refractory aml
Recently Published Documents


TOTAL DOCUMENTS

386
(FIVE YEARS 112)

H-INDEX

19
(FIVE YEARS 3)

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Shilin Xu ◽  
Meichen Zhang ◽  
Xiaocui Fang ◽  
Jie Meng ◽  
Haiyan Xing ◽  
...  

AbstractAcute myeloid leukemia (AML) is a common malignant heterogeneous hematopoietic disease with very low average 5-year survival rate due to the refractory feature and high rate of relapse. CD123 is highly expressed on multiple types of AML cells, especially leukemia stem cells, and closely associated with the poor prognosis of AML. Aiming to meet the urgent demand to targeted therapeutics for the refractory AML patients, herein we synthesize a CD123 antagonistic peptide (PO-6) loaded in nanomicelles (mPO-6), and investigated its therapeutic effect and pharmacokinetics on a lab-established refractory AML mice model (AE & CKITD816V). It is shown that the PO-6 can effectively bind to the CD123+ AML cells and the micellar formulation mPO-6 increases the dissolution stability and the specific binding capacity. When injected intravenously, mPO-6 significantly prolongs the survival of the refractory AML mice by interfering CD123/IL-3 axis, evidenced by the down regulation of phosphorylation of STAT5 and PI3K/AKT and the inhibition of activated NF-κB in the nucleus, as well as by the analysis results of next generation RNA-sequencing (RNA-seq) with the bone marrow of the AML mice. The antagonistic effect leads to the significantly reduction of AML cells infiltration in the bone marrow of the AML mice. In conclusion, mPO-6 could provide a potent antagonistic therapeutic approach for targeted treatment of AML.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3411-3411
Author(s):  
Maro Ohanian ◽  
Martha L. Arellano ◽  
Moshe Y. Levy ◽  
Kristen O'Dwyer ◽  
Hani Babiker ◽  
...  

Abstract INTRODUCTION: APTO-253 represses expression of the MYC oncogene by targeting a conserved G-quadruplex structure in its promoter, down-regulates MYC mRNA and protein levels and induces apoptosis in AML cell lines and marrow samples from patients with AML, MDS, and MPN in vitro. After injection, a large fraction of APTO-253 binds iron and transforms to the Fe(253) 3 complex which retains full activity. APTO-253 has been granted orphan drug designation for AML by the US FDA and is being studied in a Phase 1a/b clinical trial in patients with relapsed or refractory AML (R/R AML) or high-risk myelodysplasias (high-risk MDS) (NCT02267863). AIMS: Primary objectives are to determine the safety and tolerability of APTO-253, MTD, dose limiting toxicities (DLT), and the RP2D. Key secondary objectives are to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of antitumor activity. METHODS: Eligible patients have R/R AML or high-risk MDS for which either standard treatment has failed, is no longer effective, or can no longer be administered safely. Treatment- emergent adverse events (TEAEs) and tumor responses are evaluated using International Working Group criteria. APTO-253 is administered by IV infusion once weekly on days 1, 8, 15, and 22 of each 28-day cycle; ascending dose cohorts were enrolled at a starting dose of 20 mg/m 2 with planned escalation to 403 mg/m 2. RESULTS: As of June 7, 2021, a total of 18 patients (median age 64.0 years, 16 AML and 2 high-risk MDS) with a median of 2.5 prior treatments (range of 1 - 9) have been treated with APTO-253 at doses of 20 (n=1), 40 (n=1), 66 (n=4), 100 (n=4) and 150 mg/m 2 (n=8). Most patients were RBC (87.5% of AML and 100% of MDS) and/or platelet (75% of AML and 50% MDS) transfusion-dependent. No DLTs or drug-related serious adverse events have been reported. Only 1 patient had a drug-related TEAE of grade 3 or greater (fatigue, Grade 3, probably related). Preliminary PK analysis (Figure 1) showed that serum levels of APTO-253 were dose proportional. C max and AUC 0-72h for C1D1 dosing were 0.06, 0.02, 0.36 ± 0.37, 0.44 ± 0.41 and 0.72 ± 0.70 µM and 0.11, 0.15, 3.98 ± 1.77, 4.79 ± 0.87 and 2.51 ± 1.73 µM*h for dose levels of 20, 40, 66, 100 and 150 mg/m 2, respectively. Plasma levels for Fe(253) 3 were significantly higher than those for the APTO-253 monomer. For example, C max and AUC 0-72h of Fe(253) 3 for C1D1 dosing of patients in Cohort 150 mg/m 2 were 2- and 20- fold higher than the ATPO-253 monomer at 15.09 ± 0.42 µM and 51.52 ± 28.26 µM*h, respectively. Following dosing at 150 mg/m 2, serum concentrations of Fe(253) 3 were above 0.5 µM for > 48 h, which approaches the therapeutic range based on in vitro studies. CONCLUSIONS: APTO-253 has been well-tolerated at doses of 20, 40, 66, 100 and 150 mg/m 2 over multiple cycles and escalated to 210 mg/m 2 (Cohort 6). PK analysis revealed that APTO-253 is rapidly transformed to and co-exists with the Fe(253) 3 in serum from R/R AML and high-risk MDS patients. Enrollment of patients at the 210 mg/m 2 dose level is ongoing and updated clinical data will be presented at the meeting. Figure 1 Figure 1. Disclosures Arellano: KITE Pharma, Inc: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Levy: AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Epizyme: Consultancy, Other: Promotional speaker; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Mahadevan: caris: Speakers Bureau; Guardanthealt: Speakers Bureau; PFIZER: Other: Clinical trial Adverse events committee; TG Therapeuticals: Other: Clinical trial Adverse events committee. Zhang: Aptose Biosciences, Inc.: Current Employment. Rastgoo: Aptose Biosciences, Inc.: Current Employment. Jin: Aptose Biosciences, Inc.: Current Employment. Marango: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Howell: Aptose Biosciences, Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rice: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties; Oncolytics Biotech Inc.: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Bejar: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company; Takeda: Research Funding; BMS: Consultancy, Research Funding; Gilead: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Astex: Consultancy; Silence Therapeutics: Consultancy.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4423-4423
Author(s):  
Mohammmad Alwadi ◽  
Jude Howaidi ◽  
Abdullah M Alrajhi ◽  
Adel Alnakhli ◽  
Mohammed A. Marei ◽  
...  

