Large Interindividual Differences in In Vitro Calicheamicin Sensitivity May Underly Gemtuzumab Ozogamicin Resistance in Acute Myeloid Leukemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 107-107
Author(s):  
Bianca F. Goemans ◽  
Gertjan J.L. Kaspers ◽  
Susanne J.H. Vijverberg ◽  
Anne H. Loonen ◽  
Ursula Creutzig ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Drug Sensitivity ◽  
Gemtuzumab Ozogamicin ◽  
Cross Resistance ◽  
Newly Diagnosed ◽  
Primary Resistance ◽  
In Vitro Sensitivity ◽  
Resistant Patient ◽  
Pediatric Aml

Abstract Gemtuzumab ozogamicin (GO or Mylotarg®) is increasingly being used in the treatment of AML. GO consists of a cytotoxic drug - calicheamicin which is conjugated to an anti-CD33 antibody. Most AML patients highly express CD33 on their blasts. Studies relating CD33 expression to response to GO have failed to show an association. Although 30–50% of patients respond to Mylotarg®, the causes of primary resistance to this drug remain unclear. Previous reports have studied P-gp status and CD33 expression as a cause of resistance to GO. Another factor that might determine response to GO is cellular drug resistance to calicheamicin. In this study we examined in vitro resistance to calicheamicin in 90 initially diagnosed and 32 relapsed pediatric AML samples using the 4 day MTT assay (concentration range 0.000004 – 0.4 μg/ml). The LC50 value, the drug concentration at which 50% of the cells is killed by the drug, is used as a measure of sensitivity. In addition to calicheamicin, some samples were also tested successfully for in vitro sensitivity to etoposide, cytarabine, daunorubicin, idarubicin, mitoxantrone, 6-thioguanine, vincristine and L-asparaginase. The characteristics of the 122 pediatric AML samples included are as follows: 62% boys, median age 9.6 years, median WBC 53.0*109/L, FAB types M0 n=9, M1 n=10, M2 n=18, M3 n=9, M4 n=33, M5 n=24, M7 n=3, unknown n=16. There was a more than 100,000 fold difference in calicheamicin sensitivity between the most sensitive and the most resistant patient samples. FAB M2 samples taken at initial diagnosis (n=13) were significantly more resistant to calicheamicin compared to the other FAB types (Resistance Ratio (RR)=2.5, median LC50 0.033 vs. 0.013 μg/ml, p=0.008). Newly diagnosed AML samples were significantly more sensitive to calicheamicin compared to relapsed AML samples (RR=0.68, median LC50 0.023 vs. 0.034 μg/ml, p=0.042) (although these patients had not been treated with calicheamicin). There was strong cross-resistance between calicheamicin and the anthracyclines idarubicin (Spearmans rho = 0.73, p<0.0001, n=23), daunorubicin (rho=0.61, p<0.0001, n=103) and mitoxantrone (rho=0.52, p=0.039, n=16). In addition, there was moderate cross-resistance with etoposide (rho=0.42, p<0.0001, n=101). No cross-resistance was observed between calicheamicin and cytarabine (rho=0.11, p=0.28, n=106), 6-thioguanine (rho=0.20, p=0.054, n=97), vincristine (rho=0.12, p=0.44, n=46) or L-asparaginase (rho=0.21, p=0.16, n=45). In conclusion, the interpatient differences in calicheamicin sensitivity are the largest differences in in vitro drug sensitivity we have ever observed in pediatric AML. FAB M2 samples are 2.5 fold more resistant to calicheamicin than samples with other FAB types. Initially diagnosed pediatric AML samples are 1.5 fold more sensitive to calicheamicin than relapsed AML samples. There is marked cross-resistance between calicheamicin and the related anthracyclin compounds. Given the large differences in sensitivity to calicheamicin in pediatric AML samples, it is likely that calicheamicin resistance plays a role in resistance to Mylotarg®.

