scholarly journals Characteristics and Outcome of Patients with Core Binding Factor Acute Myeloid Leukemia and FLT3-ITD: Results from an International Collaboration

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2693-2693
Author(s):  
Sabine Kayser ◽  
Michelle A Elliott ◽  
Marlise Luskin ◽  
Andrew M. Brunner ◽  
Michael Kramer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Complex Karyotype ◽  
Core Binding Factor ◽  
Advisory Committees ◽  
Allelic Ratio ◽  
Binding Factor ◽  
Acute Myeloid

Background: Core binding factor acute myeloid leukemia (CBF-AML) is defined by the presence of either t(8;21)(q22;q22) or inv(16)(p13.1q22)/t(16;16)(p13.1;q22) and is associated with a favorable outcome, particularly if treated with repetitive cycles of high-dose cytarabine as post-remission therapy. Long-time 10-year overall survival (OS) rate was reported of 58% in FLT3-ITD negative patients (pts; Allen et al. Leukemia 2013). Nevertheless, 30-40% CBF-AML pts experience relapse. FLT3-ITD mutations occur in roughly 5-10% of adult CBF-AML. However, their prognostic relevance is still controversial. Aims: To characterize CBF-AML with FLT3-ITD and compare outcomes according to their genetic background. Methods: We retrospectively studied 65 AML pts with CBF-AML and FLT3-ITD (median age at diagnosis, 54 years; range, 22-81 years) diagnosed between 1996 and 2018 within seven study groups/institutions of the US and Europe. Results: Thirty-two (49%) of the 65 pts harbored t(8;21). Median white blood cell and platelet counts at diagnosis of patients with t(8;21) and inv(16) were 18.3/nl (range, 1.8-202/nl) and 31/nl (range, 7-372/nl), respectively. AML diagnoses were de novo in 61 (94%) and therapy-related in 4 (6%) of the pts. Thirty (46%) pts were female. Cytogenetic analysis revealed additional abnormalities (abn) in 38 (58%) pts, most frequently loss of X or Y (n=13; n=12 associated with t(8;21)), complex karyotype (≥3 abn; n=12; n=7 occurring in t(8;21)), trisomy 22 (n=7, all associated with inv(16)) or trisomy 8 (overall n=6, n=5 occurring in inv(16)). Four pts were positive for both mutations, FLT3-ITD as well as FLT3-TKD. Median ITD allelic ratio were 0.44 (range, 0.003-50) and median ITD size 60 bp (range, 3-120 bp). Three older pts (median age, 75.5 years) were treated with either azacitidine + sorafenib, azacitidine + venetoclax or with etoposide + tipifarnib. All three patients receiving non-intensive therapy died within one year and were excluded from further analysis. Complete remission (CR) after anthracycline-based induction therapy was achieved in 98% (n=61/62) of patients fit for intensive treatment including two pts treated with 7+3 ± midostaurin within the RATIFY trial. One patient died during induction. Fifteen (24%) pts underwent allogeneic hematopoietic cell transplantation. Of those, 10 pts were transplanted in 1st and 5 pts in 2nd CR. Median follow-up for the entire cohort was 4.43 years (95%-CI, 3.35-8.97 years). Median and 4-year relapse-free survival (RFS) rates were 3.41 years (95%-CI, 1.26 years - not reached) and 44.9% (95%-CI, 32.9-61.4%). Median and 4-year overall survival rates (OS) were 4.48 years (95%-CI, 2.26 years - not reached) and 51.8% (95%-CI, 39.6.2-67.9%). Neither type of CBF-AML (p=0.60), nor additional chromosomal abn (p=0.80), nor presence of a complex karyotype (p=0.50) had a prognostic impact on OS. Higher age (≥60 years) was an in trend negative prognostic factor on RFS and OS (p=0.07, each). High allelic ratio (≥0.5) had no impact on RFS (p=0.3), but in trend on OS (p=0.10). Conclusions: Despite a high remission rate pts with FLT3-ITD had an inferior outcome as compared to previously published data on CBF-AML without FLT3-ITD. Thus, CBF-AML with FLT3-ITD should not be classified within the low-risk category. CBF pts with FLT3-ITD warrants further study and should be included in FLT3-inhibitor trials. Disclosures Brunner: Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Novak:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel,Accommodations; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Travel,Accommodations; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stoelzel:Neovii: Other: Travel funding; Shire: Consultancy, Other: Travel funding; JAZZ Pharmaceuticals: Consultancy. Thiede:Daiichi Sankyo: Honoraria; AgenDix GmbH: Employment, Equity Ownership; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Diaceutics: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Levis:Agios: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo Inc: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

Trends In Outcomes In Core Binding Factor Acute Myeloid Leukemia: A SEER Database Analysis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3880-3880 ◽  
Author(s):  
Andrew M. Brunner ◽  
Traci Blonquist ◽  
Hossein Sadrzadeh ◽  
Yi-Bin Chen ◽  
Donna S. Neuberg ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Seer Database ◽  
Core Binding Factor ◽  
Advisory Committees ◽  
Patients Âgés ◽  
Binding Factor ◽  
Acute Myeloid

