A phase 1 trial of the anti-inhibitory KIR mAb IPH2101 for AML in complete remission

Blood ◽  
2012 ◽  
Vol 120 (22) ◽  
pp. 4317-4323 ◽  
Author(s):  
Norbert Vey ◽  
Jean-Henri Bourhis ◽  
Nicolas Boissel ◽  
Dominique Bordessoule ◽  
Thomas Prebet ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Phase 1 ◽  
Receptor Expression ◽  
Clear Correlation ◽  
Hematologic Toxicity ◽  
The European Union ◽  
Acute Myeloid

Abstract IPH2101 is an anti-killer inhibitory receptor (anti-KIR) mAb that can block KIR-mediated inhibition of natural killer (NK) cells to enhance cytotoxicity against acute myeloid leukemia blasts. We have conducted a phase 1 study of IPH2101 in elderly patients with acute myeloid leukemia in first complete remission. Patients received escalating doses (0.0003-3 mg/kg) of IPH2101 following a 3 + 3 design. Safety, toxicity (primary end points), pharmacokinetics, outcome, and immunologic correlates were evaluated. Twenty-three patients (median age, 71 years), were enrolled. Adverse events were mild and transient, consisting mainly of infusion syndrome and erythema. The maximum tolerated dose was not reached, although full KIR saturation (> 90%) was sustained for more than 2 weeks at 1 and 3 mg/kg. There was a clear correlation between mAb exposure and KIR occupancy. Neither hematologic toxicity nor significant changes in the numbers and distribution of lymphocyte subsets, NK cell receptor expression, or in vitro cytotoxicity were seen. At the highest dose levels (0.3, 1, and 3 mg/kg), transient increases in TNF-α and MIP-1β serum concentrations and NK cell CD69 expression were observed. Overall and relapse-free survival in the present study compared favorably to reports in comparable patient populations. We conclude that IPH2101 administration is safe and can block KIR for prolonged periods of time with limited side effects. Registered with the European Union Drug Regulating Authorities Clinical Trials (EUDRACT) as 2005-005298-31.

scholarly journals A phase 1 study of azacitidine with high-dose cytarabine and mitoxantrone in high-risk acute myeloid leukemia

2020 ◽  
Vol 4 (4) ◽  
pp. 599-606 ◽  
Author(s):  
Kirk E. Cahill ◽  
Yasmin H. Karimi ◽  
Theodore G. Karrison ◽  
Nitin Jain ◽  
Margaret Green ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
High Dose ◽  
Phase 2 ◽  
Phase 1 Study ◽  
High Dose Cytarabine ◽  
Acute Myeloid

Abstract In this phase 1 study, azacitidine (AZA) was given before high-dose cytarabine (HiDAC) and mitoxantrone (mito) based on the hypothesis that epigenetic priming with a hypomethylating agent before cytotoxic chemotherapy would improve response rates in patients with high-risk acute myeloid leukemia (AML), including relapsed/refractory disease. The primary objective was to establish the recommended phase 2 dose of AZA given before standard HiDAC/mito. In a dose escalation scheme, 46 patients (median age, 66 years) received AZA at 37.5, 50, or 75 mg/m2 subcutaneously or IV once daily on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10 (the HiDAC/mito dose was reduced 33% in elderly subjects). Two dose-limiting toxicities occurred (both in the same patient): acute liver failure and kidney injury at the 50 mg/m2 dose. The 30-day induction death rate was 2.2% (1 of 46). The overall response rate, including complete remission and complete remission with incomplete count recovery, was 61% (28 of 46). Previously untreated patients aged ≥60 years with therapy-related AML and de novo AML were more likely to respond than untreated patients with AML progressing from an antecedent hematologic disorder (myelodysplastic syndrome and chronic myelomonocytic leukemia). Patients with favorable European Leukemia Network risk (P = .008), NPM1 mutations (P = .007), or IDH2 mutations (P = .03) were more likely to respond, and those with TP53 mutations (P = .03) were less likely to respond. The recommended phase 2 dose of AZA is 75 mg/m2 per day on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10. This trial was registered at www.clinicaltrials.gov as #NCT01839240.

