysis of the presenting clinical, cytogenetic and molecular characteristics of de novo AML during the COVID-19 pandemic. In contrast to other diseases, we did not see fewer de novo AML presentations during the peak of the COVID pandemic. While the reasons are unknown and require validation in large cohorts, the symptoms of leukemia including symptomatic anemia (low hematocrit) and higher WBC and blast count possibly driven by FLT3 mutations may drive patients to seek emergent clinical evaluation despite COVID pandemic barriers. The lack of difference in cytogenetic or other prognostic entities may demonstrate a lack of symptom correlation causing patients to present for care. The higher incidence of FLT3 mutations and lower hematocrit could reflect more symptomatic presentation of AML during the COVID pandemic. Since these differences may be a surrogate for a higher disease burden, it will be important to compare outcomes at longer time points. Figure 1 Figure 1. Disclosures DeAngelo: Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Incyte: Consultancy; Forty-Seven: Consultancy; Autolus: Consultancy; Amgen: Consultancy; Agios: Consultancy; Takeda: Consultancy; Glycomimetrics: Research Funding; Blueprint: Research Funding; Abbvie: Research Funding; Servier: Consultancy. Stone: Bristol Meyers Squibb: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Boston Pharmaceuticals: Consultancy; Innate: Consultancy; Foghorn Therapeutics: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Glaxo Smith Kline: Consultancy; Celgene: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; OncoNova: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Agios: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Arog: Consultancy, Research Funding; Jazz: Consultancy; Macrogenics: Consultancy; Novartis: Consultancy, Research Funding; Actinium: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy. Garcia: AstraZeneca: Research Funding; Prelude: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: 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. Winer: Abbvie: Consultancy; Takeda: Consultancy; Novartis: Consultancy.

scholarly journals Single-Cell Mutational Profiling of Clonal Evolution in De Novo AML during Therapy and Relapse

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1469-1469
Author(s):  
Alexey Aleshin ◽  
Robert Durruthy-Durruthy ◽  
M. Ryan Corces ◽  
Melissa Stafford ◽  
Michaela Liedtke ◽  
...  
Keyword(s):  
Single Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
De Novo ◽  
Sequencing Data ◽  
Employment Equity ◽  
Advisory Committees ◽  
Single Cell Sequencing ◽  
Equity Ownership ◽  
De Novo Aml

Abstract Background: De novo acute myeloid leukemia (AML) is a molecularly heterogeneous disorder with clinically variable outcomes. Recent studies on the mutational landscape of AML have been informative in better stratifying risk of relapse. However, bulk sequencing techniques have been limited in their ability to delineate the true complexity of tumoral molecular heterogeneity and allow for efficient identification of drug resistant subclones. Here, we applied high-throughput single cell sequencing technique to identify patterns of clonal heterogeneity and evolution in longitudinal samples from patients with AML undergoing induction chemotherapy. Methods: Matched diagnosis, remission, and relapse samples were examined for 20 de novo AML cases including 15 relapsed and 5 non-relapsed controls. Mutational bulk sequencing was performed by NGS panel sequencing and exome sequencing was available in select cases. Single cell processing was performed using the Tapestri (Mission Bio) platform. Briefly, individual cells were isolated using a microfluidic approach, followed by barcoding and genomic DNA amplification for individual cancer cells confined to droplets. Barcodes were then used to reassemble the genetic profiles of cells from next generation sequencing data. We applied this approach to individual AML samples, genotyping the most clinically relevant loci across upwards of 10,000 individual cells. Results: Targeted single-cell sequencing was able to recapitulate bulk sequencing data from both peripheral blood and bone marrow aspirate samples. We observed high concordance between bulk VAFs and sample level VAFs derived from single cell sequencing data. Additionally, single cell analysis allowed for resolution of subclonal architecture and tumor phylogenetic evolution beyond what was predicted from bulk sequencing alone. Rare subclones associated with disease relapse, were identified in initial diagnostic samples that were frequently under the limit of detection of bulk NGS. Conclusions:Taken together, our results suggest a greater degree of heterogeneity in de novo AML samples than suggested with bulk sequencing methods alone and shows the utility of single-cell sequencing for longitudinal monitoring and identification of resistant clones prior to therapy initiation in select patients. We show here that this approach is a feasible and effective way to identify and track heterogeneous populations of cells in AML and may be valuable for MRD identification. Disclosures Aleshin: Mission Bio, Inc.: Consultancy; Natera, Inc.: Employment. Durruthy-Durruthy:Mission Bio, Inc.: Employment, Equity Ownership. Liedtke:Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Amgen/Onyx: Consultancy, Honoraria, Research Funding; BlueBirdBio: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; celgene: Research Funding. Medeiros:Celgene: Consultancy, Research Funding; Genentech: Employment. Eastburn:Mission Bio, Inc.: Employment, Equity Ownership.