Abstract Background: Venetoclax combined with hypomethylating agents is a new standard of care for newly diagnosed patients with acute myeloid leukemia (AML) 75 years or older, or unfit for intensive chemotherapy. As precision therapy in AML expanded with the addition of venetoclax among others in the therapeutic armamentarium of AML, efficacy and safety reports in ethnic minorities are limited, with a background of well recognized inter-ethnic differences in drug response. Phase III data from VIALE-A, as well as VIALE-C, was limited for the Arab population as no site opened in the Arab world. We herein report our experience on the use of venetoclax with azacitidine in patients with newly diagnosed or relapsed/refractory AML in the Arab population. Methods: Retrospective-single center review on the use of Azacitidine with venetoclax in older patients (aged ≥60 years) with newly diagnosed AML, not eligible for intensive chemotherapy; secondary AML and relapsed or refractory AML. All patients self-identified of Arabic ethnicity. Patients who received previous BCL2-inhibitor therapy were excluded. Patients who received at least one dose of treatment (Azacitidine ≥3 days, >14 days of venetoclax) were included in the intention to treat analysis. Patients typically received azacitidine 75 mg/m2 intravenously for 7 days with oral venetoclax 400 mg daily for induction, with appropriate dose adjustment for concomitant use of azoles. This is followed by the same regimen in consolidation, with adjustment according to response and side effects at the treating physician's discretion. The primary endpoint was overall survival. The secondary endpoints include response rate, safety, and relapse-free survival. Results: Between July 2019, and July 2021, we identified 19 patients; 13 (68%) had newly diagnosed AML (ND-AML), and 6 (32%) had relapsed or refractory AML (R/R AML). The median age was 70 years (17-82). In the ND-AML, most patients had an adverse ELN 2017 AML (69%) with 23% having either intermediate or adverse AML (Negative for CBF, NPM1, FLT3-ITD and biCEBPA, but missing NGS data for adverse mutations Tp53/ASXL1 and RUNX1). Only one patient was classified as intermediate-risk AML. The overall response rate in the ND-AML was 77%, with 46% achieving complete remission (CR), and 23% CR with incomplete count recovery (CRi) [Table]. One patient achieved PR after the first cycle (blast 7% by morphology and 1.5% by flow cytometry) and did not have a subsequent bone marrow evaluation, however had a full count recovery. Among the responders in the ND-AML cohort, 4 deaths were noted. One death was related to COVID-19 associated pneumonia, one due to graft failure (at day 42 post Haplo-SCT), one due to septic shock, and one was related to relapse disease. The overall survival and relapse-free survival for ND-AML were 5.6 months for both [Figure]. In the R/R AML, 66% had prior HMA exposure, and all patients did receive high-intensity chemotherapy. The median number of prior treatments was 3 (1-5). the response rate was 80% (4/5), with 60% achieving CR. All patients are still alive with a median follow-up of 7.6 months. One patient had progressive disease. One patient is early to evaluate and was not included in the response analysis [Table]. The 30-day mortality was zero in both ND-AML and R/R AML cohorts. Conclusions: In a majority of adverse risk ND-AML, and in heavily pretreated R/R AML, the response rate and overall survival is comparable to what has been previously reported. Our data support the use of this regimen in older patients with newly diagnosed AML, patients with relapsed or refractory disease, and those with adverse-risk features. This analysis is limited by the small number of patients, and by the lack of ELN 2017 favorable-risk AML. Future prospective and randomized studies are needed to clarify activity and safety in the Arab population, as well as in the high-risk AML subset. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4432-4432
Author(s):  
Gautam Borthakur ◽  
Brian A. Jonas ◽  
Emily L Roberts-Thomson ◽  
Glenn C. Michelson ◽  
Mark R Bray