Tumor-Derived Microvesicles From Sera of Patients with Acute Myeloid Leukemia Suppresses NK Cell Cytotoxicity Via Transforming Growth Factor Beta-1.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2678-2678
Author(s):  
Miroslaw J Szczepanski ◽  
Marta E Szajnik ◽  
Malgorzata Czystowska ◽  
Magis Mandapathil ◽  
Ann Welsh ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Receptor Expression ◽  
Cell Cytotoxicity ◽  
Western Blots ◽  
Cell Suppression ◽  
Nk Cell Cytotoxicity ◽  
Acute Myeloid

Abstract Abstract 2678 Poster Board II-654 Natural killer (NK) cell cytotoxicity in patients with acute myeloid leukemia (AML) is significantly decreased relative to that in normal controls (NC). However, the mechanisms responsible for low NK cell activity in AML are not known. We considered the possibility that tumor-cell-derived microvesicles (MV) mediate suppression of NK cells. MV originate from the endosomal compartment of activated normal and neoplastic cells. Evidence suggests that tumor-derived MV exert detrimental effects on cells of the immune system and may play a role in tumor progression. To determine their contribution to immune suppression in AML, MV were isolated from sera of patients newly diagnosed with AML prior to any treatment and used to evaluate MV-mediated NK cell suppression. The protein content of MV isolated using exclusion chromatography and ultracentrifugation from sera of 19 AML patients was significantly higher than that of MV isolated from sera of 25 NC (75μg±12/mL vs 1.2μg±0.4/mL, p<0.001 ). MV from AML patients were positive for membrane-associated TGFb-1 and FasL in Western blots, whereas no TGFb-1 or FasL was detected in MV from NC. For functional assays, NK cells sorted from peripheral blood of NC were cultured with MV isolated from sera of the AML patients. A significant decrease in NK cell cytotoxicity was observed after co-incubation with MV (2412 LU before vs 1640 LU after, p<0.002). Concomitantly, a decrease in the expression of the NK cell activating receptor, NKG2D, was observed (57% before vs 38% after, p<0.001). The addition of TGFb1-neutralizing antibody abrogated the effects of MV on the NK cell cytotoxicity and receptor expression. The increased levels in sera of AML patients of MV mediating potent NK cell suppression is likely to compromise anti-tumor immune responses. Therefore, modulation of the levels and functions of MV might provide new immunotherapeutic approaches in AML. Disclosures: No relevant conflicts of interest to declare.

Microtransplantation: HLA-Mismatched Allogeneic Cellular Therapy of Acute Myeloid Leukemia (HMMACT)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5944-5944 ◽  
Author(s):  
Ann Mohrbacher ◽  
Ibrahim Syed ◽  
Noah Merin ◽  
Giridharan Ramsingh ◽  
Susan Groshen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Cellular Therapy ◽  
Nk Cell ◽  
Complete Response ◽  
Cell Phenotype ◽  
Platelet Recovery ◽  
Acute Myeloid

