AJH Educational Material
`
`Meeting Report
`
`ASH 2010 meeting report—Top 10 clinically-oriented abstracts
`in myelodysplastic syndromes (MDS)
`David P. Steensma*
`
`The December 2010 American Society of Hematology (ASH) annual
`meeting in Orlando, Florida included more than 150 abstracts in the
`myelodysplastic syndromes (MDS) category. Thirty-six MDS-focused
`abstracts were presented in 6 oral sessions, and 120 additional
`abstracts were presented in 3 poster sessions. Although the 2010 ASH
`annual meeting included relatively little new MDSclinical trial data,
`with only one large randomized trial presented (the Intergroup E1905
`study), it was an exciting conference from the standpoint of molecular
`discoveries in myeloid neoplasms, as various investigative groups pre-
`sented results offering novel insights into MDS pathobiology, gener-
`ated via high-throughput genomic sequencing and other innovative
`laboratory techniques. Here | summarize and discuss 10 MDS-related
`abstracts of special
`interest, which contain information that informs
`clinical practice. All 10 of these abstracts are published in full in the
`November19, 2010 issue of Blood (volume 116, issue 21) and are iden-
`tified here by their abstract numberandtitle.
`
`Diagnosis and Prognosis
`No. 1
`Discrepancy in diagnosis of myelodysplastic syndrome (MDS) between
`referral and tertiary care centers: experience at MD Anderson cancer center
`(MDACC)(Abstract # 1870).
`Abstract summary
`The MD Anderson cancer center (MDACC) leukemia group reviewed data
`from 915 patients who presented to their institution in Houston, Texas
`between 2005 and 2009 carrying an outside diagnosis of myelodysplastic
`syndrome (MDS). Among these 915 patients, there was discordancein diag-
`nosis between the referring practice and the referral center in 150 patients
`(16%). Sixty of the 150 patients had been diagnosed prior to MDACCrefer-
`ral with forms of MDS without excess marrowblasts [i.e., refractory anemia
`(RA), refractory anemia with ring sideroblasts (RARS), and refractory cyto-
`penias with multilineage dysplasia (RCMD)]; 46 of these 60 were reas-
`sessed at MDACCashaving refractory anemia with excess blasts (RAEB),
`and 6 were rediagnosed as RAEBin transformation (RAEB-t; these patients
`would be classified as having acute myeloid leukemia (AML) by World
`Health Organization (WHO) diagnostic criteria [1]). Fifteen patients diag-
`nosed with RAEBon the outside were assessed as having lower-risk MDS
`at MDACC(i.e., with less than 5% blasts), while 40 patients diagnosed with
`RAEB on the outside were rediagnosed with RAEB-t. A handful of other
`patients labeled as MDS underwentdiagnostic revision to one of the myelo-
`proliferative neoplasms (MPN), MDS/MPN overlap syndromes, AML, or a
`benign disorder or indeterminate condition. Causes of diagnostic discrep-
`ancy included inadequateinitial diagnostic material, differences in sample
`preparation and staining, over-reliance on flow cytometric assessment of
`blast proportion, and interpretive differences. While the changesin diagnosis
`did not have a significant global impact in terms of median survival orclinical
`outcome, new diagnosesdid alter treatment recommendations,clinicaltrial
`eligibility, and prognosis for individual patients.
`Discussion
`MDS remains a challenging diagnosis for clinicians and morphologists
`[2,3]. The MDACC observations concerning a substantial degree of diag-
`nostic discordance between referring practices and a tertiary care referral
`center were first reported in 1998 in a much smaller group of patients
`[4], and are consistent with my own clinical experience, both at Mayo
`Clinic and at
`the Dana-Farber Cancer Institute, where at
`least 15% of
`referred patients undergo diagnostic revision to another disease or reas-
`signment to another risk category within the same disease cluster (unpub-
`lished data).