Abstract Background: CFI-400945 is a potent, selective, orally administered, first-in-class inhibitor of the serine/threonine kinase, Polo-like kinase 4 (PLK4). PLK4 is a highly conserved master upstream regulator of centriole duplication and is critical for maintenance of genomic integrity. Aberrant expression of PLK4 results in a number of effects including the centrosome amplification often seen in aneuploid cancers, pointing to a potentially causative role for PLK4 in genome instability and cancer progression. A Phase 1 study has been completed evaluating CFI-400945 as a monotherapy in solid tumors, showing a tolerable safety profile and promising signs of activity. Given acute myeloid leukemia (AML) is characterized by genomic instability, CFI-400945 has been evaluated in pre-clinical and clinical studies in AML. In pre-clinical studies, CFI-400945 showed potent activity towards leukemia cell lines and primary human samples in vitro, as well as marked efficacy in two subcutaneous models of leukemia. A prior Phase 1 trial in AML was initiated at the Princess Margaret Cancer Center (PMCC), and of six patients evaluable for response, two (33%) achieved complete remission (CR) at 96 mg and 128 mg, and 3 patients (50%) had stable disease (with one patient having a 78% reduction in marrow blast count) at 64 mg (2 patients) and 96 mg [re: Murphy et al, ASH 2020]. Responses were seen in patients with adverse cytogenetics. The optimal dosing of CFI-400945 and its potential role as a combination agent are not yet clinically defined. Study Design and Methods: The study (TWT-202) has 4 parts, Part 1A (1A): a single agent dose escalation portion, Part 1B (1B): a food effect portion once the MTD of 1A is determined, and combinations with azacitidine (2A), and decitabine (2B). TWT-202 uses an updated version of investigational product which is identical in formulation to the drug used in the PMCC study, but which may result in higher exposures at a given dose. This study will therefore refine the dose through escalation cohorts. For parts 1A and 1B, patients with relapsed and/or refractory AML, MDS, or CMML after >1 prior therapy will be included. Patients with MDS or CMML must have progressed or had a lack of response after at least 4 cycles of hypomethylating agents. For parts 2A and 2B, patients should have relapsed and/or refractory AML or untreated MDS or CMML. Untreated patients who decline or are ineligible for intensive therapy may be included. The study will use a standard 3 + 3 design. The maximum tolerated dose (MTD) will be defined as the dose level where the number of dose limiting toxicities (DLTs) is <1 out of 6 at highest dose level below the maximally administered dose. Pharmacokinetics (PK) and pharmacodynamic (PD) markers will be assessed. Results: As of June 21, 2021, 2 patients had been enrolled into the study, one of the patients (50%) received >3 prior therapies (including venetoclax). Neither patient had had stem cell transplant at study entry. Both patients had secondary AML (one with antecedent MDS with excess blasts and the other with CMML). Both patients received 32 mg of CFI-400945 for 21 days followed by a 7-day rest. Both patients completed cycle 1 and neither experienced a DLT. Both patients experienced a single serious treatment emergent adverse event (SAE) of febrile neutropenia each, with neither event considered related to CFI-400945. There were 13 Grade 3 or greater TEAE's, including anemia, thrombocytopenia (3 events each), febrile neutropenia (2 events), agitation, angioinvasive fungal sinusitis, acute kidney injury, hypotension and neutropenia (1 event each). None of the grade 3 or greater TEAE's were considered related to CFI-400945. Neither patient responded to therapy at 32 mg and both came off treatment after one cycle due to progressive disease. PK and PD studies are pending. Conclusion: CFI-400945 has been generally well tolerated and TWT-202 continues to enroll in the Part 1A and Part 1B monotherapy cohorts. Updated safety, efficacy, PK, and PD data for the study will be presented at the time of the meeting. Disclosures Borthakur: University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Protagonist: Consultancy; Astex: Research Funding; Ryvu: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees. Jonas: 47, AbbVie, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, Treadwell: Research Funding; AbbVie: Other: Travel reimbursement; AbbVie, BMS, Genentech, GlycoMimetics, Jazz, Pfizer, Takeda, Treadwell: Consultancy. Roberts-Thomson: Treadwell Therapeutics: Current Employment. Michelson: Treadwell Therapeutics: Consultancy. Bray: Treadwell Therapeutics: Current Employment.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4909-4909
Author(s):  
Evgeny Klyuchnikov ◽  
Anita Badbaran ◽  
Radwan Massoud ◽  
Ulrike Fritsche-Friedland ◽  
Maximilian Christopeit ◽  
...  