Abstract Background: This clinical trial addressed feasibility and safety of microtransplantation by HLA-mismatched allogeneic cellular therapy (HMMACT) in poor risk acute myeloid leukemia patients. A secondary objective was to estimate complete response rate, infections, GVHD incidence, and induction mortality. Methods: Patients with high risk AML were enrolled: 4 were > 75 yo, 3 with MLL+ ((t(6;11), 11+ and t(10;11)), 3 complex/del7, one FLT3+. Patients received induction chemotherapy with mitoxantrone (10 mg/m2 IV for 3 days) and cytarabine (150 mg/m2 IV for 7 days) and received HLA-mismatched GCSF mobilized PBSCs on day 9 or 10. Family donors were concurrently HLA typed and best available donor underwent GCSF mobilization (5 mg/kg SQ BID x 4 days) and leukapheresis after medical evaluation and safety testing. HLA partial mismatch patients (4- 5/10 antigen) were chosen. Apheresis cells were counted and analyzed by flow cytometry for CD34+ cells; CD3+, CD4+CD25+ and CD8 + cells; and CD3-CD56+ NK cells. Target CD3 cell dose was 1 x 108/kg per cycle; cells cryopreserved as for standard stem cell donors. Family donor HLA-mismatched GCSF mobilized peripheral blood cells were infused fresh on day 9 or 10 (up to day 16), 36-50 hours after end of cytarabine. Bone marrow biopsy was evaluated on day 14 and 28 for AML remission status, and T/NK cell number. Patients achieving a complete response proceeded to consolidation with cytarabine 0.5 -1.0 gram/m2 x 6 doses with fresh or cryopreserved HMMACT cells from their donor for 2 courses a month apart. Patients: 10 patients age 31 – 80 yo consented: 8 received allo cells; 1 screen failure (no haplo family member identified); 1 patient too ill after initiating chemo to collect donor. Eight patients received at least one course of HMMACT; 1 withdrew early due to AML progression, a second for poor performance status. Three patients had de novo AML; 5 patients had secondary AML. Six Patients had2 or more cycles of HMMACT: four achieved CR: Pt 1 and 4 received 3 cycles, Pt 2 and 6 received 2 cycles of cell infusions and all achieved CR. Pt 9 received 2 inductions with cells, and sustained a partial clinical remission for 6 months. Two Patients had 1 cycle of HMMACT:Pt 3: received 1 cycle cells, but response not assessed; Pt 8: received 1 cycle cells, and achieved CR 3+mos but declined further therapy. Safety: Acute reactions to cell infusions were minimal. Delayed reactions attributed to cell infusions included fever grade 1-2, rash grade 1-2, diarrhea grade 1-2 resolving in 7-10 days. Patients with prior MDS or refractory leukemia requiring 2 inductions had a longer time to ANC and platelet recovery. Feasibility: Two patients had no donor; 2 donors only collected enough for 2 cell infusions. Response: 5/8 pts receiving cells had CR/CRi (62.5%) lasting 3 to 10+ months. Conclusions: Although there were the usual significant complications of treating leukemia and infections, the cellular therapy itself was well-tolerated. Patients often had fevers in first week after cell infusions, or experienced transient rash and diarrhea in the same time period, which were self resolving in all cases and may reflect elimination of allogeneic cells by the patient’s immune system. No patient developed GVHD. Feasibility of obtaining family donors was as expected for this diverse US population. Infectious complications were low by AML treatment standards. Complete remission rates are encouraging, but not as durable as hoped, likely reflecting the fact that all of our patients had high risk cytogenetics in contrast to the prior published studies by Chinese investigators. The majority were elderly who would not otherwise be offered intensive therapy. Family donors achieved expected cell targets and tolerated mobilization/collection procedures well. All but one patient receiving 2 to 3 cycles achieved complete remission. Two elderly patients who received one or two cell infusions during induction sustained prolonged survival of 6 months in spite of no further therapy, one achieving a CR and the other a sustained PR. Neutrophil and platelet recoveries tended to follow the pattern of the patient's prior secondary leukemia or myelodysplastic disorder. Once patients achieved complete remission however, recovery of blood counts was relatively rapid on further cycles of consolidation. We are now assessing Treg, T and NK cell phenotype of patient and donor cells by flow cyAtometry as biological correlates. Disclosures Chaudhary: University of Southern California: Inventor on a patent application relevant to this work filed to US patent office (No. 62/031,053). Patents & Royalties.

scholarly journals Phenotypic and functional changes of NK cells in patients with myelodysplastic syndrome and acute myeloid leukemia treated with hypomethylating drugs

2021 ◽  
Vol 23 (2) ◽  
pp. 223-230
Author(s):  
D. I. Zhigarev ◽  
M. V. Khoreva ◽  
L. V. Gankovskaya
Keyword(s):  
Immune Response ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Nk Cells ◽  
Critical Analysis ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Receptor Expression ◽  
Functional Characteristics ◽  
Acute Myeloid