`
`It is possible that some patients whoare reclassified from lower-risk MDS
`at aninitial local evaluation to higher-risk disease at the time of referral to a
`center like MDACC have experienced rapid disease progression between
`the two assessments, but re-interpretation of the outside slides used for
`original diagnosis is also common [3]. The degree of discordance in MDS
`diagnosis between different tertiary centers is unknown, but the extent of
`disagreement among expert hematopathologists in workshops sponsored by
`the MDS Foundation and other groups suggests that
`lack of consensus
`would be widespread[5].
`These results underscore the complexity of clinicopathologic diagnosis of
`MDS,the value of expert morphologists, and thelimitations of current morphol-
`ogy-based diseaseclassifications. We need better molecular diagnostic tools
`for diagnosis and sub-classification of chronic myeloid disorders. In the case of
`MDS,thereis a particular need with respect to better assessmentof patients
`with idiopathic cytopenia(s) of undetermined significance (ICUS), as patients
`with ICUS may have MDSoranotherclonal neoplasm limiting life expectancy,
`but mayalso have a reactive condition thatis unlikely to progress [6,7].
`No. 2
`Point mutations in myelodysplastic syndromes are associated withclinical
`features and are independentpredictors of overall survival (Abstract # 300).
`Abstract summary
`Bejar et al.
`in the Ebert laboratory in Boston assessed marrow samples
`from a cohort of 439 patients (samples were obtained from MDACC and
`from Azra Raza’s tissue bank; corresponding buccal samples were available
`for 219 patients) for mutations in a series of cancer-associated genes,
`including a comprehensive assessment of known MDS-associated muta-
`tions. The investigators began by screening 191 samples using an OncoMap
`platform, which allowed assessment for the presence of 953 described
`oncogenic mutations in 111 cancer-related genes. Genes with identified
`mutations were then examined in a larger cohort of 439 patient samples.
`The investigators found somatic mutations in six genes,
`including three
`patients with activating mutations of GNAS, which wasnotpreviously recog-
`nized as an MDS-associated gene. The other somatic mutations detected
`using OncoMap(e.g., KRAS, NRAS, and JAK2) are well-described in MDS
`[8]. Germline mutations or polymorphisms were detected in MET, EGFR,
`and CDH1 (<1% of cases for each) and were not evaluated further.
`Using the full cohort of 439 patients, the investigators pyrosequenced or
`Sanger sequenceda series of other genes previously associated with hema-
`tological malignancies,
`including (listed together with the six OncoMap
`genes in the order of the frequency in which mutations were detected)
`TET2, ASXL1, RUNX1, TP53, EZH2, NRAS, JAK2, ETV6, CBL,
`IDH2,
`NPM1,
`IDH1, KRAS, GNAS, PTPN11, BRAF, PTEN, and CDKNZ2A.Bejar
`et al. then correlated mutations in these 18 genes with clinical features and
`overall survival.
`The investigators found that 51% of samples had at least one point muta-
`tion. The most frequently mutated gene was TET2 (in 21% of samples,simi-
`lar to the frequency reported in the populations evaluated by the Nijmegen
`and Paris laboratories where this mutation wasfirst described [9,10]), fol-
`lowed by ASXL1 (14%), RUNX1 (9%), and TP53 (8%). TP53 mutations
`were uSually found in isolation, and were associated with a complex karyo-
`type and with abnormalities of chromosome 17 where 7TP53 is physically
`localized. TET2 mutations,
`in contrast, were regularly detected in associa-
`tion with other gene mutations, and were overrepresented in cases with nor-
`mal cytogenetics. A lower platelet count was associated with mutations in
`RUNX1, NRAS, and TP53. The association of
`thrombocytopenia with
`somatic mutations RUNX1is interesting, given the known association of
`germline RUNX1 mutations with familial platelet disorder associated with
`predisposition to AML (FPD-AML, Online Mendelian
`Inheritance
`in
`Man #601399) [11]. Mutations in CBL, RUNX1, NRAS, and TP53 were
`
`© 2011 Wiley-Liss,Inc.