scholarly journals Clinical Significance of CD33 Non-Synonymous Single Nucleotide Polymorphisms (SNPs) in Pediatric Patients with Acute Myeloid Leukemia Treated with Gemtuzumab Ozogamicin-Containing Chemotherapy,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3489-3489
Author(s):  
Jatinder Lamba ◽  
Leslie J. Mortland ◽  
Amit Mitra ◽  
Roland B. Walter ◽  
Jessica A. Pollard ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Risk Group ◽  
Gemtuzumab Ozogamicin ◽  
Phase Iii ◽  
Nucleotide Polymorphisms ◽  
Newly Diagnosed ◽  
Single Nucleotide ◽  
Expression Levels ◽  
Pediatric Aml ◽  
White Patients

Abstract Abstract 3489 Introduction: Acute myeloid leukemia (AML) remains a difficult-to-treat disease, and outcome with standard conventional chemotherapeutics is often poor. An emerging approach uses monoclonal antibodies as a means to deliver targeted therapy. The antigen currently most exploited is CD33, in particular with gemtuzumab ozogamicin (GO), an immunoconjugate with a toxic calicheamicin derivative that causes DNA strand breaks, apoptosis, and cell death. However, while efficacious in some patients with untreated or relapsed/refractory disease, clinical response to GO is heterogeneous, emphasizing the need for studies to determine the subsets of patients that will benefit from GO. Although response to therapy is generally multi-factorial in origin, there is often a significant contribution of host genetic factors. Since GO targets CD33, we sought to determine the clinical impact of CD33 single nucleotide polymorphisms (SNPs) in a larger cohort of pediatric AML patients enrolled on Children's Oncology Group (COG) AAML03P1 pilot Phase III study, which explored the safety of GO addition to standard induction chemotherapy for newly-diagnosed AML. Methods: We genotyped four CD33 SNPs [rs35112940 (G>A; Arg304Gly), rs12459419 (C>T; Ala14Val), rs2455069 (A>G; Arg69Gly), and rs1803254 (G>C; 3'UTR)] occurring with an allelic frequency greater than 10% in genomic DNA samples in 242 pediatric AML patients. These were treated on trial COG-AAML03P1, and determined the associations between CD33 SNPs with CD33 protein expression levels in diagnostic leukemic cells and clinical outcome. Results: CD33 coding SNPs, rs35112940 (G>A; Arg304Gly) and rs12459419 (C>T; Ala14Val), and the 3'UTR SNP rs1803254 demonstrated significant associations with outcome or CD33 expression levels. Specifically, among white patients (which consisted of the major group 166/242=68.6%) homozygous for wild-type allele (GG) for the SNP rs35112940, a lower 3-year relapse risk from the end of course 1 was observed as compared to other genotypes (GG vs. AG vs. AA; 24±9% vs. 41±17% vs. 67±38%; p=0.018 Figure. 1A). Similarly, the 3-year overall survival from end of course 1 for among white patients homozygous for G allele in complete remission was 84±8% versus 68±15% for other genotypes (p=0.036; Figure. 1B). Patients homozygous for variant allele (TT) for SNP rs12459419 had a 3-year overall survival of 88±13% compared to 69±6% for other genotypes (p=0.056). Among white patients, the homozygous TT genotype also had a lower mean CD33 expression compared to other genotypes at this SNP (mean fluorescence intensity, 42 vs. 145, p=<0.001). Additionally, we observed an increased proportion of patients homozygous for variant allele (TT) for rs12459419 in the favorable risk group compared to genotypes CC and CT (52% vs. 31 %, p=0.034). Conclusion: In conclusion, our findings suggest that CD33 SNPs are associated with clinical disease features such as CD33 expression levels and risk group as well as outcome after GO-containing chemotherapy in patients with newly diagnosed AML. The recently completed COG-AAML0531 randomized Phase III trial will allow validation of our findings. If their usefulness as a prognostic marker for treatment outcome of GO-based therapy is confirmed in an independent cohort, CD33 SNPs may serve to optimize the clinical use of this immunoconjugate; by extrapolation, prognostic information provided by CD33 SNPs may also be applicable to novel, second-generation CD33-targeting immuno-conjugates that have entered preclinical and clinical testing. Disclosures: No relevant conflicts of interest to declare.