Natural killer cells (NK cells) are cytotoxic lymphocytes that play a pivotal role in maintaining immunological surveillance and in developing an innate immune response. Since the discovery of NK cells in 1973, the mechanisms of their functioning have been studied in details, and there is currently no doubt that they play a special role in the process of recognition and destruction of transformed and malignant cells. Understanding the role of NK cells in antitumor immunity, on the one hand, leads to emergence of new immunotherapeutic strategies and, on the other hand, allows to adjust the existing treatment regimens for tumor diseases, in accordance with the principle of primum non nocere. Optimization of cancer therapy protocols executed in order to protect immune cells from death and functional impairment is an important problem that cannot be successfully resolved without regular aggregation of the results from disparate studies and critical analysis of the all accumulated data.The objective of this review is to create a relevant and holistic picture of changes in the phenotypic and functional characteristics of NK cells in patients with two related hematological diseases – myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). For the treatment of both illnesses, drugs from the group of hypomethylating agents are used, the acting mechanism of which, unlike classical cytostatic agents, is based on modulation of the tumor cell genes expression. All the cells of the body are being affected, including NK cells, since these drugs act nonspecifically. Such an interaction leads to a hypomethylation of NK cell DNA and changes the expression of functional receptors, which, in turn, provide the development of antitumor NK cell immune response.Of course, just the fact of changing gene expression in certain cells does not allow us to fully judge the drug’s impact on the state of immune system. Meanwhile, the origin of this change and its role are important in the context of the disease pathogenesis. Ultimately, a simple description of an increase or decrease in a single receptor expression is not illustrative, since it can lead to uncertain consequences. For this reason, the current review, in addition to describing the existing data on the changes of NK cell receptors expression under the influence of hypomethylating drugs, gives a special attention to critical analysis of functional characteristics of NK cells, including their cytotoxic activity aimed at malignant blast cells, being a determinant of clinical course in the described diseases. 

scholarly journals Pegcrisantaspase in Combination with Venetoclax for Treatment of Relapsed or Refractory Acute Myeloid Leukemia: A Phase 1 Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4433-4433
Author(s):  
Sandrine Niyongere ◽  
Vu H. Duong ◽  
Dominique R Bollino ◽  
Rena G. Lapidus ◽  
Erin T. Strovel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase 1 ◽  
Advisory Committees ◽  
Poor Outcomes ◽  
Acute Myeloid

Abstract Background: Despite new therapeutic advances, acute myeloid leukemia (AML) still has poor outcomes, especially in patients with relapsed or refractory (R/R) disease with complex karyotype (CK) and/or TP53 mutation. Venetoclax (Ven), an oral BCL-2 inhibitor, in combination with DNA methyltransferase inhibitors (DNMTIs) has been approved by the FDA for treatment of newly diagnosed AML in adults who are unfit for intensive therapy with encouraging results, but the combination has been found to be less effective in patients with R/R AML. AML cells have been shown to be sensitive to extracellular glutamine depletion or manipulation of intracellular glutamine metabolism. Asparaginase converts asparagine and glutamine to aspartate and glutamate, decreasing plasma concentrations of asparagine and glutamine, with anti-leukemia activity. We previously published that crisantaspase produced complete plasma glutamine depletion in patients without dose-limiting toxicities and was associated with anti-leukemic activity in R/R AML (Emadi et al. Cancer Chemother Pharmacol 2018). In preclinical studies, we found that Pegcrisantaspase (PegC), a long-acting crisantaspase, not only had potent single-agent anti-AML activity, but also synergized with Ven in CK-AML cell lines and primary cells in vitro and in vivo (Emadi et al. Leukemia 2021). Ven-PegC targets the mTOR-eIF4E-driven ribosomal translational protein synthesis apparatus in AML. With no standardized treatment and poor outcomes for R/R AML, there is an unmet need for effective treatment options. Trial Design: We present an ongoing, non-randomized, open-label Phase 1 clinical trial evaluating Ven administered orally daily in combination with PegC administered intravenously every 14 days in 28-day treatment cycles in adults patients with R/R AML. The trial consists of two phases: dose escalation (four cohorts) and dose expansion at the final recommended phase 2 doses (RP2Ds). Adult patients with a pathologically confirmed diagnosis of AML whose disease has relapsed or is refractory to at least one line of AML therapy and with adequate organ function and no prior history of pancreatitis or ≥ Grade 3 thrombohemorrhagic events are eligible for this trial. All patients with FLT3, IDH1 or IDH2 mutation must have received at least one line of therapy with an available FLT3/IDH1/IDH2 inhibitor to be eligible for this trial. The study will include CK-AML and TP53-mutated AML. The primary objectives of the trial are to evaluate the safety and tolerability of Ven-PegC and estimate the maximum tolerated doses (MTDs) and/or biologically active doses (e.g. RP2D) of Ven-PegC in patients with R/R AML. The primary endpoints of the trial are incidences of regimen-limiting toxicities (RLTs) and treatment-emergent adverse events (TEAEs). The secondary endpoints include the rates of complete remission (CR) and composite complete remission (CR+CRh+CRi), event-free survival, overall survival, the rate of conversion from transfusion dependence to transfusion independence, and achievement of MRD &lt;0.02% within 2 cycles of treatment with Ven-PegC. If a patient does not achieve at least hematologic improvement within 3 cycles of treatment, the patient will be taken off study. Responding patients can continue with the assigned doses until progression. The study uses a 3+3 design. Up to 24 subjects will be enrolled during dose escalation (in case exactly one RLT occurs in the first three patients enrolled at each of the four dose levels). Another 10 subjects will be enrolled at the final RP2D in an expansion cohort, for a total of 16 patients treated at the RP2D. The study is currently open at the University of Maryland Greenebaum Comprehensive Cancer Center. ClinicalTrials.gov Identifier is NCT04666649. Figure 1 Figure 1. Disclosures Emadi: Jazz Pharmaceuticals: Research Funding; NewLink Genetics: Research Funding; Servier: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Secura Bio.: Consultancy; KinaRx, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Co-founder.