`American Journal of Hematology
`
`CELGENE 2120
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`

`

`risk group, 22% patients in the intermediate-2 risk group, and 16% in the high
`risk group; for 11% of patients, data were incomplete and so the patients
`could not be classified. The median overall survival from the time of diagnosis
`was 92 months, 49 months, 26 months, and 15 monthsfor the low, intermedi-
`ate-1, intermediate-2, and high risk MDACC model groups, respectively. The
`median survival for the four risk groups was 58 months, 28 months, 15
`months, and 8 months from the time of presentation to Moffitt Cancer Center.
`AML transformation occurred in 5.9% of the low risk group compared to
`16.8% of intermediate-1, 36.3% of intermediate-2, and 50.4% of high risk
`MDACCrisk model-classified patients.
`Discussion
`The numerouslimitations of the 1997 IPSS risk model for MDSare well
`recognized and are reviewed elsewhere [17]. The WHOclassification-based
`prognostic scoring system (WPSS)proposed by Malcovati et al. in 2007 [18]
`and revised in 2009 [19] and the MDACC risk model appear to offer some
`advantages over the IPSS. At the 2009 ASH annual meeting, Hugoetal.
`presented data comparing these three prognostic scoring systems(i.e., the
`IPSS, WPSS,and the MDACCrisk model) in a group of 1,503 patients with
`MDSevaluated at Mayo Clinic [20]. The Mayoinvestigators confirmed the
`validity of all three systems, but found that the MDACCrisk modelclassified
`the broadest numberof patients,
`including patients with secondary, treat-
`ment-related MDS [20]. It is striking how similar the patient median survival
`times from the time of tertiary center referral are among the Mayo data, the
`Moffitt Cancer Center data, and the original 2008 paper presenting the
`MDACCrisk model, with the lowest risk group in all three studies having a
`median survival of between 51 and 58 months and the highest risk group
`having a survival of between 4 and 8 months. Such comparisons from the
`time of tertiary referral center evaluation are valid because, unlike the IPSS,
`the MDACCrisk model is dynamic and can be applied at any timein the dis-
`ease course.
`
`meeting report
`In a multivariable model,
`associated with a higher marrow blast proportion.
`there were five genes that were associated with poorer overall survival, inde-
`pendent of international prognostic scoring system (IPSS [12]) risk group,
`age, and sex: 7P53, EZH2, ETV6, RUNX1, and ASXL1. Despite a higher
`prevalence in IPSS lower-risk cases, mutations of EZH2 were associated
`with a high hazard ratio for death,
`identifying a group in which clinical risk
`may be underestimated using the IPSS alone. Overall, 31.2% of patient
`samples tested carried mutations in one or more of the five prognostic
`genes.In contrast, none of the other detected gene mutations were associ-
`ated with better survival in an IPSS-independentfashion.
`Discussion
`During the last 2 years, various investigative groups in Europe and North
`America have described a series of new MDS-associated gene mutations
`[13]. SNP array findings led to the initial discovery of several of these,
`including EZH2 and TET2 mutations, which are associated with loss of het-
`erozygosity at chromosomal
`loci 7q35 and 4q24,
`respectively [9,10,14].
`There are now more than 20 different genes that have been described as
`somatically mutated in association with MDS, but most are detected at low
`frequency (<5% of cases), which underscores the heterogeneity of this
`group of disorders. TET2 is the most commonly described mutation thus far
`in MDS, yet 75-80% of patients do not have a TET2 mutation, and further-
`more, 49% of patients in the Bejar et al. series had no detectable mutations
`at all
`in any of the 18 tested genes. Clearly, there will be many additional
`mutation discoveries in the years to come, which will hopefully be accompa-
`nied by a better understanding of how the known mutations cooperate with
`one another and with the larger-scale changesresulting from chromosomal
`rearrangements.
`If we consider these 20+ MDS-associated genes globally, some patterns
`begin to emerge. For instance, at least five of the mutated genes detected
`in this series appear to be involved in epigenetic regulation of gene expres-
`The MDACCrisk modeloffers the unique advantagethatit is sensitive to
`sion: TET2, EZH2, ASXL1,
`IDH1, and IDH2.