Abstract Acute myeloid leukemia with chromosomal alterations impacting the core binding factor transcription complex (CBF-AML), specifically t(8;21) and inv(16), are associated with a greater responsiveness to cytarabine-based chemotherapies and a more favorable prognosis. The latter has been primarily gleaned from outcomes of large clinical trials of AML. However, to date, there is limited population-based outcomes data on CBF-AML. We therefore performed an epidemiologic retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database to assess survival trends for CBF-AML at the population level between 2000 and 2010. Patients and Methods Patients with a diagnosis of CBF-AML between 2000 and 2010 were identified using the SEER 18 registries database. We included patients with a diagnosis code of inv(16)/t(16;16) AML (Code 9871) or t(8;21) AML (Code 9896) diagnosed between January 2000 and December 2010. Patients were divided into cohorts based on age at diagnosis: 15-44 years old, 45-64 years old, 65-74 years old, and 75-84 years old. Disease incidence was calculated, as were early mortality rates, defined as death within 1 month. Overall survival (OS) was estimated using the method of Kaplan and Meier. Cox regression was performed to estimate predictors of survival by specific CBF-AML type, age cohorts, race/ethnicity, gender, year of diagnosis, number of primary malignancies, and residence. Results We identified 777 patients with a new diagnosis of CBF-AML between 2000 and 2010. The incidence of CBF-AML increased with advancing age (ages 15-44, 0.06 per 100,000 people; ages 45-64, 0.13; ages 65-74, 0.25; ages 75-84, 0.28). Median OS for all patients was 22 months, and the combined 3-year OS was 44.3% (Fig. 1). Median OS increased from 16 months during the period encompassing 2000 and 2002 to 25 months during the period from 2006 to 2008 (p=0.002) (Fig. 2). The rate of early death was 13%, which increased with age (15-44 5%, 45-64 10%, 65-74 20%, 75-84 33%; P<0.0001). OS also worsened with advancing age; patients ages 75-84 had a 3 year OS of 9.3% and an increased HR for mortality compared to patients ages 15-44, who had a 3 year OS of 68.7% (HR 5.61, P<0.0001) (Fig. 3). Of note, worsening OS with advancing age was observed even among the subset of patients alive at 1 month. Black race was associated with an increased HR for mortality compared to white non-Hispanic patients (HR 1.50, P=0.03). Patients with inv(16) disease had an improved OS compared to patients with t(8;21) disease (HR for mortality 0.65, P<0.0001). The 3 year OS for patients with inv(16) disease was 57.3%, while for those with t(8;21) disease it was only 35.5% (Fig. 1). Conclusion In spite of historically favorable prognoses associated with CBF-AML in clinical trials, we found poorer survival in the general population. Unlike inv(16) disease, patients with t(8;21) CBF-AML did not appear to have a favorable OS. Survival was significantly worse among African Americans and the elderly. The reason for these differences is unknown, and merits further evaluation. Disclosures: Chen: Otsuka Pharmaceuticals, Inc.: Research Funding; Seattle Genetics: Consultancy, Research Funding; Bayer / Onyx: Research Funding. Fathi:Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity’s Board of Directors or advisory committees; Agios: Membership on an entity’s Board of Directors or advisory committees; Millenium: Research Funding.

scholarly journals Impact and Outcomes of RAS gene Mutations in Core Binding Factor Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2720-2720
Author(s):  
Hassan Awada ◽  
Ashwin Kishtagari ◽  
Teodora Kuzmanovic ◽  
Jibran Durrani ◽  
Cassandra M Kerr ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Survival Outcomes ◽  
Core Binding Factor ◽  
Advisory Committees ◽  
Ras Mutations ◽  
Binding Factor ◽  
Acute Myeloid

Acute myeloid leukemia (AML) with t(8;21) or inv(16) chromosomal rearrangements are distinct heterogeneous disease entities within AML that are classified together as core binding factor AML (CBF-AML). Given the nature of the chromosomes involved, these rearrangements lead to the production of leukemogenic chimeric transcripts (RUNX1-RUNX1T1 and CBFB-MYH11) which disrupt the physiologic activity of the heterodimeric transcription factor CBF complex. Although CBF-AML patients have a favorable prognosis and good response to treatment compared to other AML subtypes, survival outcomes are not uniform. Indeed, 30-50% of patients with CBF-AML eventually relapse, and the 5-10 yr survival ranges between 55-61% for patients < 60 yr in MRC/NCRI AML trials. Studies have analyzed the clonal architecture of CBF-AML patients and identified cooperating mutations independently of receptor tyrosine kinases (FLT3, KIT) mutations while others have found a 30% occurrence of KIT mutations. Studies of murine models of Runx1 and Cbfb have demonstrated that inactivation of both genes does not lead to leukemia, suggesting that other factors are necessary to recapitulate the leukemia phenotype fully. Although mutations in RAS family of genes (NRAS/KRAS) are among the most frequently observed mutations described in CBF-AML [54% in inv(16) and 30% in t(8;21)], no associations between those mutations and survival outcomes have been found. Because of the lack of association between RASMT and clinical outcomes, their role in CBF-AML is still unknown. Here, we focused on dissecting the impact of RAS mutations (NRAS/KRAS; RASMT) on the clinical characteristics, survival outcomes, and the molecular associations among CBF-AML patients by evaluating the clonal succession of RASMT. In total, 284 CBF-AML patients were identified, in whom inv(16) and t(8;21) represent 61% (n=173) and 39% (n=111) of the cases, respectively. Thirty-five % (99/284) of the patients carried RAS mutations (NRAS=78; KRAS=21) with 8 patients harboring 2 mutations comprising NRAS, KRAS, or both NRAS/KRAS genes. RAS mutations were point mutations affecting known hotspots in NRAS and KRAS. Both RASMT and RASWT had a median age < 60 years (55 (14-83) vs. 49 (7-83) years, P=0.9) and sex was equally distributed among the two groups. Leukopenia, defined as white blood cell count <3.5 x 109/L, was the only significant different hematological parameter between RASMT and RASWT. Fewer RASMT patients had leukopenia (3 vs. 12%; P=0.02). Compared to RASWT patients, RASMT patients had more often +8 (14 vs. 6%; P=0.02) and less -Y (7 vs. 16%; P=0.04) abnormalities. The analysis of 30 genes frequently mutated in myeloid malignancies revealed that RASMT patients had a significantly lower number of additional mutations compared to RASWT patients (n=59 vs. 197; P=0.03). Focusing on molecular associations, there were no differences in the frequency of FLT3 (TKD or ITD) mutations between RASMT and RASWT (15 vs. 18%). Although RASWT were more enriched with ASXL1, DNMT3A, IDH1/2, TET2, and WT1 mutations, no significant difference in frequencies was found when compared to RASMT. KIT mutations have been associated with poor outcomes in CBF-AML. In our cohort, KIT mutations (small deletions, points mutations), were significantly less associated with RASMT than RASWT (8 vs. 59%; P<.0001). RASMT were ancestral events in 58% of the cases (with FLT3 mutations the most common secondary lesions), secondary in 38% (with TET2,ASXL1, RUNX1 and IDH2 mutations represented the most common dominant hits), and codominant in 11% (with KIT mutations). RASMT in CBF-AML was associated with worse OS (HR: 1.520; P=0.04) compared to RASWT. Clonal hierarchy and succession analysis showedno change in OS when RASMT were secondary vs. dominant hits in CBF-AML (HR: 0.8; P=0.5). In sum, our study of the frequency, clonal architecture and impact on survival of RASMT in CBF-AML patients points out the unique characteristics of this specific disease subgroup in which sole RASMT might represent, in addition to KITMT, a mutational lesion cooperating with inv(16) and t(8;21) rearrangements in driving leukemic evolution. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Advani:Glycomimetics: Consultancy, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Kite Pharmaceuticals: Consultancy. Nazha:Abbvie: Consultancy; Incyte: Speakers Bureau; Jazz Pharmacutical: Research Funding; Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Daiichi Sankyo: Consultancy. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