A Profound Biological Difference of Chronic and Blast Phase Chronic Myeloid Leukemia in Ex Vivo Drug Responses

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3139-3139
Author(s):  
Paavo Pietarinen ◽  
Tea Pemovska ◽  
Emma I Andersson ◽  
Perttu Koskenvesa ◽  
Mika Kontro ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Drug Sensitivity ◽  
Ex Vivo ◽  
Primary Cells ◽  
Newly Diagnosed ◽  
Biological Difference ◽  
Resistant Patient

Abstract BACKGROUND Most patients with chronic phase (CP) chronic myeloid leukemia (CML) are successfully treated with tyrosine kinase inhibitors (TKIs) targeting ABL1. Despite the good results, TKI treatment rarely results in cure, and some patients relapse and progress to advanced phases of CML. Accelerated phase and blast crisis (BC) have remained a therapy challenge. We set out to identify novel candidate drugs for chronic and advanced phase CML by using an unbiased high-throughput drug testing platform and utilizing both primary patient cells (CP and BC) and cell lines. METHODS CML BC cell lines used: K562 (erythroleukemic), MOLM-1 (megakaryocytic) and EM-2 (myeloid). Primary bone marrow (BM) and peripheral blood (PB) samples were derived from 3 CML patients with BC, two of which were TKI-resistant. Patient 1 had developed resistance to imatinib and nilotinib due to an E274K mutation in ABL1 kinase domain, whereas patient 2 was resistant to imatinib, nilotinib, and dasatinib due to a T315I mutation. In addition to BC patients, samples from 23 newly diagnosed CML CP patients were screened. BM cells from 4 healthy individuals were used as controls. Functional profiling of drug responses was performed with a high-throughput drug sensitivity and resistance testing (DSRT) platform comprising 306 anti-cancer agents. Cells were dispensed to pre-drugged 384-well plates and incubated for 72 h. Cell viability was measured using a luminescence cell viability assay (CellTiter-Glo, Promega). A Drug Sensitivity Score (DSS) was calculated for each drug using normalized dose response curve values. The drug sensitivities of the primary cells were further normalized against the median values from healthy controls, resulting in leukemia-specific sensitivity scores (sDSS). RESULTS Drug sensitivities of CML cell lines correlated closely (EM-2 vs. K-562, rS=0.89; EM-2 vs. MOLM-1, rS=0.82; K-562 vs. MOLM-1, rS=0.78; p<0.0001 for all correlations). Similarly, patient samples had good correlation with cell line samples (rS=0.82 based on median values; p<0.0001). The cell lines were highly sensitive to ABL1-targeted TKIs, with the exception of the MOLM-1, which showed only modest sensitivity (Figure). The clinically TKI-resistant patient samples were also resistant to BCR-ABL1 inhibitors ex vivo (e.g. T315I sensitive only to ponatinib), further validating the DSRT assay data. Other drugs that exhibited high DSS in the CML cell lines and high sDSS in the BC patient samples included mTORC1/2 inhibitors (e.g. AZD8055, AZD2014, INK128), HSP90 inhibitors (e.g. NVP-AUY922, BIIB021) and a NAMPT inhibitor daporinad. Remarkably, the DSRT results from newly diagnosed CML CP differed clearly from those derived from the cell line and CML BC samples. In the clustering analysis, CML BC and cell line samples clustered together, whereas CML CP samples formed a separate group (Figure). The leukemia-specific scores were generally much lower in CML CP samples, which made identifying novel candidate compounds challenging. Most surprisingly the responses to TKIs were practically nonexistent in CML CP samples. CP TKI insensitivity was further assessed with primary cells sorted in CD34pos and CD34neg fractions. Preliminary results from two patients suggested that CD34pos cells were more sensitive to TKIs when compared to CD34neg or whole mononuclear fraction. CONCLUSIONS DSRT is a powerful platform for identifying novel candidate molecules for CML BC patients. Our results indicate that mTORC1/2 inhibitors (such as AZD8055, or AZD2014), HSP90 (such as NVP-AUY922/luminespib) and NAMPT inhibitors in particular warrant further clinical evaluation. TKI-insensitivity of CML CP samples suggests that the survival of mature myeloid cells in vitro is not BCR-ABL1 dependent and reflects a clear biological difference between CP and BC patient cells. Figure 1 Figure 1. Disclosures Kallioniemi: Medisapiens: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Porkka:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