`|n addition,
`two recurrently
`the degree of peripheral blood cytopenias. Several studies presented at the
`mutated genes not
`identified as somatic mutations in this study are also
`2010 ASH annual meeting again highlighted the IPSS-independent adverse
`involved in regulation of DNA or histone methylation: mutations in KDM6A
`predictive value of severe thrombocytopenia (ASH 2010 Abstracts #4021 and
`(UTX), encoding a histone H3K27 demethylase, were detected in 6% of 63
`#2905), an observation that has been published by several groups [21,22].
`chronic myelomonocytic leukemia (CMML) samples by Jankowska and cow-
`The IPSSis currently under revision using international multi-center data
`orkers in Jaroslaw Maciejewski’s laboratory at Cleveland Clinic (ASH 2010
`from more than 10,000 patients, and a draft versionwill likely be presented at
`Abstract #611), and Walter and coworkers at Washington University in St.
`the 11th International Symposium on MDSin Edinburgh, Scotland in May
`Louis described mutations in DNMT3A (encoding DNA methyltransferase
`2011 (http://www.kenes.com/mds/). Although details of the draft model have
`3A) for the first time in MDS,in 12 out of 150 patients assayed (8%) (ASH
`not yet beenfinalized,it is anticipated that the new IPSSwill be more sensi-
`2010 Abstract #299).
`In a recent New England Journal of Medicine paper
`tive to degree of cytopenias and will incorporate a broader range of cytoge-
`published by Ley et al.
`(from the sameinstitution as Matthew Walter),
`netic abnormalities, as data continue to emerge on the importance of various
`DNMTS3A mutations were associated with adverse prognosis in AML, were
`recurrent but uncommonkaryotypesnotincludedin the original IPSS [23].
`detected primarily in patients with intermediate-risk cytogenetics, and were
`No. 4
`not found in patients with core binding factor leukemias [15].
`Comorbidities and overall survival in myelodysplastic syndromes (MDS):
`Soon,clinical laboratory testing for these mutations will be widely available
`development of a prognostic model incorporating IPSS and age with ACE-
`and will inform how physicians assess and treat patients with MDS. Begin-
`27 comorbidity index (Abstract #605).
`ning in early 2011, for example, Dana-Farber CancerInstitute will perform
`custom OncoMaptesting on all new patients who undergo a biopsy at the
`Abstract summary
`institution for any neoplasm, including hematological neoplasms, and other
`To better understand how comorbidities influence outcomes in patients
`institutions are developing similar initiatives. This 500+ gene assay will
`ini-
`with MDS, the MDACC leukemia group reviewed medical records of 600
`tially not be charged to patients or their insurance companies, butis part of
`consecutive patients with MDS whopresentedto their center between Janu-
`a broad-based personalized medicine effort funded by philanthropic dona-
`ary 2002 and June 2004. The severity of comorbid conditions was assessed
`tions.
`In addition to prognostic value, several of these mutations may also
`in this cohort using the Adult Comorbidity Evaluation-27 (ACE-27) tool, a
`alter the effectiveness of treatment with specific drugs, such as the hypome-
`well-validated 27-item comorbidity index that has been usedin patients with
`thylating agents in MDS (see No. 6 below), or might promptrationaloff-label
`cancerfor more than 10 years [24]. While 28.8% of the patients had no sig-
`use of compoundsinitially developed for other conditions.
`nificant comorbidities, an ACE-27 comorbidity score of “mild” was assigned
`No. 3
`to 42.3% of patients, “moderate” to 21.2% of patients, and “severe” to
`13.7% of patients. The overall median survival
`in this group was 18.6
`Validation of the newly proposed MD Anderson prognostic risk model for
`months, and median survival stratified according to ACE-27 results was
`patients with myelodysplastic syndromes(Abstract # 444).
`31.8, 16.8, 15.2, and 9.7 months for no, mild, moderate, and severe comor-
`Abstract summary
`bidity score, respectively, (P < 0.0001). The investigators developedafinal
`Komrokji presented data from 844 patients with MDS evaluated at the H.