scholarly journals First-in-human trial of rhIL-15 and haploidentical natural killer cell therapy for advanced acute myeloid leukemia

2019 ◽  
Vol 3 (13) ◽  
pp. 1970-1980 ◽  
Author(s):  
Sarah Cooley ◽  
Fiona He ◽  
Veronika Bachanova ◽  
Gregory M. Vercellotti ◽  
Todd E. DeFor ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Therapy ◽  
Natural Killer ◽  
Cell Expansion ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Phase 1 ◽  
Therapeutic Benefits ◽  
Acute Myeloid

Abstract In vivo expansion of haploidentical natural killer (NK) cell infusions with interleukin-2 (IL-2) can induce remission of refractory acute myeloid leukemia, but efficacy may be hampered by concurrent stimulation of host regulatory T cells. To overcome this limitation, we substituted the NK homeostatic factor IL-15 in 2 phase 1/2 trials. Forty-two patients received either intravenous (IV) (NCT01385423) or subcutaneous (SC) (NCT02395822) recombinant human IL-15 (rhIL-15) after lymphodepleting chemotherapy and haploidentical NK cells. Escalating doses of rhIL-15 (0.3-1.0 μg/kg) were given on 12 consecutive days in a phase 1 trial. Of 26 patients, 36% had robust in vivo NK-cell expansion at day 14, and 32% achieved complete remission. Hypothesizing that SC dosing of rhIL-15 would be safer and better tolerated, 16 patients received 10 once per day doses of SC rhIL-15 at 2.0 μg/kg on a phase 2 trial. NK-cell expansion at day 14 was seen in 27% of the patients, and 40% achieved remission. rhIL-15 induced better rates of in vivo NK-cell expansion and remission compared with previous trials with IL-2, but it was associated with previously unreported cytokine release syndrome (CRS) after SC but not IV dosing. CRS was observed in 56% of patients given SC rhIL-15 (with concurrent neurologic toxicity in 5 of 9 patients) and was responsive to steroids and tocilizumab. SC administration was associated with slower pharmacokinetic clearance and higher levels of IL-6 than IV dosing. These novel trials testing the use of IL-15 to potentiate cell therapy suggest that dosing schedules based on pharmacokinetics and pharmacodynamics will preserve the therapeutic benefits of IL-15 and minimize CRS. These trials were registered at www.clinicaltrials.gov as #NCT01385423 and #NCT02395822.