scholarly journals In Vitro Approach for the Identification of Exceptional Responders in Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2212-2212
Author(s):  
Eric O'Brien ◽  
Brett VanCauwenbergh ◽  
Luke Byerly ◽  
Alexander Merk ◽  
Mayur Sarangdhar ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Drug Sensitivity ◽  
Cell Function ◽  
Ex Vivo ◽  
In Vitro Drug Screening ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Each case of Acute Myeloid Leukemia (AML) represents a unique ecosystem. Despite recent advances in our understanding of the genetic landscape of AML, this information remains insufficient to accurately match patients with targeted therapies. While pediatric and adult AML share phenotypic similarities, pediatric AML represents a genetically distinct disease from adult AML, and will benefit from independent genomic studies and novel therapeutic strategies. Real-time ex-vivo functional screening can identify mechanisms underpinning drug response and diversity between tumors, aiding in patient stratification. We established an in vitro drug screening system that incorporates cytokine signaling to better model inflammation, stem cell function, and niche derived support of leukemic blasts. This approach provided insight into variability between patients who currently would be placed on the same therapeutic regimen. Samples were acquired from 12 pediatric AML patients, after informed consent was obtained. Samples were enriched for blasts, and cultured in the presence of SCF, TPO, FLT3-L, IL-3, and IL-6 (KTF36). A panel of 38 drugs was selected from a larger screen of 1839 compounds done on commercially available hematological malignancy cell lines. Drugs included standard chemotherapy agents used in AML and drugs currently under clinical development. Cells were exposed to drugs for 72hrs. An MTS assay was performed and results reported as % of viable cells remaining, after normalization to vehicle control wells. Targeted DNA NGS sequencing of 406 genes, 31 introns, and RNA sequencing of 265 genes was performed for genetic characterization. In vitro drug screening revealed variations in drug sensitivity between samples and revealed time ex-vivo and cytokine milieu to be important factors affecting response of the same cells to the same drugs. Engraftment of long term cultures into immunodeficient mice produced aggressive disease in all cases, indicating robust support of stem cell function via addition of KTF36 cytokines. When possible, clinical response to therapy was compared with in vitro response to the same drugs. This screening approach highlighted well established agents that showed significant activity in highly refractory disease providing rationale for further clinical trial development. An unsupervised clustering showed drug sensitivity primarily correlated with the presence of MLL-X fusion, NRAS/KRAS and PTPN11 alterations. Linear Regression with interaction effects showed drug sensitivity/resistance to be highly selective for single/signature of specific molecular alterations. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Sequential Combination of Gemtuzumab Ozogamicin and Standard Chemotherapy in Older Patients With Newly Diagnosed Acute Myeloid Leukemia: Results of a Randomized Phase III Trial by the EORTC and GIMEMA Consortium (AML-17)

2013 ◽  
Vol 31 (35) ◽  
pp. 4424-4430 ◽  
Author(s):  
Sergio Amadori ◽  
Stefan Suciu ◽  
Roberto Stasi ◽  
Helmut R. Salih ◽  
Dominik Selleslag ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Gemtuzumab Ozogamicin ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Standard Chemotherapy ◽  
Sequential Combination ◽  
Grade 3 ◽  
Acute Myeloid