`prognostic model
`incorporating comorbidity scores with patient age and
`Lee Moffitt Cancer Center in Tampa, Florida between January 2001 and
`IPSS risk group (Table 1).
`December2009; the investigators assessed the validity of the MDACC risk
`Discussion
`model for MDS published by Kantarjian et al. in 2008 [16]. Komrokji et al. con-
`firmed the prognostic value of the MDACCrisk model, including the model's
`Patients with MDSin the United States (US) are diagnosed at a median
`ability to distinguish subsets of patients with higher and lowerrisk within IPSS
`age of ~71 years [25]. As a result of their advanced age, patients with MDS
`risk groups. Using the MDACCrisk model, 20% of the 844 Moffitt patients
`frequently suffer from other nonhematologic medical conditions, which may
`were classified in the low risk group, 30% of patients in the intermediate-1
`alter the patients’ symptoms or expected survival, and mayalso influence
`
`386
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`American Journal of Hematology
`
`

`

`TABLE |. Proposed IPSS-Based Prognostic Scoring System Incorporating
`ACE-27 Comorbidity Index
`
`
`
`Risk factor Points(Sum, 0-8)
`
`Age: >65 years
`IPSS risk group: Intermediate-2
`IPSS risk group: High
`ACE-27 score: Mild or moderate
`ACE-27 score: Severe
`
`o-onnm
`
`
`
` Risk group Mediansurvival (months)
`
`Low (0-1 points)
`Intermediate (2-4 points)
`High (5-8 points)
`
`43
`23
`9
`
`the success of treatments directed at the MDS [26-28]. Comorbidities are
`not included in any of the prognostic scoring systems or risk models for
`MDSdescribed above. Investigators are now paying more attention to the
`importance of comorbidities, since serious diseases like MDS cannot be
`considered in isolation from patients’ other medical problems. To use an
`extreme example, a patient with one of the lowest-risk forms of MDS(e.g.,
`RARSwith a normal karyotype) who has advanced pancreas cancer or New
`York Heart Association Class 4 congestive heart failure has a life expect-
`ancy of only a few months, but that patient’s clinical course will be deter-
`mined by the comorbid condition rather than by the bone marrow disorder.
`Therefore, when developing a treatment plan, one must considernot just the
`bone marrow status but the whole patient.
`It is not yet clear which of the
`several
`tools now available for measuring comorbidities (e.g., ACE-27,
`Charlson Comorbidity Index, Hematopoietic Stem-Cell Transplantation-Spe-
`cific Comorbidity Index) performs the best—several research groups have
`recently published comorbidity assessments in MDS populations using tools
`other than ACE-27 [26-28]—butit seems apparent that further refinement of
`comorbidity assessment in MDSwill help hematologists estimate patient out-
`comes more accurately.
`No. 5
`Highly transfused MDS patients often have cardiac iron overload, as
`shown by MRI assessment(Abstract #2906).
`Abstract summary
`(GFM) co-operative
`The Groupe Francophone des Myélodysplasies
`group prospectively evaluated 73 patients with MDS who were chronically
`receiving red blood cell transfusions from four centers using cardiac T2*
`MRI methods, and also assessed those patients’ cardiac function by rou-
`tine echocardiography. Patients in this study had a median serum ferritin
`level of 1,750 ng mL~', and 54 of 73 (74%) of patients were receiving iron
`chelation therapy. Patients were,
`in general, heavily transfused, having
`received a median number of 68 U of red blood cells (range, 5-574 U).
`Evidence of cardiac iron overload, defined by MRI T2* time less than or
`equal to 20 ms, waspresent in 14 of 73 patients (19%).
`In 13 of 59 (22%)
`patients who underwent echocardiography, the left ventricular ejection frac-
`tion (LVEF) was below normal. However, while there was a correlation
`between cardiac T2* time and the number of red cell units transfused,
`there was no correlation between cardiac T2* and serum ferritin level or
`hepatic liver iron correlation, nor was there a correlation between LVEF and
`cardiac T2* result.
