In vitro sensitivity of hematopoietic progenitors to Tiazofurin in refractory acute myeloid leukemia and in the blast crisis of chronic myeloid leukemia

Abstract Abstract 2657 Poster Board II-633 For most patients with relapsed and refractory acute myeloid leukemia, therapeutic success is unpredictable with current cytotoxic chemotherapeutic regimens. Moreover, multiple courses of therapy have been shown to result in co-morbid conditions, which can often preclude the patient from being able to receive the potentially curative therapy of allogeneic bone marrow transplantation. With the aim of identifying a successful chemotherapy regimen for these patients, based on patient-specific myeloid blast cell chemo-sensitivities, we have developed a high-throughput screening assay that utilizes primary (patient-derived) leukemia cells and tested for chemo-sensitivity against a panel of established chemotherapeutic agents as well as novel agents. In our laboratory, we were able to identify in vitro resistance against the various drugs already clinically administered, including cytarabine, etoposide, and anthracyclines. Importantly, we were able to show in vitro sensitivity to chemotherapy agents that had not been previously administered. The index patient was a 32-year-old woman with primary refractory acute myeloid leukemia who had received six different therapeutic regimens prior to our testing, all of which demonstrated in vitro resistance using our assay. The blasts were sensitive, however, to 6-thioguanine with an inhibitory concentration (IC50) of 70 nM. Based on the in vitro data, the patient began a combination treatment regimen containing oral 6-thioguanine as her white blood cell (WBC) count had increased to greater then 50,000 cells/ml on her previous therapy. Following a maintenance regimen with these agents, her circulating blast count decreased to less then 10,000 cells/ml, and she had partial recovery of the neutrophil count, resulting in a decrease in the overall leukemia burden. This result was not seen with her previous treatment regimens. Importantly, the majority of this therapy was administered in the outpatient setting. Subsequently, we have collected specimens from more than ten patients with AML and used this screening assay to predict their response to various chemotherapeutics. In each case, we have accurately predicted the in vivo clinical response (both sensitivity and resistance) to different chemotherapeutic agents. This demonstrates that the technology currently being used to screen drug therapy for patients with relapsed and refractory AML is clinically useful and has a potential role in designing individualized drug treatment regimens. Disclosures: No relevant conflicts of interest to declare.

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Myeloblasts from Doen syndrome children with acute myeloid leukemia have increased in vitro sensitivity to cytosine arabinoside and daunorubicine

Leukemia ◽

10.1038/sj.leu.2400747 ◽

1997 ◽

Vol 11 (9) ◽

pp. 1594-1595 ◽

Cited By ~ 21

Author(s):

JW Taub ◽

ML Stout ◽

SA Buck ◽

X Huang ◽

RA Vega ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Cytosine Arabinoside ◽

Myeloid Leukemia ◽

In Vitro Sensitivity ◽

Acute Myeloid

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First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.19.03250 ◽

2020 ◽

Vol 38 (36) ◽

pp. 4260-4273

Author(s):

Olga Salamero ◽

Pau Montesinos ◽

Christophe Willekens ◽

José Antonio Pérez-Simón ◽

Arnaud Pigneux ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Phase I ◽

Myeloid Leukemia ◽

Single Agent ◽

Antileukemic Activity ◽

Open Label ◽

Refractory Acute Myeloid Leukemia ◽

Acute Myeloid

PURPOSE Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML). METHODS This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor. RESULTS Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m2/d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 µg/m2/d of iadademstat as a single agent. This dose was chosen to treat all patients (n = 14) in an EC enriched with patients with MLL/KMT2A-rearranged AML. Most adverse events (AEs) were as expected in R/R AML and included myelosuppression and nonhematologic AEs, such as infections, asthenia, mucositis, and diarrhea. PK data demonstrated a dose-dependent increase in plasma exposure, and PD data confirmed a potent time- and exposure-dependent induction of differentiation biomarkers. Reductions in blood and bone marrow blast percentages were observed, together with induction of blast cell differentiation, in particular, in patients with MLL translocations. One complete remission with incomplete count recovery was observed in the DE arm. CONCLUSION Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36).

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Plag1 and Plagl2 are oncogenes that induce acute myeloid leukemia in cooperation with Cbfb-MYH11

Blood ◽

10.1182/blood-2004-09-3630 ◽

2005 ◽

Vol 105 (7) ◽

pp. 2900-2907 ◽

Cited By ~ 80

Author(s):

Sean F. Landrette ◽

Ya-Huei Kuo ◽

Karen Hensen ◽

Sahar Barjesteh van Waalwijk van Doorn-Khosrovani ◽

Paola N. Perrat ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Fusion Protein ◽