Purpose This randomized trial evaluated the efficacy and toxicity of sequential gemtuzumab ozogamicin (GO) and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia (AML). Patients and Methods Patients (n = 472) age 61 to 75 years were randomly assigned to induction chemotherapy with mitoxantrone, cytarabine, and etoposide preceded, or not, by a course of GO (6 mg/m2 on days 1 and 15). In remission, patients received two consolidation courses with or without GO (3 mg/m2 on day 0). The primary end point was overall survival (OS). Results The overall response rate was comparable between the two arms (GO, 45%; no GO, 49%), but induction and 60-day mortality rates were higher in the GO arm (17% v 12% and 22% v 18%, respectively). With median follow-up of 5.2 years, median OS was 7.1 months in the GO arm and 10 months in the no-GO arm (hazard ratio, 1.20; 95% CI, 0.99 to 1.45; P = .07). Other survival end points were similar in both arms. Grade 3 to 4 hematologic and liver toxicities were greater in the GO arm. Treatment with GO provided no benefit in any prognostic subgroup, with the possible exception of patients age < 70 years with secondary AML, but outcomes were significantly worse in the oldest age subgroup because of a higher risk of early mortality. Conclusion As used in this trial, the sequential combination of GO and standard chemotherapy provides no benefit for older patients with AML and is too toxic for those age ≥ 70 years.

scholarly journals Single-agent and combination biologics in acute myeloid leukemia

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 548-556 ◽  
Author(s):  
Guillaume Richard-Carpentier ◽  
Courtney D. DiNardo
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Gemtuzumab Ozogamicin ◽  
Targeted Agents ◽  
Newly Diagnosed ◽  
Rational Drug ◽  
Genomic Characterization ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by recurrent genetic, epigenetic, and metabolic abnormalities. As a result of our increasing knowledge of the underlying biology of AML leading to rational drug development, several new targeted agents have been recently added to our therapeutic arsenal. The BCL2 inhibitor venetoclax in combination with low-dose cytarabine (LDAC) or hypomethylating agents (HMAs) is safe and effective in older patients with newly diagnosed AML ineligible for intensive chemotherapy. Glasdegib, a hedgehog pathway inhibitor, may be used in combination with LDAC for the same indication and improves survival compared with LDAC alone. In newly diagnosed, fit, older patients with therapy-related AML or AML with myelodysplasia-related changes, the liposome-encapsulated combination of daunorubicin and cytarabine (CPX-351) has shown superiority over the 7 + 3 regimen. The presence of an IDH1 or IDH2 mutation can be effectively targeted by ivosidenib or enasidenib, respectively. Gemtuzumab ozogamicin improves event-free survival in CD33+ patients with favorable or intermediate-risk cytogenetics. With new targeted agents available, comprehensive genomic characterization of AML at diagnosis and relapse is increasingly necessary to select optimal treatment. Herein, we review the new single-agent and combination biologics (omitting FLT3 inhibitors, which are discussed separately) and provide recommendations on how to best use and manage patients on these regimens in clinical practice.

Gemtuzumab ozogamicin with or without interleukin 11 in patients 65 years of age or older with untreated acute myeloid leukemia and high-risk myelodysplastic syndrome: comparison with idarubicin plus continuous-infusion, high-dose cytosine arabinoside

Blood ◽  
2002 ◽  
Vol 99 (12) ◽  
pp. 4343-4349 ◽  
Author(s):  
Elihu H. Estey ◽  
Peter F. Thall ◽  
Francis J. Giles ◽  
Xue-Mei Wang ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Cytosine Arabinoside ◽  
Myeloid Leukemia ◽  
Gemtuzumab Ozogamicin ◽  
High Dose ◽  
Newly Diagnosed ◽  
Covariate Effects ◽  
Interleukin 11 ◽  
Acute Myeloid