`Discussion
`The clinical importance of iron overload in MDS andthe risk-benefit bal-
`ance of iron chelation therapy are incompletely understood and controversial
`topics at present [29,30]. There have been at least three prior publications
`assessing cardiac iron overload measured noninvasively using newer T2*/
`R2* MRI techniquesin heavily transfused MDS populations, and these three
`studies all suggested that cardiac iron overload is infrequent and is less
`commonthan hepatic iron overload in heavily transfused patients with MDS
`[31-33]. The new GFM cardiac MRI study reported at ASH 2010 included a
`cohort of patients with a high median numberofred cell units transfused (68
`U), but so did the three previous studies: a median of 63 U in the 11-patient
`United Kingdom study by Chackoetal., 90 U in the 10-patient Israeli study
`by Konenetal., and 36 U in the 11-MDS-patient Chinese study by Auet al.
`[31-33] It is notable that serum ferritin did not predict cardiac iron overload
`
`meeting report
`in any of these studies, which emphasizes the poor test characteristics of
`serum ferritin measurement. Most of the existing expert consensus guide-
`lines for iron chelation therapy in MDS, such as those of the National Com-
`prehensive Cancer Network [34] or the MDS Foundation [35], suggest that
`clinicians should initiate chelation treatment on the basis of serum ferritin
`measurements and numberof red cell units transfused, but this recommen-
`dation is highly problematic, as serum ferritin is subject to many influences
`including inflammatory state, and maynottruly reflect the degree of organ
`iron deposition or iron-related clinical risk.
`Some patients who do not have excessive tissue iron loading mightstill
`be at risk for complications related to reactive nontransferrin-bound iron spe-
`cies,
`including labile plasma iron or labile cellular iron molecules that are
`highly redox active and could contribute to genomic instability or risk of
`infection with siderophoric microorganisms [36]. This hypothesis remains
`unproven. The ongoing industry-sponsored TELESTOclinicaltrial, which will
`enroll more than 600 patients with lower-risk MDS whoarereceiving red cell
`transfusions and have a serumferritin >1,000 ng mL”, andwill treat these
`patients with either deferasirox or placebo for up to 5 years, should help to
`better define the risk-benefit balance of iron chelation therapy in the MDS
`population,
`including whether this intervention has any effect on morbidity
`and mortality.
`TreatmentIncluding Biomarkers of Response
`No. 6
`Presence of TET2 mutations predicts a higher response rate to Azaciti-
`dine in MDS and AML Post MDS(Abstract # 439).
`Abstract summary
`The highly productive GFM MDS group assessed 103 patients with MDS,
`AML, or CMML who hadreceivedat least one cycle of azacitidine and who
`either had a bone marrow evaluation after at least four cycles of treatment,
`or died or progressed before completion of four cycles (the latter patients
`were considered treatment failures). Azacitidine responses were scored
`according to standardized International Working Group (IWG) 2006 MDS
`treatment responsecriteria [37]. The median number of azacitidine cycles
`administered was 7. TET2 mutations were found in 17 (17%) of the 103
`patients. Patients with TET2-mutant MDS had less frequent unfavorable
`cytogenetics than TET2 wild-type (6% vs. 37%, respectively). Notably, the
`overall response rate washigherin patients with TET2 mutations, with 11 of
`17 complete responses (CRs) or marrow CRs (mCRs) in this group (65%)
`versus 26 of 86 CRs/mCRs (30%) among TET2 wild-type patients (P =
`0.01). The treatment response duration wassimilar in the two groups.If one
`includes
`stable marrow disease with hematologic improvement as a
`response, then 14 of 17 patients (82%) with TET2 mutations responded to
`azacitidine versus 39 of 86 (45%) TET2 wild-type patients (P = 0.007).