Myeloid Leukemia ◽

Fusion Gene ◽

Cell Renewal ◽

Chromosome 16 ◽

Hematopoietic Progenitors ◽

Acute Myeloid

AbstractRecurrent chromosomal rearrangements are associated with the development of acute myeloid leukemia (AML). The frequent inversion of chromosome 16 creates the CBFB-MYH11 fusion gene that encodes the fusion protein CBFβ-SMMHC. This fusion protein inhibits the core-binding factor (CBF), resulting in a block of hematopoietic differentiation, and induces leukemia upon the acquisition of additional mutations. A recent genetic screen identified Plag1 and Plagl2 as CBFβ-SMMHC candidate cooperating proteins. In this study, we demonstrate that Plag1 and Plagl2 independently cooperate with CBFβ-SMMHC in vivo to efficiently trigger leukemia with short latency in the mouse. In addition, Plag1 and Plagl2 increased proliferation by inducing G1 to S transition that resulted in the expansion of hematopoietic progenitors and increased cell renewal in vitro. Finally, PLAG1 and PLAGL2 expression was increased in 20% of human AML samples. Interestingly, PLAGL2 was preferentially increased in samples with chromosome 16 inversion, suggesting that PLAG1 and PLAGL2 may also contribute to human AML. Overall, this study shows that Plag1 and Plagl2 are novel leukemia oncogenes that act by expanding hematopoietic progenitors expressing CbFβ-SMMHC.

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Identification of Molecular Predictors of Response to ZARNESTRA™ (Tipifarnib, R115777) in Relapsed and Refractory Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v104.11.861.861 ◽

2004 ◽

Vol 104 (11) ◽

pp. 861-861 ◽

Cited By ~ 7

Author(s):

Mitch Raponi ◽

Bob Lowenberg ◽

Jeffrey E. Lancet ◽

Jean-Luc Harousseau ◽

Richard Stone ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Expression Profiles ◽

Blast Crisis ◽

Gene Expression Signature ◽

Open Label ◽

Gene Expression Signatures ◽

Refractory Acute Myeloid Leukemia ◽

Acute Myeloid

Abstract The orally available farnesyltransferase inhibitor (FTI) tipifarnib has demonstrated clinical efficacy in hematological disease. In an effort to identify patients with a higher likelihood of response, we have employed microarray technology to identify gene expression markers that predict response to tipifarnib. In an open label, single arm, Phase II study of patients with relapsed or refractory acute myeloid leukemia, tipifarnib was administered at a dose of 600 mg twice daily for the first 21 days of each 28-day cycle. Gene expression profiles from 80 bone marrow samples, collected before drug treatment, were analyzed on the Affymetrix U133A gene chip that contains approximately 22,000 genes. Statistical analyses were performed to identify genes that predict patient outcome following treatment with tipifarnib. Nineteen genes were selected because they showed significant differences in gene expression between the responder group and the non-responder group of patients. Several of these genes are associated with oncogenesis, cell proliferation, and FTI biology. One of the candidate genes, lymphoid blast crisis oncogene (oncoLBC or AKAP13), was over-expressed in patients who were resistant to tipifarnib. A leave-one-out cross validation (LOOCV) showed that the predictive value of this gene provided a sensitivity of 93% in identifying responders and a specificity of 61%, providing an overall diagnostic accuracy of 69%. In addition, supervised analysis identified a combination of 3 gene expression markers that together can potentially be used to predict patient response to the drug with the best overall accuracy of 74%. This 3-gene expression signature provided a sensitivity of 86% and a specificity of 70% in the LOOCV. In both instances, classification of patients using the gene expression signatures demonstrated significantly enhanced overall survival in those predicted to be responders. These data indicate that diagnostic gene expression signatures can potentially double the response rate to tipifarnib from 24% to 48%. The identification of these gene expression markers is an important step towards defining diagnostic signatures that could be used to identify AML patients who are likely to respond to tipifarnib and for understanding pathways that are affected by farnesyltransferase inhibition in AML.

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Philadelphia Chromosome Positive Acute Myeloid Leukemia: An Aggressive Acute Leukemia with Clinicopathologic Features Distinct from Chronic Myeloid Leukemia in Blast Crisis.

Blood ◽

10.1182/blood.v106.11.3290.3290 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3290-3290

Author(s):

Chad P. Soupir ◽

Jo-Anne Vergilio ◽

Paola Dal Cin ◽

Alona Muzikansky ◽

Hagop M. Kantarjian ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Blast Crisis ◽