scholarly journals Outcomes By Best Response with Hypomethylating Agent Plus Venetoclax in Adults with Previously Untreated Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2292-2292
Author(s):  
Virginia Olivia Volpe ◽  
Akriti G Jain ◽  
Onyee Chan ◽  
Eric Padron ◽  
David A. Sallman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Free State ◽  
Advisory Committees ◽  
Best Response ◽  
Baseline Characteristics ◽  
Acute Myeloid

Abstract Background: Venetoclax plus hypomethylating agents (HMA) (HMA+VEN) is a standard of care treatment for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. In the phase 3 VIALE-A trial, azacididine (aza)+VEN compared to aza alone demonstrated an improved overall survival of 14.7 months versus 9.6 months, respectively. A common toxicity with HMA+VEN is myelosuppression. The prognostic implications of incomplete count recovery despite leukemia free state after HMA+VEN treatment in AML is unclear. We aimed to compare the outcomes of those who achieved complete remission (CR), complete remission with incomplete hematologic recovery (CRi), or morphologic leukemia-free state (MLFS) in AML patients treated frontline with HMA+VEN. Methods: Patients seen at Moffitt Cancer Center between 2019 and 2021 diagnosed with AML and treated with frontline HMA+VEN were retrospectively evaluated and included for analysis. Patients were stratified by best response; either CR, CRi, or MLFS. Baseline characteristics were compared by chi square (categorical variables) and t- test (continuous variables). Survival estimates were calculated using the Kaplan-Meier method from date of diagnosis and groups were compared using log-rank test. Results: Of the 102 patients treated with HMA+VEN in the frontline setting, 48% (n=49) had blast clearance with a best response of CR in 27/102 (26.4%), CRi in 16/102 (15.7%), or MLFS in 6/102 (5.9%). The remainder had residual disease. Baseline characteristics were similar among the three response groups (Table 1) as was mutational distribution (Table 2). There was no difference between AML WHO classification subtype (p= .148). Decitabine or aza was used at the discretion of the treating physician did not significantly impact responses (p= .225). In those who achieved CR, 14% had prior therapy related AML compared to 37.5% in CRi and 33.3% in MLFS (p= .314). Antecedent MDS or MPN with transformation to AML was seen in 22.2%, 18.8%, and 66.7% of CR, CRi, and MLFS respectively (p= .029). Of those, 3.7% in CR group had HMA use for prior MDS/MPN compared to 0% in CRi and 50% in MLFS (p= .000). The median relapse free survival was not reached for CR, CRi, and MLFS (Figure 1), it is important to note that 3 of the 6 MLFS patients died without relapse . At median follow up of 23 months, median overall survival (OS) in the CR group was significantly longer, 31 months, compared to 18 months in the CRi group and 8.5 months in the MLFS group (p=0.0415) (Figure 2). Transplant was achieved in 26% of CR and 6.3% of CRi and 0% of MLFS and was not significant among the groups (p = .124). Conclusion: Patients who received frontline HMA+VEN for AML directed therapy and achieved CR/CRi had better survival compared to those who achieved MLFS. Our data suggest that incomplete recovery of blood counts plays a significant role in overall survival regardless of leukemia free state. Further, the data demonstrate significantly higher secondary AML with antecedent MDS or MPN in the MLFS group compared to CR and CRi groups. Of those, prior HMA therapy was also identified as significantly higher in the MLFS group compared to CR and CRi groups which may contribute to the prolonged cytopenias and worse OS. While the limitation to this study is overall small number of patients, it suggests that a goal of CR over CRi or MLFS is desirable for superior OS. In the future, it would be of interest to incorporate the rates of responses and variables that may have an impact such as therapy dose adjustment, time to response, and delays in therapy due to cytopenia. Additional studies identifying dose adjustments or other ways to improve hematologic recovery would be valuable to potentially improve outcomes in this difficult to treat population. Figure 1 Figure 1. Disclosures Padron: Stemline: Honoraria; Taiho: Honoraria; BMS: Research Funding; Incyte: Research Funding; Blueprint: Honoraria; Kura: Research Funding. Sallman: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Intellia: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees. Komrokji: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acceleron: Consultancy; Jazz: Consultancy, Speakers Bureau; Geron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees. Lancet: AbbVie: Consultancy; Astellas: Consultancy; Jazz: Consultancy; Agios: Consultancy; Millenium Pharma/Takeda: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; BerGenBio: Consultancy. Sweet: AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Characteristics and Outcomes Of Patients (pts) With Multiple Myeloma (MM) Who Develop Therapy (t)-Related Myelodysplastic Syndrome (MDS), t-Chronic Myelomonocytic Leukemia (CMML), Or t-Acute Myeloid Leukemia (AML)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1424-1424
Author(s):  
Naveen Pemmaraju ◽  
Dhaval Shah ◽  
Hagop M Kantarjian ◽  
Verena Wagner ◽  
Robert Z. Orlowski ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chemotherapeutic Agents ◽  
Chronic Myelomonocytic Leukemia ◽  
Advisory Committees ◽  
Myelomonocytic Leukemia ◽  
Acute Myeloid