`Discussion
`At present, despite several earlier proposals that could not be confirmed
`(such as monosomy 7 karyotype [38]) and extensive efforts at identifying a
`predictive global methylation profile [39], there is as yet no biomarker that
`can help clinicians predict MDS patients’ response to hypomethylating agent
`therapy. Although the GFMfindings of TET2 mutation status predictingclini-
`cal response to azacitidine are not as dramatic in terms of the magnitude of
`responsedifference as is seen with KRAS mutation status and cetuximabin
`colorectal cancer [40] or gefitinib and EGFR mutation status in non-small
`cell
`lung cancer [41],
`it is notable that overall azacitidine response rate in
`this cohort was nearly twice as high among patients with TET2 mutations
`compared to those without mutations. This is a mechanistically plausible
`association because, as detailed in ASH annual meeting Abstract #1 (in the
`Plenary Scientific Session), the TET2 protein is involved in converting 5-
`methylcytosine to 5-hydroxymethylcytosine in DNA [42], a process that has
`substantial implications for epigenetic regulation in myeloid malignancies.If
`azacitidine and decitabine indeed work via epigenetic mechanisms,pretreat-
`mentepigenetic patterns may influenceclinical response to these drugs.
`TET2 mutation testing is expected to be available clinically in early 2011.
`However, the GFM cohort reported here wasrelatively small, and the result
`needs to be confirmed by others. There was also an ASH 2010 annual
`meeting abstract by Kulasekararaj and coworkers from Ghulam Mufti’s group
`in the United Kingdom (Abstract #125), which hypothesized that EZH2
`mutations (the EZH2 protein also affects epigenetic gene regulation, spe-
`cifically by catalyzing H3K27 trimethylation) may predict
`response to
`
`American Journal of Hematology
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`387
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`

`meeting report
`potential explanation is that entinostat may have been the wrong HDAC
`In that series, seven of eight patients (88%)
`hypomethylating agent therapy.
`inhibitor to use, particularly becauseit is a potent inhibitor of the cell cycle,
`with detectable EZH2 mutations responded to azacitidine therapy. Further
`and azacitidine’s clinical activity appears to be cell-cycle dependent. How-
`assessmentusing large cohorts of patients, e.g., from prior multicenterclini-
`cal trials of azacitidine or decitabine, will be of considerable interest.
`ever, it is possible that HDACinhibitors as a class will not be usefulclinically
`in patients with MDS. HDACinhibitors seem to have only modestactivity as
`No. 7
`single agents in MDS [44].
`Prolonged administration of Azacitidine with or without entinostat
`The investigators’ comparison of response rates in E1905 to historical
`increases rate of hematologic normalization for myelodysplastic syndrome
`results from CALGB 9221 is of uncertain validity. Patients enrolled in the
`and acute myeloid leukemia with myelodysplasia-related changes:results of
`E1905 study might have beenbetter selected for potential response to hypo-
`the US leukemia intergroup trial E1905 (Abstract 601).
`methylating agent therapy than participants in CALGB 9221, given the dec-
`Abstract summary
`adeofclinical experience with azacitidine between the twotrials. In addition,
`The current standard of care for disease-modifying treatment of higher-
`the median numberof azacitidine cycles that patients enrolled in E1905
`risk patients with MDS is a hypomethylating agent, with azacitidine now the
`received (six cycles) is more than was administered in the CALGB study
`preferred drug because of data from the AZA-001clinicaltrial indicating that
`(<4 cycles), and there may be a correlation between number of hypomethy-
`azacitidine treatment improves survival compared to supportive care alone
`lating agent cycles administered and response rate or depth of response
`[34,43]. However, up to one-half of patients with MDS do not receive any
`[51]. Further exploration of different doses and schedules of hypomethylating
`benefit from azacitidine therapy, and the median response duration to hypo-
`agents, alone and in combination with other HDACinhibitors, is ongoing in
`methylating agent treatment is less than 2 years, so new approaches are
`patients with MDS.
`needed to build on azacitidine’s encouraging but modest success.
`In vitro,
`No. 8
`hypomethylating agents and histone deacetylase (HDAC)
`inhibitors have
`Evaluation of oral Azacitidine using extended treatment schedule: a Phase
`synergy with respect to gene expression and cellular effects [44]. Therefore,
`| study (Abstract # 603).