Abstract Introduction Patients with relapsed/refractory (r/r) AML have in general a dismal prognosis. Allogeneic stem cell transplantation (allo-SCT) provides a curative approach for these patients, however the overall survival (OS) remains still low achieving 20-40%. Though post-transplant minimal residual disease (MRD) monitoring has been shown to be predictive for development of post-transplant relapses and lower survival, data focusing on pre-transplant relapsed/refractory AML patients is scarce. In this study, we investigated the impact of achieving MRD negativity on day +100 for relapses and survival for this high risk patients. Patients and Methods We analyzed post-transplant outcomes for pre-transplant r/r AML patients depending on their post-transplant MRD status at day +100. The day +100 was chosen concerning the possibility of early post-transplant interventions (e.g. tapering of immunosuppression or administration of donor lymphocytes). Fifty six consecutive adult patients (≥18 years old) with r/r AML (median age 58, range 20-76; male, n=34, 61%) who underwent allo-SCT (first, n=44, 79%; second, n=12, 21%) between 2015-2020 at the Department for Stem Cell Transplantation at the University Medical Center Hamburg (Germany) were included. The MRD was assessed on day +100 using multiparameter flow cytometry according to "different from normal" strategy. The patients experienced rather primary refractory disease (64%), secondary/therapy-related AML (55%) and abnormal cytogenetics (59%) at diagnosis. The median pre-transplant blast count was 25% (6-91%). A number of 29 patients (52%) showed blasts in peripheral blood. Myeloablative conditioning was used in 31 (55%) patients, whereas 25 (45%) patients received reduced intensity regimens. A number of 29 patients (52%) received a FLAMSA-based conditioning. Post-transplant donor lymphocyte infusions as well as other treatment were given to 13 (23%) and 17 (30%) patients, respectively. Results The median follow up was 20 months (range 4-66). Forty patients (71%) achieved MRD negativity on day +100 and 16 (29%) remained MRD positive. The 2-year OS, LFS, relapses and NRM at 2 years for day +100 MRD negative patients were: 76% (95% CI: 60-87%), 59% (95% CI: 41-75%), 31% (95% CI: 17-50%) and 8% (95% CI: 3-19%), respectively. The 2-year OS, LFS, relapses and NRM at 2 years for day +100 MRD positive patients were: 35% (95% CI: 17-59%, p=p=0.001), 23% (95% CI: 9-46%, p<0.0001), 70% (95% CI: 45-87%, p=0.0002) and 6% (95% CI: 1-28%, p=0.88), respectively. Several factors were evaluated for possible association with day +100 MRD negativity (Table 1). There were no significant associations. Further, the incidence of acute (grade II-IV) GvHD at 100 days was not significantly different between the day 100 MRD positive und negative patients. Following factors had impact on post-transplant outcomes in multivariate analysis: presence (no vs yes) of peripheral blasts prior to allograft (OS: HR 0.3, 95% CI: 0.1-0.9, p=0.03; LFS: HR 0.4, 95% CI: 0.1-0.9, p=0.03; relapses: HR 0.4, 95% CI: 0.1-0.99, p=0.048; NRM: HR 0.5, 95% CI: 0.2-1.3, p=0.17), FLAMSA vs other preparative regimens (OS: HR 0.4, 95% CI: 0.1-0.93, p=0.03; LFS: HR 0.4, 95% CI: 0.2-0.98, p=0.04; relapses: HR 0.4, 95% CI: 0.2-1.0, p=0.05; NRM: HR 0.4, 95% CI: 0.2-1.0, p=0.06), and day +100 MRD (negative vs positive) (OS: HR 0.3, 95% CI: 0.1-0.7, p=0.009; LFS: HR 0.2, 95% CI: 0.1-0.6, p=0.001; relapses: HR 0.2, 95% CI: 0.1-0.4, p=0.0001; NRM: HR 0.2, 95% CI: 0.1-0.5, p=0.0006). Conclusions Post-transplant MRD detection plays predictive role in pre-transplant r/r AML patients and may help to define possible candidates for early post-transplant interventions. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4980-4980
Author(s):  
Roger Lyons ◽  
Sneha Sura ◽  
Srinivas Annavarapu ◽  
Jackie Kwong ◽  
Albert Fliss