Abstract Background There has been a significant improvement in the outcome for patients (pts) with MM over the last decade, mainly due to the availability of immunomodulatory (IMiD) drugs and proteasome inhibitors (PI). The improvement in survival has also increased the risk of second primary malignancies (SPM), such as therapy-related myelodysplastic syndrome (t-MDS), therapy-related chronic myelomonocytic leukemia (t-CMML) or therapy-related acute myeloid leukemia (t-AML). However, little is known about the characteristics and outcomes of pts with t-MDS, t-CMML or t-AML. Methods We aimed to study the characteristics and outcome of pts who developed t-MDS, t-AML and t-CMML as SPM after the treatment of MM. We reviewed our database of pts with MM who were treated at our institution between 1993 and 2011. We identified 49 pts who were diagnosed to have t-MDS, t-CMML, or t-AML. The primary objective of this study was to evaluate the time to develop t-MDS, t-AML and t-CMML, their response to treatment and overall survival. Results Median age of pts at diagnosis of MM was 61 years. Forty-seven (96%) pts had symptomatic MM, while 2 (4%) had asymptomatic myeloma. Forty-seven (95%) pts with symptomatic myeloma received systemic therapy. Eleven (22%) pts were treated with IMiD or PI: lenalidomide 3, thalidomide 6 and bortezomib 2. Thirty-eight (78%) pts were treated with various conventional chemotherapeutic agents including melphalan, cyclophosphamide, doxorubicin, vincristine, etoposide, cisplatin, idarubicin, thiotepa, busulfan, carmustine and cytarabine. Fourteen (28%) pts also received radiation therapy to the affected areas. Twenty (41%) pts underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT). Fourteen pts received maintenance therapy after auto-HCT with either thalidomide, lenalidomide, dexamethasone or bortezomib. Median time from the diagnosis of MM to t-MDS, t-CMML or t-AML was 6 years [0 – 24]. Thirty-four (69 %) pts developed t-MDS, 12 (24%) t-AML, and 3 (6%) t-CMML. Median age at diagnosis of t-MDS, t- CMML, or t-AML was 65 years. Twenty-seven (79%) pts with t-MDS and all 12 pts with t-AML had complex/high risk cytogenetics. Most common cytogenetic abnormalities involved chromosome 5 and 7. Thirty four (69%) pts received at least 1 cycle of induction chemotherapy either with conventional chemotherapeutic agents or investigational drugs. Only 9 pts (26%) achieved complete remission (CR). Median duration of CR in these pts was 4 months [1 – 62]. Median overall survival (OS) of pts who received induction therapy was 6.0 months [0-30]. Five (11%) pts received an allogeneic stem cell transplant with three achieving CR. Median OS in this subgroup of pts was 18 months [9 – 23]. Median OS for all 49 pts after diagnosis of t-MDS, t-CMML or t-AML was 6.0 months [0 – 30] Conclusion Development of t-MDS, t-CMML, or t-AML in pts with MM is associated with a poor outcome. These pts in general have complex cytogenetic abnormalities, chemo-resistant disease, a short CR and OS. A better understanding of disease biology and novel therapeutic approaches are warranted. Disclosures: Orlowski: Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Qazilbash:Otsuka: Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium Pharmaceuticals: 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.

scholarly journals Acute Myeloid Leukemia with Myelodisplasia-Related Changes (AML-MRC) Defined Only By Morphological Findings May Not Represent a Poor Prognosis AML

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2612-2612
Author(s):  
Ana Pérez ◽  
Olga Salamero ◽  
Helena Pomares ◽  
Maria Julia Montoro ◽  
Montserrat Arnan Sangerman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Poor Prognosis ◽  
Advisory Committees ◽  
Group 3 ◽  
Group 2 ◽  
Acute Myeloid ◽  
Group 1