`the Eastern Cooperative Oncology Group (ECOG), together with other US
`Abstract summary
`leukemia co-operative groups, undertook a randomizedclinical trial, ECOG-
`Garcia-Manero from MDACCreported results from an ongoing multi-cen-
`led Intergroup trial E1905, to assess whether combining azacitadine with
`ter Phase | exploration of extended oral azacitidine therapy in patients with
`entinostat (formerly MS-275, SNDX-275), an orally bioavailable HDACinhibi-
`MDS.Enrolled patients had to be cytopenic, and could not have received
`tor, would be moreeffective than azacitidine alone.
`prior azanucleoside therapy. Patients received oral azacitidine either once or
`The E1905 study used a 10-day azacitidine schedule, 50 mg m~? per day
`twice daily on 14 or 21-day schedules,at total daily doses of either 300 or
`subcutaneously for 10 out of every 28 days, which had been shownto be
`400 mgperday. Data on 15 patients with MDSwere presented at the meet-
`effective in MDSin a Phase| trial combining azacitidine and sodium phenyl-
`ing. Using IWG 2006criteria, two patients had a CR andsix patients experi-
`butyrate conducted by Gore et al. at Johns Hopkins University in Baltimore,
`enced hematologic improvement. When assessing the pharmacokinetics of
`Maryland [45].
`In the E1905 combination therapy randomization group, 10-
`the 300 mg orally once daily every 21 days, the cumulative exposure was
`day azacitidine treatment was combined with entinostat, 4 mg m~? per day
`~58% of the drug exposure that would be expected with the subcutaneous
`orally, administered on Days 3 and 10.
`schedule. The extension phase will be a PhaseII study of 21-day dosing.
`The E1905 study randomized 150 patients, of whom 136 were botheligi-
`The oral azacitidine was quite well tolerated overall, with febrile neutropenia
`ble and evaluable. This included 88 patients with MDS, 5 with CMML, and
`being the most commonadverseeffect in the daily dosing schedules;febrile
`43 with AML with trilineage dysplasia (eligible AML patients were required to
`neutropenia appeared more commonin the 21-day cohort compared to the
`have a white blood count WBC <30,000/mm*, measured on two occasions
`14-day cohort.
`4 weeksapart). Among patients with MDS, 72% were in higher-risk IPSS
`Discussion
`categories. The primary endpoint was trilineage hematologic improvement,
`As stated above, azacitidine is currently the standard of care for higher
`including either CR, partial response (PR), or hematologic improvementin
`risk patients with myelodysplastic syndrome, but parenteral administration is
`all three lineages, assessed using IWG 2,000 responsecriteria [46].
`inconvenient for some patients, especially patients who must travel from a
`There was nodifference in the overall trilineage hematological response
`distance toaclinical facility to receive azacitidine multiple consecutive days
`rate between arms: 31% in the azacitidine monotherapy arm, versus 24% in
`each month. Oral azacitidine might offer some advantages for
`those
`the azacitidine plus entinostat combination therapy arm. Non-trilineage hem-
`patients, and oral azacitidine will also allow exploration of longer-term, low-
`atologic improvement was seen in 12% of patients in the monotherapy arm
`dose schedules that more closely mimic predicted optimal dosing based on
`and 19% in the combination arm, so the total response rate was 43% vs.
`in vitro results, but which are not currently feasible in the US with aninject-
`44%. As expected,
`there was more thrombocytopenia and fatigue in the
`able agent such as azacitidine due to Medicare regulations preventing self-
`combination therapy arm;
`thrombocytopenia and fatigue are common
`administration of parenteral therapy. Although the oral azacitidine data pre-
`adverse effects in HDAC inhibitor trials. The investigators compared the
`sented by Garcia-Manero etal. are preliminary, this new formulation is wor-
`hematologic normalization rate in E1905 to the Cancer and Leukemia Group
`thy of further exploration. In early studies of oral azacitidine, there was wide
`B (CALGB) 9221 study conducted during the 1990s [