Abstract Introduction: Molecular genetic testing is essential to inform disease diagnosis, prognosis, and treatment selection for patients with acute myeloid leukemia (AML). The standard treatment is induction chemotherapy followed by post-remission consolidation therapy including chemotherapy and allogeneic hematopoietic stem cell transplantation. Since May 2017, targeted therapies such as midostaurin, ivosidenib, enasidenib, and gemtuzumab ozogamicin were introduced for the treatment of AML. The use of targeted therapies is driven in part by the results of molecular genetic testing. The aim of this study was to determine molecular genetic testing utilization among patients with AML before and after the introduction of targeted therapies in May 2017 within community oncology clinics. Methods: A retrospective observational cohort study was conducted using de-identified data from The US Oncology Network iKnowMed electronic health record database and chart review. The iKnowMed is an oncology-specific system that captures outpatient practice encounter history for patients under care, including (but not limited to) laboratory tests, diagnosis, therapy administration, line of therapy, staging, and performance status information. These structured data were supplemented by targeted chart review to capture unstructured data. All patients aged 18 years or older with newly diagnosed or relapsed/refractory AML who received treatment in The US Oncology Network from January 2014 through February 2019 were included in the study cohort. Patients enrolled in clinical trials were excluded. Patients were classified into two groups: those who received treatment prior to May 2017 and those who received it after May 2017. Molecular genetic testing included IDH1, IDH2, FLT3-ITD, FLT3-TDK and CD33 genes. We assessed the proportion of newly diagnosed or relapsed/refractory AML patients who received molecular genetic testing in the inpatient setting, outpatient setting and prior to treatment initiation before and after May 2017. Results: The study population consisted of 434 patients diagnosed with AML, of whom 313 had newly diagnosed and 121 had relapsed/refractory AML. The median age of the study cohort was 73 (interquartile range: 63.0, 79.0) years. Most of the study cohort were male (57.6%, n=250) and Caucasian (77.0%, n=334). Approximately 75% (235/313) of newly diagnosed patients (75.1%; 235/313) and 81.0% (98/121) of patients with relapsed/refractory AML had molecular genetic testing. The proportion of patients who had molecular genetic testing before and after May 2017 were similar for newly diagnosed AML patients (72.2% vs. 78.1%; p=0.2260) and relapsed/refractory AML patients (80.0% vs. 83.9%; p=0.6357). The proportion of newly diagnosed AML patients who received molecular genetic testing in the inpatient setting (18.5% vs. 23.8%; p=0.3403) and outpatient setting (49.4% vs. 51.0%; p=0.4223) did not change before and after May 2017. Likewise, among patients with relapsed/refractory AML, the proportion of molecular genetic testing in the inpatient setting (31.1% vs. 35.5%; p=0.8523) and outpatient setting (44.4% vs. 51.6%; p=0.7749) were similar before and after May 2017. In addition, the proportion of newly diagnosed AML patients (55.6% vs. 62.9%; p=0.3835) and relapsed/refractory AML patients (45.6% vs. 61.3%; p=0.3063) who received molecular genetic testing prior to AML treatment initiation did not change before and after May 2017. Time from test order date to test result availability was not significantly different before [mean (SD) =9.3 days (16.8)] and after May 2017 [mean (SD)=9.0 days (9.9)]. Conclusion: Introduction of targeted therapies for AML did not increase molecular genetic testing rates nor improve the turnaround time for test result availability in newly diagnosed and relapsed refractory AML patients by February 2019. Two out of 5 patients did not have molecular genetic testing performed prior to initiation of AML therapy after May 2017 when targeted therapies became available. Patients age, comorbidities and drug access issues may have contributed to under-utilization of molecular genetic testing. Further research is needed to identify barriers to molecular genetic testing in patients with AML. Disclosures Sura: McKesson Life Sciences: Current Employment. Annavarapu: McKesson Life Sciences: Current Employment. Kwong: Daiichi Sankyo, Inc: Current Employment. Fliss: Daiichi Sankyo, Inc: Current Employment.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 876-876
Author(s):  
Juliette Lambert ◽  
Pierre Peterlin ◽  
Cecile Pautas ◽  
Emmanuel Raffoux ◽  
Denis Caillot ◽  
...  