scholarly journals Impact of NK Cell Activating Receptor Gene Variants on Receptor Expression and Outcome of Immunotherapy in Acute Myeloid Leukemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Brwa Ali Hussein ◽  
Alexander Hallner ◽  
Lovisa Wennström ◽  
Mats Brune ◽  
Anna Martner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Receptor Gene ◽  
Receptor Expression ◽  
Gene Variants ◽  
Nk Cell Receptors ◽  
Activating Receptor ◽  
Acute Myeloid

Natural killer cells are important effector cells in the immune response against myeloid malignancies. Previous studies show that the expression of activating NK cell receptors is pivotal for efficient recognition of blasts from patients with acute myeloid leukemia (AML) and that high expression levels impact favorably on patient survival. This study investigated the potential impact of activating receptor gene variants on NK cell receptor expression and survival in a cohort of AML patients receiving relapse-preventive immunotherapy with histamine dihydrochloride and low-dose IL-2 (HDC/IL-2). Patients harboring the G allele of rs1049174 in the KLRK1 gene encoding NKG2D showed high expression of NKG2D by CD56bright NK cells and a favorable clinical outcome in terms of overall survival. For DNAM-1, high therapy-induced receptor expression entailed improved survival, while patients with high DNAM-1 expression before immunotherapy associated with unfavorable clinical outcome. The previously reported SNPs in NCR3 encoding NKp30, which purportedly influence mRNA splicing into isoforms with discrete functions, did not affect outcome in this study. Our results imply that variations in genes encoding activating NK cell receptors determine receptor expression and clinical outcome in AML immunotherapy.

scholarly journals Bortezomib + MEC (Mitoxantrone, Etoposide, Cytarabine) for Relapsed/ Refractory Acute Myeloid Leukemia: Final Results of an Expanded Phase 1 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 978-978 ◽  
Author(s):  
Anjali S. Advani ◽  
Paul Elson ◽  
Matt E. Kalaycio ◽  
Sudipto Mukherjee ◽  
Aaron T. Gerds ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase 1 ◽  
Advisory Committees ◽  
Phase 1 Trial ◽  
Poor Risk ◽  
Acute Myeloid