scholarly journals Allogeneic Transplantation for Myelodysplastic Syndrome in Adults over 50 Years Old Using Reduced Intensity/Non-Myeloablative Conditioning: Haploidentical Relative Versus Matched Unrelated Donor

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3323-3323
Author(s):  
Michael R. Grunwald ◽  
Mei-Jie Zhang ◽  
Hany Elmariah ◽  
Mariam H Johnson ◽  
Andrew St. Martin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
De Novo ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Advisory Committees ◽  
Free Survival ◽  
Donor Type ◽  
Disease Free

Background: Allogeneic hematopoietic cell transplantation (HCT) has been a successful strategy to treat myelodysplastic syndrome (MDS). With only approximately one-third of patients having an HLA matched sibling, most transplants use mismatched relative (haploidentical) or unrelated donors. In the current analysis we sought to study outcomes after haploidentical related compared to HLA-matched unrelated donor HCT for MDS (de novo or therapy-related). Methods: We retrospectively studied 176 recipients of haploidentical related donor and 427 recipients of 8/8 HLA-matched unrelated donor HCT in the United States between 2012 and 2017. The primary outcome was overall survival. The effect of donor type on survival and other transplant outcomes were studied using a Cox regression model. Results: Patient and disease characteristics are presented in Table 1. Most transplants (85%) were for de novo MDS in both donor groups. Although all patients received reduced intensity regimens, the predominant conditioning regimens were confounded by donor type. Total body irradiation (TBI) 200 cGy/cyclophosphamide/fludarabine (TBI/Cy/Flu; 82%) was the predominant regimen for haploidentical HCT and fludarabine with busulfan or melphalan (Flu/Bu or Flu/Mel; 79%) without in vivo T-cell depletion was the predominant regimen for unrelated donor HCT. Similarly, graft-versus-host disease (GVHD) prophylaxis was also confounded by donor type. Posttransplant cyclophosphamide/calcineurin inhibitor/mycophenolate (PT-Cy/CNI/MMF) was the prophylaxis regimen for all haploidentical transplants. CNI/MMF (31%) or CNI/methotrexate (69%) was used for unrelated donor transplants. Peripheral blood was the predominant graft for both donor types. The median follow-up was 24 months (range 3-77) after haploidentical and 36 months (range 3-74) after unrelated donor HCT. Results of multivariate analysis, adjusted for HCT-CI, prior treatment with hypomethylating agents (HMAs), and IPPS-R did not show differences in survival by donor type (HR 0.98, p=0.85; 40% vs. 37%), Figure 1. However, the relapse rate (adjusted for prior HMAs, IPSS-R, and recipient sex) was higher after haploidentical compared to unrelated donor HCT (HR 1.60, p=0.002, 53% vs. 34%), which led to lower disease-free survival after haploidentical HCT (HR 1.30, p=0.03; 21% vs. 32%), Figure 1. To further test the effect of regimen intensity, low dose TBI regimens were compared to Flu/Bu and Flu/Mel; we did not observe a difference in relapse risk (HR 0.95, p=0.76). Non-relapse mortality did not differ by donor type (HR 0.88, p=0.46). Interval between diagnosis and transplant was also not associated with outcomes. Acute grade II-IV acute GVHD (HR 0.46, p<0.001) and chronic GVHD (HR 0.34, p<0.001) was less common after haploidentical HCT. The 1-year graft failure rate was higher after haploidentical compared to unrelated donor HCT (15% and 8%, respectively, p=0.02). Conclusion: Although the current analysis did not show differences in survival between haploidentical related and matched unrelated donor HCT, the higher relapse and consequently lower disease-free survival associated with the haploidentical HCT approach in this analysis (primarily TBI/Cy/Flu with PT-Cy/CNI/MMF) warrants caution. A more definitive comparison of the two donor types can be accomplished only if more haploidentical transplants were to use Flu/Bu or Flu/Mel conditioning. Figure 1 Disclosures Grunwald: Celgene: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Merck: Consultancy; Abbvie: Consultancy; Medtronic: Equity Ownership; Incyte: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Amgen: Consultancy; Trovagene: Consultancy; Cardinal Health: Consultancy; Janssen: Research Funding; Genentech/Roche: Research Funding; Novartis: Research Funding; Forma Therapeutics: Research Funding. Bolanos-Meade:Incyte Corporation: Other: DSMB fees. Bredeson:Otsuka: Research Funding. Gupta:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Mussetti:Takeda: Honoraria; BMS: Honoraria; Novartis: Honoraria; Italfarmaco: Honoraria. Nakamura:Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: support for an academic seminar in a university in Japan; Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Kirin Kyowa: Other: support for an academic seminar in a university in Japan. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Solh:Celgene: Speakers Bureau; Amgen: Speakers Bureau; ADC Therapeutics: Research Funding. Weisdorf:Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy; Incyte: Research Funding.