Abstract Introduction: In 2010 the French Health Agency opened a compassionate patient named program of gemtuzumab ozogamicin (GO, Mylotarg®) in relapsed/refractory (R/R) patients with acute myeloid leukemia (AML). Of note, since 2012, it was recommended to use GO at the dose of 3 or 6 mg/m 2 in addition to chemotherapy. We conducted a retrospective trial (NCT03287128) to evaluate the efficacy and the safety of GO-based regimen in R/R adult AML patients. Patients and methods: We retrospectively collected data of patients older than 18 years treated with GO-based regimen for AML in first relapse or for refractory AML, defined by failure after a prior standard intensive chemotherapy, in 18 French centers between December 15, 2011 and November 10, 2016. The primary objective was to assess the response to GO-based regimen. Patients were considered in response if reaching complete remission (CR), CR without platelet recovery (CRp) or CR with incomplete hematological recovery (CRi). Secondary objectives were the cumulative incidence of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the safety of the use of GO-based regimen. Results: Three hundred and thirty-five adult patients with R/R AML were included. Median age was 58 years (20 to 80 years). At diagnosis, cytogenetics was favorable in 50 (17%) patients, intermediate in 173 (59%) and adverse in 60 (20%). ELN distribution was favorable: 35%, intermediate: 42% and unfavorable: 23%. NPM1 mutation was present in 29% of patients and FLT3 mutation in 23%. Most patients had de novo AML (84%). Two hundred and thirty-eight patients (79%) were in first relapse and 65 (21%) had a refractory AML. The time between first diagnosis of AML and treatment with GO-based regimen was 4 to 16 months (median 9.4 months). Most patients (88%) received GO in combination with various intensive chemotherapy scheme including "7+3" with anthracycline/cytarabine (n=39 patients), intermediate and high-dose cytarabine (n=68), cytarabine in continuous intravenous infusion (n=78), mitoxantrone/cytarabine (n=49) and fludarabine/cytarabine and/or amsacrine and/or etoposide chemotherapy (n=35). Median follow-up time was 11 months. Among the 305 patients, 191 responded to GO-based regimen: 110 (36%) were in CR, 62 (20%) were in CRp and 19 (6%) in CRi for an overall response rate (CR+CRp+CRi, ORR) of 63%. In multivariate analysis, response was associated with age <50 years, de novo AML and relapse status. Among the 191 responders, 110 received additional courses of chemotherapy, 69 with GO. Main reason to not receive additional course (with or without GO) was allo-HSCT project. In the whole population, median overall survival (OS) after day 1 of treatment with GO was 11.2 months. In the population of responders, median OS after response was 20.4 months. In multivariate analysis, longer survival was associated with age < 50 years, de novo AML and favorable ELN group. Cumulative incidence of relapse at 24 months after response was 46%. One hundred and forty-seven patients received allo-HSCT, including 122 responders after GO-based regimen and 25 patients in treatment failure. Cumulative incidence of allo-HSCT at 18 months was 48%. Four-year OS was 48% in transplanted patients versus 19% in non-transplanted patients (Figure 1). Regarding safety of GO-based regimen, early deaths occurred within <30 days after the first dose of GO in 14 patients, and within <60 days in 35 patients. Myelosuppression was observed in all patients. Mean duration of thrombocytopenia <100 G/L was 35 days in responders. Bleeding grade 3 or more was observed in 22 patients (7%). Infection grade 3 or more was observed in 112 patients (30%). Sinusoidal obstruction syndrome (SOS) after GO treatment was reported in 6 patients, resolving in 4 of them. Four cases of fatal SOS were reported after allo-HSCT. Toxic deaths, i.e., not related to worsening leukemia, were reported in 20 patients after the first course of chemotherapy, 3 after additional courses and 33 after allo-HSCT. Conclusion. Our study is the first to report efficacy data in the real-world setting of R/R AML adult patients treated with GO-based regimen. In our cohort of 305 patients, response rate was 63% and GO-based regimen appears as a valuable bridge-to-transplant option. Safety analysis showed toxicities consistent with the known safety profile of GO and chemotherapy. Figure 1 Figure 1. Disclosures Lambert: ASTELLAS: Consultancy; CELGENE/BMS: Consultancy. Pautas: PFIZER: Consultancy; ABBVIE: Consultancy. Raffoux: ASTELLAS: Consultancy; PFIZER: Consultancy; ABBVIE: Consultancy; CELGENE/BMS: Consultancy. Legrand: Servier: Consultancy. Gastaud: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; GSK: Consultancy. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Mathilde: SERVIER: Consultancy; ABBVIE: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Castaigne: PFIZER: Consultancy.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3827-3827
Author(s):  
Uday Prakash Kulkarni ◽  
Arun Kumar Arunachalam ◽  
Hamenth Kumar Palani ◽  
Nithya Balasundaram ◽  
Arvind Venkatraman ◽  
...  