According to the 2016 WHO classification, AML-MRC encompasses an heterogeneous group of acute myeloid leukemias (AML) comprising: AML emerged from a previous myelodysplastic syndrome (MDS) or myeloproliferative /myelodysplastic disease (group 1), AML with MDS-defining cytogenetic abnormalities (group 2), or acute myeloid leukemia (AML) with dysplasia in at least 2 cell lineages without the above mentioned (group 3). In spite that AML-MRC has been considered a high-risk entity with poor prognosis, little is known on the relationship of clinical and biological characteristics with outcomes in these three groups. The aim of this study was to describe the clinical and biological characteristics of patients with AML-MRC and analyze their prognostic variables and outcomes. We retrospectively analyzed AML-MRC cases diagnosed between January-2009 and December- 2018 in two institutions. Descriptive variables were studied to compare the three AML-MRC groups. AML cytogenetic risk and response were defined according to the European Leukemia Net recommendations. Overall survival (OS) was considered as the time from the diagnosis to the last visit. Survival analysis were performed with Kaplan Meier method and comparisons with the log-rank test. Among 575 cases of AML identified, 186 (32.3%) met AML-MRC criteria and were included in the study. The main patient characteristics are shown in Table1. Median age was 72 (range, 22-88) years and 32% were female. Adverse karyotype was present in 29% of patients, being more prevalent in the AML-MRC group 2. Sixty one patients (33%) received an intensive chemotherapy approach and 36 (19%) an allogeneic stem cell transplantation. Patients in group 3 exhibit a higher probability of achieving a complete response than groups 1 and 2 (Table 2). After a median follow-up for survivors of 28.5 months (range, 5-130), 149 (80%) died in this period. Three years Overall Survival (OS) for patients in groups 1, 2 and 3 was 3 (0-117), 5 (0-93) and 10 (0-130) months, respectively (p=0.012) (Figure 1). Type of treatment (intensive, non intensive or best supportive care) and cytogenetic risk also showed impact on OS. Multivariant analysis adjusting these factors showed that patients in group 3 also presented better OS than patients in group 1 (HR=0,42 [IC95% 0,18-0,84], p=0,02), both with around a 30% of patients with adverse cytogenetics. To conclude the present study suggests that group 3 of AML-MRC, for which the diagnosis is based solely on morphologic findings, showed better prognosis than the other groups. A more detailed molecular characterization might contribute to improve prognostic stratification of this heterogeneous AML entity, particularly in patients with non-high risk cytogenetics. Disclosures Salamero: Pfizer: Honoraria; Daichii Sankyo: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Valcárcel:Jazz Pharmaceuticals: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: spouse is an employee in the company, Speakers Bureau; Pfizer: Honoraria. Bosch:AstraZeneca: Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Venetoclax Therapy in a Heavily Treated Cohort of Patients with Relapsed or Refractory Acute Myeloid Leukemia: Update of the Pethema Registry Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2325-2325
Author(s):  
Jorge Labrador ◽  
Miriam Saiz-Rodríguez ◽  
Maria Dunia De Miguel ◽  
Almudena De Laiglesia ◽  
Carlos Rodriguez ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Tumor Lysis Syndrome ◽  
Advisory Committees ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract Introduction The prognosis of patients with relapsed or refractory acute myeloid leukemia (RR-AML) is very poor, and treatment options are very limited. The exciting results of venetoclax (VEN) in untreated AML have led to its off-label use in RR-AML. However, evidence in RR-AML is still scarce and the available data are mostly from retrospective and single-center studies. The aim of our study was to analyze the effectiveness of VEN use in patients with RR-AML reported to the PETHEMA AML epidemiological registry. Initial results were presented previously (Labrador J, et al. ASH 2020). Here, we report an updated analysis. Methods We conducted a retrospective, multicenter, observational study of a cohort of patients with AML-RR who were treated with venetoclax in the hospitals of the PETHEMA group. We evaluated efficacy, CR/CRi rate and overall survival (OS). We performed a descriptive analysis. Overall survival (OS) was calculated using the Kaplan-Meier method. Results Fifty-one patients were included, 33 men and 18 women, with a median age of 68 years (25-82). The main characteristics of the included patients are shown in Table 1. With a median follow-up of 167 days, 10/51 patients (19%) continued to receive VEN at the time of analyses. Patients received a median of 2 cycles (0-8). VEN was administered with azacitidine (AZA) in 59%, with decitabine (DEC) in 29% and with low-dose cytarabine (LDAC) in 12% of patients, respectively. The CR/CRi and partial response (PR) rates were 12.4% and 10.4%, respectively. The CR/RCi and overall response (ORR, CR/CRi+PR) was higher in patients receiving VEN+AZA (17.9% and 32.1%) than in those receiving DEC + VEN (6.7% and 13.3%) or LDAC + VEN (0%). The presence of NPM1 or CEBPA variants were the only two variables associated with increased CR/CRi with VEN in RR-AML. Median OS was 104 days (95% CI: 56 - 151) (Figure 1A), 120 days in combination with AZA, 104 days with DEC, and 69 days with LDAC; p=0.875. Treatment response (Figure 1B) and ECOG 0 were the only variables that influenced OS in a multivariate model adjusted for age and sex (Table 2). VEN-resistant patients who received subsequent salvage therapy had superior median OS (98 vs. 5 days, p=0.004).Twenty-eight percent of patients required discontinuation of VEN due to toxicity. Sixty-one percent of patients required admission, mainly due to infections (45%), 10% due to bleeding and other causes in 12%. One case of tumor lysis syndrome was described. Conclusions Our real-life series depicts a marginal probability of CR/CRi and poor OS after venetoclax-based salvage. Patients treated with this regimen had very poor-risk features, and were heavily pre-treated, which could explain in part the observed poor outcomes. Although follow-up is still short, the small proportion of responders did not reach the median OS. Further studies will help to identify those patients potentially benefiting from venetoclax-based salvage regimens. Figure 1 Figure 1. Disclosures Belén Vidriales: Roche: Consultancy; Novartis: Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Pérez-Encinas: Janssen: Consultancy. Tormo: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Montesinos: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: 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, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Tolero Pharmaceutical: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. OffLabel Disclosure: Venetoclax for Patients with Relapsed or Refractory Acute Myeloid Leukemia

Impact of Myocardial Infarction On Survival in Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4321-4321
Author(s):  
Joshua Lukenbill ◽  
Paul Elson ◽  
Sanjay Mohan ◽  
Ramon V. Tiu ◽  
Yogen Saunthararajah ◽  
...  
Keyword(s):  
Risk Factors ◽  
Myocardial Infarction ◽  
Overall Survival ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Case Control ◽  
Advisory Committees ◽  
St Elevation ◽  
Acute Myeloid