Abstract MEC (mitoxantrone, etoposide, cytarabine) is a standard regimen for relapsed/ refractory (R/R) acute myeloid leukemia (AML), but outcomes remain poor. The overexpression of proteasomes and constitutive activation of NF-KB in AML cells suggest that proteasome inhibitors (PI) such as bortezomib (Bz) may be effective anti-leukemia therapy. PI or a decoy NF-KB oligonucleotide increase chemosensitivity to both anthracyclines and cytarabine. To test the hypothesis that PI may improve the efficacy of MEC, we conducted a phase 1 trial of Bz in combination with MEC. Here, we present final results of this trial: response rate, toxicity, and correlation of outcomes with mutation analysis. As CD74 expression may identify a subset NF-KB-dependent AML with predicted increased sensitivity to PI (Clin Can Res 2008; 14: 1446-54), we also explored this correlation. Methods: All pts were treated at the Cleveland Clinic from Aug 2010-Mar 2014. This protocol was approved by the institution’s review board. Eligibility included: age 18-70 yrs, R/R AML, cardiac ejection fraction ≥ 45%. CD74 was assessed by flow cytometry using CD45 PE (BD Biosciences San Jose, CA) and CD74-Alexa 488 (AbD Serotec Raleigh, NC). A myeloid panel mutational analysis was performed on extracted DNA in pts with banked samples (n=26). All pts received 1 cycle of MEC: mitoxantrone (6 mg/m2/d), etoposide (80 mg/ m2), and cytarabine (1000 mg/ m2) Days 1-6. Bz was administered IV on Days 1, 4, 8, and 11. Dose was escalated using a standard 3 x 3 design. Dose levels (DL) were: -1 (0.40 mg/ m2), 1 (0.70 mg/ m2), 2 (1.0 mg/ m2), and 3 (1.3 mg/m2). Response was defined by IWG criteria (Cheson, 2006). The maximum tolerated dose (MTD) of Bz with MEC was 1.0 mg/m2 (Advani et al, ASH 2012, Abstract 3595). Results: Of 35 pts enrolled, the median age was 55 yrs (range 33-69), 13 (38%) were male, and median baseline WBC was 4.0 K/ µL (range 0.82-84.7). The median time from initial diagnosis of AML to enrollment was 8.4 months (range 1.1-88.2) and 6 pts (17%) had an antecedent hematologic disorder. Salvage status (S) at enrollment: S1 (24 pts, 69%), S2 (7 pts, 20%), S4 (4 pts, 11%). Nine pts (26%) were refractory to all prior therapies, and 3 pts (9%) had received prior allogeneic hematopoietic cell transplant (AHCT). Adverse cytogenetics per CALGB/ Alliance 8461 criteria occurred in 19% of pts at study entry and 15 of 26 pts (58%) had poor-risk molecular mutations (RUNX1, ASXL1, TET2, p53, IDH1, MECOM, FLT3 ITD). Ten pts were enrolled on DL1, 13 pts on DL2, 11 pts on DL3, and 1 pt died prior to treatment. Overall, 3 pts (9%) died during induction. In addition to febrile neutropenia and Gr 4 hematologic toxicity, the most commonly reported adverse events (AEs) were metabolic, constitutional, gastrointestinal (GI), and dermatologic, with the majority of these being Gr 1 or 2. GI toxicity was the only reported AE attributable to Bz: 12 pts had constipation or ileus (10: Gr 1 or 2; 2: Gr 3 or 4). Seventeen of the 33 evaluable pts (52%) have achieved a complete remission (CR) or complete remission with incomplete count recovery (CRi); with 1 pt inevaluable due to donor lymphocyte infusion. The estimated median overall survival was 7.2 months; median duration of response was 10.3 months. DL did not correlate with response. Eleven pts (32%) went on to receive AHCT. Among pts with poor-risk molecular mutations, 64% achieved CR/ CRi. Inhibition of NF-KB signaling in leukemia cells with mutated RUNX1 efficiently blocks growth and development of leukemia (Blood 2011; 118: 6626-37). Of the 5 pts with RUNX1 mutations, 3 (60%) achieved CR/ CRi, suggesting that Bz may have promising clinical benefit in this difficult subset of pts. Among the 17 pts with CD74 expression testing who were evaluable for response, the mean CD74 expression trended higher in non-responding pts (32.6%) than in responders (11.1%) (p=0.14). Conclusions: The combination of MEC/Bz was well-tolerated and resulted in high response rates, even within a molecularly-defined poor risk population of pts with R/R AML. Our data do not confirm the expectation that higher CD74 expression would correlate with response in this R/ R AML cohort, but larger pt numbers are needed. These results, especially in pts with poor-risk mutations, support development of a randomized study to address the benefit of adding Bz to MEC in the treatment of R/R AML. Disclosures Advani: Takeda: Research Funding. Carew:Takeda: Research Funding. Sekeres:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees.