Abstract Refractory acute myeloid leukemia (AML), defined as failure of 2 cycles of induction therapy at diagnosis or of 1 cycle at relapse, represents a subgroup with poor clinical outcomes. In our transplant cohort, the 5-year overall survival in this subgroup was 16% (Ganapule at al. JGO 2017). Haploidentical natural killer cell (NK) therapy is a strategy that is being explored in refractory malignancies. Our in-vitro and animal model data suggest that exposure to arsenic trioxide (ATO) results in enhanced NK cytotoxicity (Alex AA et al. Front. Immunol 2018). Historically, at our center, patients with refractory AML have been treated with cytoreductive therapy (FLAG ± idarubicin or mitoxantrone + etoposide for 3 to 5 days) followed by 1-week rest and then a reduced-intensity transplant with fludarabine + melphalan conditioning while in peak cytopenia. From February 2019, we initiated a phase II single arm clinical trial (CTRI/2019/02/017505) enrolling patients with refractory AML planned for a stem cell transplant in peak cytopenia. Patients received CD56-positive cells from an HLA haploidentical related family donor (other than the stem cell donor, wherever feasible) following cytoreductive chemotherapy. The NK cell donor preference strategy included presence of KIR ligand mismatch, greater number of KIR B motifs (or the B score), lower donor age, and negative donor specific antibodies tested using flowcytometry crossmatch (Figure 1a). CD56-positive selection was done using CliniMACS prodigy system. This was followed by overnight incubation of the CD56 positive cells in autologous plasma with 2 micromolar ATO and 500 U/mL of interleukin-2. The CD56 positive cells were then infused to the patient 1-day after the completion of cytoreductive chemotherapy. This was followed by a reduced intensity stem cell transplant (Figure 1b). The primary outcome variable was 1-year relapse free survival. From February 2019, 14 patients with median age 28 years (IQR: 15.75-31.5) were enrolled in this trial. Six were females. Six had primary-refractory AML while 8 had relapsed-refractory AML. The cytoreductive chemotherapy was FLAG ± idarubicin (n=7), Mitoxantrone + Etoposide (n=6) and GCLAC (n=1). The median blast percentage on flowcytometry MRD testing prior to NK infusion was 15.9% (IQR: 9.1%-54.5%) (n=11). The median B score for the NK cell donors was 2 (IQR: 1-3). The median age of the NK cell donor was 43 years (IQR: 36-49.5). KIR ligand mismatch with the patient was noted in 2 donors. The median CD56-cell dose infused was 46.16 x 10 6/kg (IQR: 25.06-70.36) (Figure 1c). Pre-defined release criteria, including sterile cultures, and endotoxin negativity were met in all cases. There was no infusion related toxicity. The median blast percentage on flowcytometry MRD testing done following NK cell infusion was 11.9% (IQR: 4.9%-47.6%) (n=8). One patient withdrew consent after NK cell infusion and did not undergo transplant. For the remaining 13 patients, the stem cell donor was HLA matched (n=4), HLA 9/10 matched (n=1) or HLA haplomatched (n=8). The median CD34 cell dose infused was 10 x 10 6/kg (IQR:7.51-11.6). Five (38.5%) patients died of immediate post-transplant complications (sepsis (n=3) on days 1, 2 and 28, cerebral venous sinus thrombosis (n=1) on day 1 in a patient treated with hormonal contraceptives for menorrhagia, and veno-occlusive disease (n=1) on day 15 in a patient undergoing a second transplant) while 2 (15.4%) did not engraft (both subsequently died of infective complications following engraftment post-second transplant). Of the remaining 6 (46.2%) patients who engrafted and survived beyond 1 month of the transplant, the day 28 post-transplant MRD was negative for 5 patients while it was positive in 1 patient (0.13%). On follow up, 2 (15.4%) patients developed disease relapse (on days 54 and 218 respectively) and died. The remaining 4 (30.8%) patients are alive and relapse free at last follow up (mean follow up of surviving patients is 16 months). One patient received a CD34 cell boost on day 96 (cell dose - 8.55 x 10 6/kg) for poor graft function. For the entire cohort, the estimated 1-year event free survival is 28.8% ± 13.1%(Figure 1d). Whereas, acute GVHD was noted in 3 patients (50%; out of 6 evaluable patients) and chronic GVHD was noted in 3 patients (50%; out of the 6 evaluable patients). Thus, haploidentical NK cell therapy as an adjunct to transplant is safe and merits further evaluation in patients with AML. Figure 1 Figure 1. Disclosures Mathews: Christian Medical College: Patents & Royalties: US 2020/0345770 A1 - Pub.Date Nov.5, 2020; AML: Other: Co-Inventor.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2297-2297
Author(s):  
Han Wang ◽  
Kathy Chan ◽  
Po Yi Lee ◽  
Alex WK Leung ◽  
Chi Kong Li ◽  
...  

Abstract Background/Aims: Despite advances in chemotherapy-based treatment protocols, the outcomes of children with acute myeloid leukemia (AML) remain suboptimal. Implementation of targeted therapy based solely on genomics is challenging due to the complex mutational patterns and scarcity of pharmacologic agents for most lesions. In addition, pediatric and adult AML are genetically and biologically distinct, which poses a major hurdle for extrapolation of new agents approved for adult AML to the pediatric population. This study aims to adopt a functional approach that directly measure the response of patient-derived leukemic cells to targeted agents, and to establish the drug sensitivity pattern and identify candidates of immediate clinical relevance for precision usage in high-risk pediatric AML. Methods: A high-throughput drug screening, comprising 39 targeted agents (2 in Phase I, 10 in Phase II, 5 in Phase III, 22 FDA-approved) and 6 conventional chemotherapeutics, was performed on 30 pediatric AML samples collected at diagnosis or relapse using a serum-free, cytokine-supported culture system. A counter-screen of active drugs on cord blood hematopoietic stem cells was accomplished to reveal leukemia-selective activities. The robustness of the drug testing platform for predicting in vivo activities was validated in xenograft models. Genomic profiling was complementarily performed to identify the genetic markers and underlying mechanisms of drug sensitivity. Patients with refractory AML were treated with targeted agents based on drug profiling results, and assessed for clinical responses. Results: Unsupervised clustering revealed 5 distinct clusters of drug response: highly active compounds (IC50 <15 nM, 5 drugs); generally active compounds (IC50 <250 nM, 11 drugs); compounds with bimodal activities (wide IC50 ranges, 3 drugs); generally inactive compounds (16 drugs); and inactive compounds (IC50>2000 nM, 10 drugs). Targeted agents, including Bcl-2, HDAC, proteasome, HSP and survivin inhibitors, had substantially higher potency and selectivity over standard chemotherapeutic agents. New agents approved for adult AML were essentially inactive in pediatric AML. Drug sensitivity ex vivo accurately predicted in vivo single-agent and combinatorial activities with cytarabine in cell line- and patient-derived xenografts. Targeted resequencing of a 141-gene panel revealed novel mutations of prognostic relevance, such as KMT2C, in pediatric AML and their vulnerability to targeted agents. Whole-genome RNA-sequencing identified distinct gene expression signatures shaping the response to individual drugs. Administration of venetoclax to a child with refractory AML resulted in rapid blast clearance and achieved long-term remission. Complementary genomic profiling on serial specimens dictated the dynamic drug responses during disease evolution. Conclusions: Our study establishes a reliable drug testing platform and a pediatric-specific drug response profile of AML, which enables an evidence-based selection of targeted agents for patients without treatment options and endows therapies increasingly precise and personalized. The study also generates a valuable gene-drug-clinical dataset that could be leveraged to address the fundamental and translational biology of pediatric AML. It will ultimately impact the future design of clinical trials and protocols for managing this life-threatening malignancy. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4825-4825
Author(s):  
Moazzam Shahzad ◽  
Sibgha Gull Chaudhary ◽  
Ali Hussain ◽  
Fatima Ali ◽  
Ayesha Khalid ◽  
...  