Pevonedistat (MLN4924), an Investigational, First-in-Class NAE Inhibitor, in Combination with Azacitidine in Elderly Patients with Acute Myeloid Leukemia (AML) Considered Unfit for Conventional Chemotherapy: Updated Results from the Phase 1 C15009 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2313-2313 ◽  
Author(s):  
Ronan T Swords ◽  
Michael R Savona ◽  
Michael B Maris ◽  
Harry P Erba ◽  
Jesus G. Berdeja ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
De Novo ◽  
Single Agent ◽  
Clinical Activity ◽  
Conventional Chemotherapy ◽  
Advisory Committees ◽  
De Novo Aml ◽  
Grade 3

Abstract Background: Treatment of elderly AML patients considered unfit for conventional chemotherapy is inadequate and hypomethylating agents are commonly used alternatives. In the case of azacitidine, responses are typically seen after 3–6 cycles of therapy, and a recent large randomized trial in elderly unfit patients reported a complete response (CR)/CR with incomplete blood count recovery rate of 28% (Dombret et al, EHA 2014). Pevonedistat (MLN4924) is an investigational, first-in-class NEDD8-activating enzyme (NAE) inhibitor. A phase 1 trial previously reported pevonedistat single-agent clinical activity in relapsed/refractory AML patients. Preclinical studies of pevonedistat and azacitidine identified synergistic lethality in AML cell lines and murine xenografts. The current phase 1b dose-escalation study evaluated the safety and tolerability of pevonedistat combined with azacitidine in elderly AML patients considered unfit for conventional chemotherapy. Methods: The primary objective was to assess the safety and tolerability of pevonedistat combined with azacitidine. Secondary objectives included assessment of pevonedistat pharmacokinetics (PK) and clinical activity. Treatment-naïve AML patients aged ≥60 years who were considered unfit for standard induction therapy received pevonedistat via 1-hour IV infusion on days 1, 3, and 5 of 28-day cycles. Dose escalation began at 20 mg/m2 and used an adaptive Bayesian continual reassessment method. Azacitidine 75 mg/m2 was administered (IV or SC) on days 1–5 and 8–9. Patients were treated until disease progression or unacceptable toxicity. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Responses were assessed according to International Working Group response criteria for AML. Serial blood samples were obtained for PK analysis following dosing on days 1 and 5 of cycle 1. Results: As of May 30, 2014, 25 patients (median age 75.0 years [range 63–85]; 16 [64%] male) had received pevonedistat 20 mg/m2 (n=22) and 30 mg/m2 (n=3). Primary diagnoses were 16 (64%) de novo AML and 9 (36%) secondary AML. Fourteen (56%) patients had intermediate- and 6 (24%) had adverse-risk cytogenetics (5 [20%] undetermined). During dose escalation, dose-limiting toxicity (DLT) at the 30 mg/m2 pevonedistat dose level included reversible