Philadelphia Chromosome ◽

Rare Entity ◽

Median Response ◽

Acute Myeloid ◽

Philadelphia Chromosome Positive

Abstract Philadelphia chromosome positive acute myeloid leukemia (Ph+ AML) is a rare entity reported to comprise 1% of tumors bearing the Philadelphia chromosome. Controversy exists over whether this represents a distinct entity or is merely presentation of patients in the blastic phase of chronic myeloid leukemia (CML). Our study sought to determine the clinicopathologic characteristics of Ph+ AML in comparison to CML in blast crisis. We searched the archival files of Massachusetts General Hospital, Brigham and Women’s Hospital, Dana Farber Cancer Institute, and MD Anderson Cancer Center from 1995 to 2005 for cases of apparent de novo Ph+ AML. After excluding biphenotypic leukemias and cases with any evidence of prior CML or other myeloid neoplasia, we retrieved 18 Ph+ AML cases. 20 cases of documented CML in myeloid blast crisis (CML-MBC) who had not received prior imatinib mesylate therapy or bone marrow transplant were used as a control group. The clinical and laboratory features, bone marrow morphology, immunophenotype, cytogenetics, and type of BCR/ABL transcript were analyzed. The Ph+ AML patients included 13 males and 5 females with a median age of 55 years, which was not significantly different from CML-MBC patients. The median WBC at presentation was 15.7 x 109/L. Compared to CML-MBC patients, the Ph+ AML patients were less likely to have splenomegaly (22% vs. 68%, p=0.008) or peripheral basophilia (median absolute basophil count 0.16 vs. 1.24 x 109/L, p=0.003). The bone marrow in Ph+ AML patients was less cellular (median cellularity 80% vs. 98%, p=0.002) with a lower myeloid:erythroid ratio (1.3 vs. 4.8, p=0.01), but more prominent erythroid and myeloid lineage dysplasia (p=0.04) than that of CML-MBC patients. While cytogenetic abnormalities in addition to t(9;22) occurred in 67% of Ph+ AML cases, the typical additional cytogenetic changes of CML-MBC (+8, +19, iso17q, and +Ph+) were uncommon (22% vs. 87% for CML-MBC, p=0.0004). In 5/6 Ph+ AML cases with multiple clones, the Ph+ was present in all clones, suggesting that this represents an early event in the evolution of these leukemias. RT-PCR revealed a predicted BCR/ABL product of p210 (10/13 cases), p190 (2/13 cases) or p230 (1/13 cases). 6/7 Ph+ AML patients treated with imatinib showed at least a partial hematologic response, but this was of a short duration (median 2.5 months, range 1–6 months) in comparison to the reported median response duration of 10 months in imatinib-responsive CML-MBC. The median survival of the Ph+ AML patients was 10.5 months, similar to that of CML-MBC and AML with adverse cytogenetics. In summary, Ph+ AML is a rare entity distinct from CML-MBC, with an aggressive clinical course and only transient response to imatinib.

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A Phase I/II Dose Escalation Trial of ONCOHIST® (Recombinant Human Histone H1.3) in Patients with Relapsed or Refractory Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v110.11.918.918 ◽

2007 ◽

Vol 110 (11) ◽

pp. 918-918 ◽

Cited By ~ 2

Author(s):

Michael Zeppezauer ◽

Grazina Formicka-Zeppezauer ◽

Peter Gross ◽

Hans Joernvall ◽

Joerg Schubert ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Side Effects ◽

Phase I ◽

Dose Level ◽

Myeloid Leukemia ◽

Study Drug ◽

Acute Myelogenous ◽

Refractory Acute Myeloid Leukemia ◽

Acute Myeloid

Abstract Background: Histone H1.3 suppresses tumor growth of leukemic cells in vitro, ex vivo and in animal models. To evaluate toxicity and efficacy of ONCOHIST, recombinant human histone H1.3 (rhH1.3) in patients suffering from acute myelogenous leukemia, we initiated a phase-I/II dose escalation study. Methods: This was an open-label unicentric phase I/II study. Nine patients suffering from relapsed or refractory acute myeloid leukemia (median age: 69 years, range 49 to 83 years) with a life expectancy of at least one month who were unable or unwilling to receive curative chemotherapy without major organ dysfunction were eligible for the trial. Exclusion criteria were presence of HIV, HBV, or HBC infection, heparin treatment during the 2 weeks before enrolment, and medical conditions known to potentially interfere with rhH1.3 treatment such as rheumatoid arthritis or SLE, as well as circulating anti-histone H1.3 antibodies. One treatment course consisted of 9 applications in 3 weeks. 3 patients were treated at each dose level. Starting dose level was 245 mg/m2 and in the absence of dose-limiting toxicities, the dose was increased to the next higher dose level (392 and 628 mg/m2 rhH1.3) in the third week of the treatment course. Primary endpoints of the study was the definition of the maximal tolerated dose and dose-limiting toxicities of the study drug. Results: To date, 9 patients have been treated and all patients are evaluable for toxicity and efficacy. No side-effects were observed except for one atrial fibrillation under infusion of rhH1.3, which was considered not to be related to the study drug. All patients completed one course of therapy (9 applications), and one responding patient received a second course without side effects. No dose-limiting toxicities were observed and the maximal tolerated dose has not been reached at 628 mg/m2. With respect to efficacy, the formal criteria of response were not met in any of the 9 patients. However, two patients had a temporary increase of their platelet counts while on therapy, and in one patient platelet counts raised from 22 000/mm3 to 100 000/mm3, remaining stable for 3 months. Two patients achieved a reduction of blasts upon treatment. Conclusion: rhH1.3 is well tolerated at the doses treated so far. While the achieved serum levels are still below the growth-inhibiting concentrations in vitro, first clinical effects have been observed. Additional patients and higher dose levels are needed to delineate the efficacy and toxicity profile of rhH1.3 for the treatment of acute myelogenous leukemias.

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