Abstract Background: Acute myeloid leukemia (AML) is a clonal hematologic malignancy that generally affects older adults. Despite achieving complete remission (CR) in over two-third of patients with initial induction therapy and subsequent allogeneic hematopoietic stem cell transplantation in intermediate-high risk patients, more than half of AML patients experience disease relapse. The prognosis of patients with relapsed/refractory AML (RR-AML) is often poor and treatment modalities are limited. Chimeric antigen receptor T cell (CAR-T) therapy has shown promising results in lymphoid malignancies and myeloma, and these are now being explored for the management of RR-AML. In this systematic review and meta-analysis, we aimed to investigate the outcomes of CAR-T therapy in RR-AML patients. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on three databases (PubMed, Cochrane Register of Controlled Trials, and Clinical trials.gov) using MeSH terms and keywords for "Leukemia, Myeloid, Acute" AND "Receptors, Chimeric Antigen" OR "adoptive immunotherapy" from the date of inception to April 2021. A total of 673 articles were screened and original studies reporting patients with RR-AML having CAR-T therapy as the only intervention were included while reviews, duplicate, and non-relevant articles were excluded. A total of 10 studies (8 clinical trials and 2 case reports) were included. The data for following outcomes were extracted: complete response (CR), partial response (PR), overall response rate (ORR), overall survival (OS), progression-free survival (PFS), stable disease (SD), progressive disease (PD), cytokine release syndrome (CRS) and neurotoxicity (NT). Quality evaluation was done using the NIH quality assessment tool. Inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with 95% confidence Interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the R programming language (version 4.16-2). Results: We identified 39 patients in 10 studies who received CAR-T therapy for RR-AML. Median age of patients was 35 (7.3-80) years and 59% (n=23) were male. The median follow-up time was 5 (0.7-23) months. (Table 1) Four patients had history of allogeneic hematopoietic stem cell transplant (HCT) prior to CAR-T therapy while subsequent HCT was performed in 5 patients. The pooled analysis showed a CR and ORR of 38.5% (95% CI 0.03-0.81, I 2 =66%, n=29) and 56% (CI 0.18-0.91, I 2=58%, n=29), respectively. Median duration of response was 5.5 (1-23) months. OS was reported from 1.9 months to 23 months. The pooled incidence of CRS and NT were 42.7% (95%CI 0.06-0.87, I 2=66%, n=28) and 1.3% (95% CI 0.00-0.16, I 2= 0%, n=21) respectively. Graft-versus-host disease (GVHD) was reported in 2 patients who had prior and subsequent HCT after CAR-T therapy; first patient developed grade IV GVHD in the setting of salvage therapy with donor lymphocyte infusions for relapsed disease 6 months' post CAR-T and 4 months post second allo-HCT while second patient received CAR-T as part of conditioning therapy and developed grade IV GVHD on day 32. Conclusion: CAR-T therapy has shown favorable results comparable to current salvage therapies for relapsed or refractory AML with an acceptable toxicity profile. However, there are several challenges including the heterogeneous biology of AML, lack of a targetable antigen expression on malignant cells, and immune escape and exhaustion. Future prospective studies with improved CAR-T constructs will hopefully improve the outcomes in this therapeutically challenging patient population. Figure 1 Figure 1. Disclosures Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: EcoR1 Capital: Consultancy; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Bellicum Pharmaceuticals: Research Funding; Gamida Cell: Research Funding; Novartis: Research Funding; Astelllas Pharma: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Fresenius Biotech: Research Funding; Novartis: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding.


Sign in / Sign up

Export Citation Format

Share Document