grade 2 increased bilirubin (n=1) and grade 3/4 increased transaminases (n=1) without clinical sequelae. In 1 of the 22 patients treated at the maximum tolerated dose (20 mg/m2 pevonedistat plus 75 mg/m2 IV/SC azacitidine), 1 additional DLT (grade 4 AST/ALT elevation) was seen in the expansion cohort. This patient was successfully re-challenged with a reduced pevonedistat dose. The most common all-grade AEs are shown in table 1. Twelve (48%) patients experienced drug-related grade ≥3 AEs (table 1). The nature and frequency of the reported toxicities (excluding DLTs) were similar to previous reports for azacitidine alone. Preliminary PK data showed that addition of azacitidine did not alter the known PK profile of single-agent pevonedistat. In the 18 response-evaluable patients, there were 6 (33%) CRs and 4 (22%) PRs (table 2), for an overall response rate of 56%. Nine of the 10 responses occurred within the first two cycles of therapy and included 1 patient with bone marrow blasts >80%. Conclusions: Combination therapy with pevonedistat and azacitidine was generally well-tolerated. The characteristics of the observed responses suggest added benefit from the addition of pevonedistat compared with azacitidine alone. Table 1 Common all-grade AEs n (%) Most frequent (≥10%) drug-related grade ≥3 AEs n (%) Febrile neutropenia 9 (36) Febrile neutropenia 4 (16) Constipation 8 (32) Thrombocytopenia 3 (12) Decreased appetite 7 (28) – – Thrombocytopenia 7 (28) – – Table 2 Responders* Tumor Type Cytogenetic Risk Group Current Status Response Molecular CR 1st Response 1st CR 1 De novo AML Adverse C12 C4 – – 2 Undetermined C4† C1 C1 Y 3 Adverse C9 C1 C1 Y 4 Undetermined C5‡ C1 C2 Y 5 Intermediate C5† C1 C2 N 6 Intermediate C7 C1 C4 Y 7 Intermediate C2 C2 – – 8 Secondary AML Undetermined C4 C2 C2 – 9 Normal C4 C1 – – 10 De novo AML – C1 C1 – – Molecular CR, complete remission confirmed by molecular studies *All received 20 mg/m2 pevonedistat except #4, who started on 30 mg/m2 and had a dose reduction to 20 mg/m2. †Patient off study ‡Patient off treatment and in follow-up Disclosures Swords: Novartis: Consultancy; KaloBios Pharmaceuticals, Inc.: Consultancy; Millennium: The Takeda Oncology Company: Consultancy. Savona:Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Erba:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding. Foran:Takeda Pharmaceuticals International Co.: Research Funding. Hua:Takeda Pharmaceuticals International Co.: Employment. Faessel:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Dash:Takeda Pharmaceuticals International Co.: Employment. Sedarati:Takeda Pharmaceuticals International Co.: Employment. Dezube:Takeda Pharmaceuticals International Co.: Employment. Medeiros:Millennium: The Takeda Oncology Company: Consultancy, Honoraria; Takeda Pharmaceuticals International Co.: Research Funding.

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