A Phase 1 Trial of MEC (Mitoxantrone, Etoposide, Cytarabine) in Combination with Bortezomib for Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3595-3595 ◽  
Author(s):  
Anjali Advani ◽  
Paul Elson ◽  
Eric D. Hsi ◽  
Randall Davis ◽  
Matt Kalaycio ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Abstract 3595 The overexpression of proteasomes and constitutive activation of NF-KB in acute myeloid leukemia (AML) cells suggest that proteasome inhibitors (PI) such as Bortezomib (Bz) may be an effective therapy. PI or a decoy NF-KB oligonucleotide increases chemosensitivity to both anthracyclines and cytarabine. Thus, PI may improve the effectiveness of MEC (mitoxantrone, etoposide, cytarabine), a standard regimen for relapsed/refractory (R/R) AML. The primary objectives of this study were to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended Phase 2 dose of Bz in combination with MEC in patients (pts) with R/R AML. Secondary objectives included evaluating the preliminary activity of this combination and correlating CD74 antigen expression with response. CD74 may identify a subset of leukemias in which NF-KB is operative, with increased sensitivity to PI (Attar et al. CCR 2008; 14: 1446–54). Methods: All pts were treated at the Cleveland Clinic from August 2010-July 2012. This protocol was reviewed and approved by the institution's review board. Eligibility included: age 18–70 yrs, R/R AML, cardiac ejection fraction ≥ 45%. CD74 was assessed by flow cytometry using CD45 PE (BD Biosciences San Jose, CA) and CD74-Alexa 488 (AbD Serotec Raleigh, NC). All pts received MEC: mitoxantrone (6 mg/m2/d), etoposide (80 mg/m2), and cytarabine (1000 mg/m2) Days 1–6. Bz was administered IV on Days 1, 4, 8, and 11 and was dose escalated using a standard 3 × 3 design. Dose levels (DL) were: −1 (0.40 mg/m2), 1 (0.70 mg/m2), 2 (1.00 mg/m2), 3 (1.30 mg/m2). One cycle of treatment was administered. Response was assessed by bone marrow aspirate/biopsy by Day 45, and CR was defined by IWG criteria (Cheson, 2006). Toxicities secondary to neutropenia or sepsis were not considered DLTs. DLT included: (1) ≥ Grade 4 non-hematologic toxicity (NHT) with the exception of nausea, vomiting, alopecia, and drug-related fevers; (2) any ≥ Grade 3 neurologic toxicity; (3) grade 4 platelet or neutrophil count 50 days beyond the start of chemotherapy (not related to leukemia); (4) Any grade 3 NHT > grade 2 by 45 days beyond the start of chemotherapy. The following were redefined as not being DLT: (1) anorexia requiring TPN; (2) fatigue requiring bed rest; (3) grade 2, 3, and 4 hyperbilirubinemia were redefined as 1.5-<10x ULN, 10.0–20.0 × ULN, and > 20 × ULN respectively. Results: Seventeen pts have enrolled; and 15 are evaluable for response. The median age was 54 years (range 33–69), 7 (47%) were male, and median baseline WBC 3.58 K/μL (range 0.96–76.53). The median time from initial diagnosis to enrollment was 7.1 months (range 1.4–84.9) and 2 pts had a history of an antecedent hematologic disorder. Nine pts (60%) were in first relapse, 2 (13%) in second relapse, and 4 (27%) refractory. One pt had received a prior allogeneic hematopoietic stem cell transplant; and 4 out of 15 pts (27%) had adverse cytogenetics at the time of relapse based on CALGB 8461 criteria. At DL 1, 1 DLT occurred (Grade 4 thrombocytopenia). No DLTs occurred at DL 2. Three pts were enrolled on DL 3, with one DLT occurring thus far (Grade 4 transaminases: likely related to leukemia). Only one pt had their Day 11 Bz held secondary to Grade 2 ileus (DL 1). Overall, 3 pts (all on DL 1) have died from blood stream infections. In addition to Grade 4 hematologic toxicity, the most commonly reported adverse events (AEs) have been gastrointestinal (GI). GI toxicities were the mostly commonly reported AEs attributable to Bz. Nine pts reported constipation and/or abdominal pain (7: Grade 1 or 2; 2: Grade 3). Six of the 15 evaluable pts (40%) have achieved a complete remission (CR) or CRp (complete remission without platelet recovery). Eight of the fifteen pts had CD74 expression testing, but only 6 of 8 were evaluable for response. The median CD74 expression was higher in refractory pts (35.9%) (range 14–87) than in responders (3.2%) (range 0.9–16). Conclusions: The MTD of MEC in combination with Bz will be reported at the meeting; but currently we are in the last DL (3) and the MTD has not been reached. The toxicities of the combination are similar to that of MEC, except potentially an increase in GI toxicities. We await the results of preliminary response in the expanded cohort of pts, once the MTD is achieved. Higher CD74 expression appears to correlate with refractory disease rather than response in this R/R AML cohort, but larger pt numbers are needed to confirm this. Disclosures: Advani: Millenium: Research Funding. Hsi:Millenium: Research Funding.

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