Abstract Abstract 4321 Acute myeloid leukemia (AML) may present with vascular phenomena, commonly manifested in the pulmonary and neurologic systems, and often attributed to leukostasis, thrombotic abnormalities as with acute promyelocytic leukemia (APL), and anemia. Myocardial infarction (MI) may be the initial presentation of these vascular changes, preceding a diagnosis of AML. We reviewed the incidence of MI in the setting of a new AML diagnosis, associated risk factors, and impact on overall survival (OS). All patients diagnosed with AML at Cleveland Clinic between 2001 and 2012 who were also diagnosed with MI (either a ST-elevation MI or a non-ST-elevation MI with compatible cardiac biomarkers) at the time of AML diagnosis (median same day, range from 2 days before to 93 days after MI diagnosis) were identified (cases). We performed a case-control analysis in which MI patients were randomly matched 3:1 to non-MI patients based on gender, age at diagnosis (±5 years), year of diagnosis (±3 years), and if available, cytogenetics and etiology. Overall survival (OS) was the primary endpoint; also compared were MI risk factors (previous MI, hypertension, hyperlipidemia, and diabetes); complete blood count (CBC) characteristics (white count, hemoglobin, and platelets); and AML type (APL and non-APL). Statistical analyses included Fisher's exact, chi-square, and Wilcoxon rank sum test (patient characteristics and MI risk factors); and the logrank test and frailty models (OS). Out of 774 AML patients, 12 (1.6%) presented with a MI: 54% were male and the median age at diagnosis was 61 years (range 19–94); 19% had one of more risk factors for MI (heart disease, hypertension, hyperlipidemia, and diabetes); 52% were non-smokers, 25% were former smokers, and 23% currently smoked. Most (71%) were newly-diagnosed, 24% had prior myelodysplastic or myeloproliferative neoplasms, 6% was therapy-related, and 6% had APL. Most (83%) received standard cytarabine-based induction therapy, and 67% achieved a complete remission. Median follow-up for patients still alive was 19.3 months. Of the patients presenting with MI, 11 of 12 have died with a median OS of 7.9 months, compared with a median OS of 13.1 months in the entire non-MI cohort (95% CI 11.0–15.1, p=.02). MI remained associated with worse OS in multivariable analyses (HR 1.71, 0.91–3.22, p=.09). In case-control analyses, controls had a median OS of 14.0 months compared to 7.9 months for MI cases (95% CI 8.7–26.6, p=.04 adjusting for the matching and number of comorbidities present, Figure). Factors associated with MI included previous MI (p=.01) and > 2 comorbidities (p=.02). Other MI risk factors, CBC characteristics, and APL compared to non-APL did not differ significantly between the two groups. In conclusion, AML patients presenting with MI have a worse OS than non-MI AML patients. Preceding comorbidities place patients at greater risk for MI than leukemia-related factors. Disclosures: Advani: Novartis: Research Funding. Maciejewski:Novartis: Research Funding. Sekeres:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Identifying Factors That Predict for Unplanned Readmissions for Acute Myeloid Leukemia Patients Receiving Consolidation Cytarabine Based Therapies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3433-3433
Author(s):  
Caitlin Siebenaller ◽  
Madeline Waldron ◽  
Kelly Gaffney ◽  
Brian P. Hobbs ◽  
Ran Zhao ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Smoking Status ◽  
Consolidation Therapy ◽  
Peripheral Vascular ◽  
Consolidation Chemotherapy ◽  
Advisory Committees ◽  
History Of ◽  
Acute Myeloid

Background: Younger patients (pts) with acute myeloid leukemia (AML) who enter a remission after intensive induction chemotherapy routinely receive at least one cycle of consolidation therapy with high dose cytarabine (HiDAC). This is commonly administered over a five-day inpatient stay, after which pts are discharged home as their blood counts nadir. It is thus a natural consequence of therapy that readmission for febrile neutropenia (FN) occurs, which can impact measures of quality and value in this population. Precise descriptions of incidence, type, and severity of infection, if identified, are lacking, and thus it is unknown to what standard cancer centers should be held for anticipated readmission. We measured these rates, and attempted to identify predictive factors for readmission. Methods: Adult AML pts ≥ 18 years of age who received at least one cycle of HiDAC consolidation (1000-3000 mg/m2 for six doses) in 2009-2019 were included. Our primary aim was to identify predictive factors for readmission after the first cycle of consolidation chemotherapy. The following pt characteristics and co-morbid conditions were analyzed: age, gender, body mass index (BMI), smoking status, AML cytogenetic risk status, history of diabetes, peripheral vascular disease, cardiovascular disease, chronic pulmonary disease, hepatic impairment, and other cancers. Secondary aims included: estimating rates of all-cause readmissions among all HiDAC cycles, defining the rate of FN readmissions, estimating rates of intensive care unit (ICU) admissions, clinical (e.g., probable pneumonia per imaging) and microbiologically-documented infections, prophylactic (ppx) medications used, and mortality. Statistical analyses interrogated potential risk factors for evidence of association with hospital readmission after the first cycle of consolidation chemotherapy. Results: We identified 182 AML pts who fit inclusion criteria. The median age was 50 years (range 19-73); 55% were female and 45% were male. Statistical analyses revealed no association with readmission after cycle 1 for cytogenetic risk (p=0.85), history of heart failure (p= 0.67), chronic pulmonary disease (p=1), connective tissue disease (p=0.53), cerebrovascular accident (p=0.63), diabetes (p=0.63), gender (p=0.07), history of lymphoma (p=0.53), other solid tumors (p=0.53), liver disease (p=1), myocardial infarction (p=0.71), peripheral vascular disease (p=1), or smoking status (p= 0.52). For 480 HiDAC cycles analyzed (88% at 3000 mg/m2), the overall readmission rate was 50% (242/480), of which 85% (205/242) were for FN. Those readmissions which were not FN were for cardiac complications (chest pain, EKG changes), non-neutropenic fevers or infections, neurotoxicity, bleeding or clotting events, or other symptoms associated with chemotherapy (nausea/vomiting, pain, etc.). Median time to FN hospital admission was 18 days (range 6-27) from the start of HiDAC. Of the 205 FN readmissions, 57% had documented infections. Of these infections, 41% were bacteremia, 23% fungal, 16% sepsis, 12% other bacterial, and 8% viral. Of 480 HiDAC cycles, ppx medications prescribed included: 92% fluoroquinolone (442/480), 81% anti-viral (389/480), 30 % anti-fungal (142/480), and 3% colony stimulating factor (14/480). Only 7% (14/205) of FN readmissions resulted in an ICU admission, and 1% (3/205) resulted in death. Conclusions: Approximately half of patients treated with consolidation therapy following intensive induction therapy can be expected to be readmitted to the hospital. The majority of FN readmissions were associated with clinical or microbiologically documented infections and are not avoidable, however ICU admission and death associated with these complications are rare. Readmission of AML pts following HiDAC is expected, and therefore, should be excluded from measures of value and quality. Disclosures Waldron: Amgen: Consultancy. Hobbs:Amgen: Research Funding; SimulStat Inc.: Consultancy. Advani:Macrogenics: Research Funding; Abbvie: Research Funding; Kite Pharmaceuticals: Consultancy; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Glycomimetics: Consultancy, Research Funding. Nazha:Incyte: Speakers Bureau; Abbvie: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmacutical: Research Funding; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee; Tolero, Karyopharma: Honoraria. Gerds:Imago Biosciences: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sierra Oncology: Research Funding. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Phase I Study of Ixazomib with Conventional Chemotherapy in the Treatment of Acute Myeloid Leukemia in Older Adults