We investigated treatment with gemtuzumab ozogamicin (GO) in 51 patients aged 65 years or older with newly diagnosed acute myeloid leukemia (AML), refectory anemia (RA) with excess of blasts in transformation, or RA with excess blasts. GO was given in doses of 9 mg/m2 of body-surface area on days 1 and 8 or, therapeutically equivalently, on days 1 and 15, with or without interleukin 11 (IL-11; 15 μg/kg per day on days 3 to 28), with assignment to IL-11 treatment made randomly. Complete remission (CR) rates were 2 of 26 (8%) for GO without IL-11 and 9 of 25 (36%) for GO with IL-11. Regression analyses indicated that IL-11 was independently predictive of CR but not survival. We compared GO with or without IL-11 with idarubicin plus cytosine arabinoside (IA), as previously administered, in similar patients. The CR rate with IA was 15 of 31 (48%), and survival was superior with IA compared with GO with or without IL-11 (P = .03). Besides accounting for possible covariate effects on outcome, we also accounted for possible trial effects (TEs) arising because IA and GO with or without IL-11 were not arms of a randomized trial. Bayesian posterior probabilities that GO with or without IL-11 produced longer survival than IA, after accounting for covariates and TEs, were less than 0.01 in patients with abnormal cytogenetic findings (AC) and less than 0.15 in patients with normal cytogenetic findings (NC). Regarding CR, the analogous probabilities were less than 0.02 for GO without IL-11 (all cytogenetic groups), and for GO with IL-11, less than 0.25 for AC groups and about 0.50 for NC groups. TEs 2 to 5 times the magnitude of those previously observed would be needed to conclude that survival with GO with or without IL-11 is likely longer than with IA. Thus, there is little evidence to suggest that GO with or without IL-11 should be used instead of IA in older patients with newly diagnosed AML or myelodysplastic syndrome.

scholarly journals Gemtuzumab ozogamicin for acute myeloid leukemia

Blood ◽  
2017 ◽  
Vol 130 (22) ◽  
pp. 2373-2376 ◽  
Author(s):  
Frederick R. Appelbaum ◽  
Irwin D. Bernstein
Keyword(s):  
Acute Myeloid Leukemia ◽  
Initial Treatment ◽  
Myeloid Leukemia ◽  
Gemtuzumab Ozogamicin ◽  
Newly Diagnosed ◽  
Antibody Drug Conjugate ◽  
The Us ◽  
Human Use ◽  
Acute Myeloid ◽  
Antibody Drug

Abstract On 1 September 2017, the US Food and Drug Administration (FDA) approved gemtuzumab ozogamicin (GO) for the treatment of adults with newly diagnosed CD33+ acute myeloid leukemia and for patients aged ≥2 years with CD33+ acute myeloid leukemia who have experienced a relapse or who have not responded to initial treatment. This signals a new chapter in the long and unusual story of GO, which was the first antibody–drug conjugate approved for human use by the FDA.

Gemtuzumab ozogamicin in acute myeloid leukemia: a remarkable saga about an active drug

Blood ◽  
2013 ◽  
Vol 121 (24) ◽  
pp. 4838-4841 ◽  
Author(s):  
Jacob M. Rowe ◽  
Bob Löwenberg
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Randomized Study ◽  
Gemtuzumab Ozogamicin ◽  
New Drugs ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Acute Myeloid

Abstract Despite living in an era of unprecedented progress in the understanding of the genetic and molecular biology of acute myeloid leukemia (AML), this has not translated into significant advances in therapy. Never before have so many potential targets been studied. Yet most have not advanced beyond the phase 1 and, occasionally, phase 2 studies. The few ongoing phase 3 studies seem unlikely to have more than a marginal benefit, if at all. Thus, it is not surprising that in past few decades almost no new drugs for AML have received regulatory approval. In 2000, gemtuzumab ozogamicin (GO) was granted accelerated approval by the US Food and Drug Administration based on promising phase 2 data in relapsed older adults with AML. GO held promise as a new agent that also could be efficacious in newly diagnosed AML with acceptable toxicity. Several phase 3 studies were designed to test GO in this setting. The results of a randomized study by the Southwest Oncology Group led in 2010 to the voluntary withdrawal of this agent when improved efficacy could not be demonstrated and toxicity appeared excessive. Since then, 4 randomized studies have been completed that, in aggregate, strongly support the efficacy of this agent in newly diagnosed AML with acceptable toxicity. There is a very plausible explanation for this discrepancy, making a compelling case for reapproval of GO in AML.

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