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Philip C. Amrein ◽  
Eyal C. Attar ◽  
Geoffrey Fell ◽  
Traci M. Blonquist ◽  
Andrew M. Brunner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Remission Rate ◽  
Conventional Chemotherapy ◽  
Advisory Committees ◽  
Secondary Aml ◽  
Grade 3 ◽  
Acute Myeloid

Introduction: Outcomes for acute myeloid leukemia (AML) among older patients has remained largely unchanged for decades. Long-term survival for patients aged &gt;60 years is poor (median survival 10.5 months). Targeting the proteasome in AML is attractive, since leukemia stem cells have demonstrated sensitivity to proteasome inhibition in preclinical models, perhaps through down regulation of nuclear NF-KB (Guzman, Blood 2001). AML cell lines are susceptible to synergistic cytotoxicity when bortezomib, a proteasome inhibitor, is combined with daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate, although grade 2 sensory neurotoxicity was noted in approximately 12% of treated patients. A newer generation proteasome inhibitor, ixazomib, is less frequently associated with neurotoxicity, and, therefore, was selected for combination with conventional chemotherapy in this phase I trial. The primary objective of this study was to determine the maximum tolerated dose (MTD) of ixazomib in combination with conventional induction and consolidation chemotherapy for AML. Herein are the initial results of this trial. Methods: Adults &gt;60 years of age with newly diagnosed AML were screened for eligibility. Patients with secondary AML were eligible, including those with prior hypomethylating agent therapy for myelodysplastic syndromes (MDS). We excluded those with promyelocytic leukemia. There were 2 phases in this study. In the first phase (A), the induction treatment consisted of the following: cytarabine 100 mg/m2/day by continuous IV infusion, Days 1-7; daunorubicin 60 mg/m2/day IV, Days 1, 2, 3, and ixazomib was provided orally at the cohort dose, Days 2, 5, 9, and 12. Consolidaton or transplant was at the discretion of the treating physician in phase A. In the second phase (B), induction was the same as that with the determined MTD of ixazomib. All patients were to be treated with the following consolidation: cytarabine at 2 g/m2/day, days 1-5 with ixazomib on days 2, 5, 9, and 12 at the cohort dose for consolidation. A standard 3 + 3 patient cohort dose escalation design was used to determine whether the dose of ixazomib could be safely escalated in 3 cohorts (1.5 mg/day, 2.3 mg/day, 3.0 mg/day), initially in induction (phase A) and subsequently in consolidation (phase B). The determined MTD of ixazomib in the first portion (A) of the trial was used during induction in the second portion (B), which sought to determine the MTD for ixazomib during consolidation. Secondary objectives included rate of complete remission, disease-free survival, and overall survival (OS). Results: Thirty-six patients have been enrolled on study, and 28 have completed dose levels A-1 through A-3 and B1 through B-2. Full information on cohort B-3 has not yet been obtained, hence, this report covers the experience with the initial 28 patients, cohorts A-1 through B-2. There were 12 (43%) patients among the 28 with secondary AML, either with prior hematologic malignancy or therapy-related AML. Nineteen patients (68%) were male, and the median age was 68 years (range 61-80 years). There have been no grade 5 toxicities due to study drug. Three patients died early due to leukemia, 2 of which were replaced for assessment of the MTD. Nearly all the grade 3 and 4 toxicities were hematologic (Table). There was 1 DLT (grade 4 platelet count decrease extending beyond Day 42). There has been no grade 3 or 4 neurotoxicity with ixazomib to date. Among the 28 patients in the first 5 cohorts, 22 achieved complete remissions (CR) and 2 achieved CRi, for a composite remission rate (CCR) of 86%. Among the 12 patients with secondary AML 8 achieved CR and 2 achieved CRi, for a CCR of 83%. The median OS for the 28 patients has not been reached (graph). The 18-month OS estimate was 65% [90% CI, 50-85%]. Conclusions: The highest dose level (3 mg) of ixazomib planned for induction in this trial has been reached safely. For consolidation there have been no serious safety issues in the first 2 cohorts with a dose up to 2.3 mg, apart from 1 DLT in the form of delayed platelet count recovery. The recommended phase 2 dose of ixazomib for induction is 3 mg. Accrual to cohort B-3 is ongoing. Notably, to date, no grade 3 or 4 neurotoxicity has been encountered. The remission rate in this older adult population with the addition of ixazomib to standard chemotherapy appears favorable. Figure Disclosures Amrein: Amgen: Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Research Funding. Attar:Aprea Therapeutics: Current Employment. Brunner:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Hobbs:Constellation: Honoraria, Research Funding; Novartis: Honoraria; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding; Jazz: Honoraria; Celgene/BMS: Honoraria. Neuberg:Celgene: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding. Fathi:Blueprint: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Novartis: Consultancy; Kura Oncology: Consultancy; Trillium: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Pfizer: Consultancy; Newlink Genetics: Consultancy; Forty Seven: Consultancy; Trovagene: Consultancy; Kite: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Amphivena: Consultancy; PTC Therapeutics: Consultancy; Agios: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz: Consultancy. OffLabel Disclosure: Ixazomib is FDA approved for multiple myeloma. We are using it in this trial for acute myeloid leukemia.

scholarly journals p53 Mediated Bone Marrow Mesenchymal Stem Cell Expansion Supports Acute Myeloid Leukemia Development

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 523-523
Author(s):  
Rasoul Pourebrahimabadi ◽  
Zoe Alaniz ◽  
Lauren B Ostermann ◽  
Hung Alex Luong ◽  
Rafael Heinz Montoya ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Osteoblast Differentiation ◽  
Hematopoietic Cells ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Mdm2 Inhibitor ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a heterogeneous disease that develops within a complex microenvironment. Reciprocal interactions between the bone marrow mesenchymal stem/stromal cells (BM-MSCs) and AML cells can promote AML progression and resistance to chemotherapy (Jacamo et al., 2014). We have recently reported that BM-MSCs derived from AML patients (n=103) highly express p53 and p21 compared to their normal counterparts (n=73 p&lt;0.0001) (Hematologica, 2018). To assess the function of p53 in BM-MSCs, we generated traceable lineage specific mouse models targeting Mdm2 or Trp53 alleles in MSCs (Osx-Cre;mTmG;p53fl/fl and Osx-Cre;mTmG;Mdm2fl/+) or hematopoietic cells (Vav-Cre;mTmG;p53fl/fl and Vav-Cre;mTmG;Mdm2fl/+). Homozygote deletion of Mdm2 (Osx-Cre;Mdm2fl/fl) resulted in death at birth and displayed skeletal defects as well as lack of intramedullary hematopoiesis. Heterozygote deletion of Mdm2 in MSCs was dispensable for normal hematopoiesis in adult mice, however, resulted in bone marrow failure and thrombocytopenia after irradiation. Homozygote deletion of Mdm2 in hematopoietic cells (Vav-Cre;Mdm2fl/fl) was embryonically lethal but the heterozygotes were radiosensitive. We next sought to examine if p53 levels in BM-MSCs change after cellular stress imposed by AML. We generated a traceable syngeneic AML model using AML-ETO leukemia cells transplanted into Osx-Cre;mTmG mice. We found that p53 was highly induced in BM-MSCs of AML mice, further confirming our findings in primary patient samples. The population of BM-MSCs was significantly increased in bone marrow Osx-Cre;mTmG transplanted with syngeneic AML cells. Tunnel staining of bone marrow samples in this traceable syngeneic AML model showed a block in apoptosis of BM-MSCs suggesting that the expansion of BM-MSCs in AML is partly due to inhibition of apoptosis. As the leukemia progressed the number of Td-Tomato positive cells which represents hematopoietic lineage and endothelial cells were significantly decreased indicating failure of normal hematopoiesis induced by leukemia. SA-β-gal activity was significantly induced in osteoblasts derived from leukemia mice in comparison to normal mice further supporting our observation in human leukemia samples that AML induces senescence of BM-MSCs. To examine the effect of p53 on the senescence associated secretory profile (SASP) of BM-MSCs, we measured fifteen SASP cytokines by qPCR and found significant decrease in Ccl4, Cxcl12, S100a8, Il6 and Il1b upon p53 deletion in BM-MSCs (Osx-Cre;mTmG;p53fl/fl) compared to p53 wildtype mice. To functionally evaluate the effects of p53 in BM-MSCs on AML, we deleted p53 in BM-MSCs (Osx-Cre;mTmG;p53fl/fl) and transplanted them with syngeneic AML-ETO-Turquoise AML cells. Deletion of p53 in BM-MSCs strongly inhibited the expansion of BM-MSCs in AML and resulted in osteoblast differentiation. This suggests that expansion of BM-MSCs in AML is dependent on p53 and that deletion of p53 results in osteoblast differentiation of BM-MSCs. Importantly, deletion of p53 in BM-MSCs significantly increased the survival of AML mice. We further evaluated the effect of a Mdm2 inhibitor, DS-5272, on BM-MSCs in our traceable mouse models. DS-5272 treatment of Osx-cre;Mdm2fl/+ mice resulted in complete loss of normal hematopoietic cells indicating a non-cell autonomous regulation of apoptosis of hematopoietic cells mediated by p53 in BM-MSCs. Loss of p53 in BM-MSCs (Osx-Cre;p53fl/fl) completely rescued hematopoietic failure following Mdm2 inhibitor treatment. In conclusion, we identified p53 activation as a novel mechanism by which BM-MSCs regulate proliferation and apoptosis of hematopoietic cells. This knowledge highlights a new mechanism of hematopoietic failure after AML therapy and informs new therapeutic strategies to eliminate AML. Disclosures Khoury: Angle: Research Funding; Stemline Therapeutics: Research Funding; Kiromic: Research Funding. Bueso-Ramos:Incyte: Consultancy. Andreeff:BiolineRx: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; NIH/NCI: Research Funding; CPRIT: Research Funding; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; AstaZeneca: Consultancy; Amgen: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy. OffLabel Disclosure: Mdm2 inhibitor-DS 5272

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