TheOncologist®
`FDA Commentary
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`FDA Drug Approval Summary: Azacitidine (5-azacytidine, Vidaza™)
`for Injectable Suspension
`
`EDVARDAS KAMINSKAS, ANN T. FARRELL, YONG-CHENG WANG, RAJESHWARI SRIDHARA,
`RICHARD PAZDUR
`
`Division of Oncology Drug Products, Center for Drug Evaluation and Research,
`U.S. Food and Drug Administration, Rockville, Maryland, USA
`
`Key Words. Azacitidine · Vidaza™ · Myelodysplastic syndromes · Refractory Anemia · Leukemia
`
`LEARNING OBJECTIVES
`After completing this course, the reader will be able to:
`
`1. Describe indication and rationale for using azacitidine.
`
`2. Discuss the relative effectiveness of azacitidine.
`
`3. Identify the limitations of treatment with azacitidine.
`
`CMECME
`
`Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
`
`ABSTRACT
`On May 19, 2004, azacitidine (5-azacytidine; Vidaza™;
`Pharmion Corporation, Boulder, CO, http://www.
`pharmion.com) for injectable suspension received regu-
`lar approval by the U.S. Food and Drug Administration
`(FDA) for the treatment of all subtypes of myelodys-
`plastic syndrome (MDS). This report summarizes the
`basis for this approval. Effectiveness was demonstrated
`in one randomized, controlled trial comparing azaciti-
`dine administered s.c. with best supportive care (obser-
`vation group) and in two single-arm studies, one in
`which azacitidine was administered s.c. and in the other
`in which it was administered i.v. The dose of azacitidine,
`75 mg/m2/day for 7 days every 28 days, was the same in
`all three studies. In the randomized trial, study partici-
`pants were well matched with respect to age, sex, race,
`
`performance status, MDS subtype, and use of transfu-
`sion during the 3 months before study entry. Patients in
`the observation arm were permitted by protocol to cross
`over to azacitidine treatment if their disease progressed
`according to prespecified criteria. During the course of
`the study, more than half of the patients in the observa-
`tion arm did cross over to the azacitidine treatment
`arm. The primary efficacy end point was the overall
`response rate. Response consisted of complete or partial
`normalization of blood cell counts and of bone marrow
`morphology. The response rate in the azacitidine arm
`was about 16%; there were no responses in the obser-
`vation arm. The response rates in the two single-arm
`studies were similar (13% and 19%). The responses
`were sustained, with median durations of 11 months
`
`Correspondence: Edvardas Kaminskas, M.D., U.S. Food and Drug Administration, 5600 Fishers Lane, HFD-150, Rockville,
`Maryland 20857, USA. Telephone: 301-594-5753; Fax: 301-594-0499; e-mail: kaminskase@cder.fda.gov Received July
`26, 2004; accepted for publication November 18, 2004. ©AlphaMed Press 1083-7159/2005/$12.00/0
`CELGENE 2018
`APOTEX v. CELGENE
`IPR2023-00512
`
`The Oncologist 2005;10:176–182 www.TheOncologist.com
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`177
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`Azacitidine for MDS
`
`and 17 months respectively. Responding patients who
`were transfusion dependent at study entry lost the need
`for transfusions. In addition, about 19% of patients had
`less than partial responses (termed improvement), and
`two-thirds of them became transfusion independent.
`Common adverse events associated with azacitidine
`treatment were gastrointestinal (nausea, vomiting,
`diarrhea, constipation, and anorexia), hematologic
`(neutropenia, thrombocytopenia), fevers, rigors, ecchy-
`moses, petechiae, injection site events, arthralgia,
`headache, and dizziness. Liver function abnormalities
`
`occurred in 16% of patients with intercurrent hepato-
`biliary disorders and in two patients with previously
`diagnosed liver cirrhosis. Renal failure occurred in
`patients during sepsis and hypotension. There were no
`deaths attributed to azacitidine. Azacitidine, the first
`drug approved by the U.S. FDA for MDS, has a favor-
`able safety profile and provides a clinical benefit of
`eliminating transfusion dependence and complete or
`partial normalization of blood counts and bone marrow
`blast percentages in responding patients. The Oncologist
`2005;10:176–182
`
`INTRODUCTION
`Azacitidine (5-azacytidine, Vidaza™; Pharmion Corporation,
`Boulder, CO, http://www.pharmion.com) is an analogue of
`the naturally occurring pyrimidine nucleoside cytidine
`(Fig. 1). Azacitidine is thought to have two main mecha-
`nisms of antineoplastic action—cytotoxicity, resulting from
`incorporation into RNA and DNA, and DNA hypomethyla-
`tion, restoring normal growth control and differentiation in
`hematopoietic cells [1]. Induction of DNA hypomethylation
`appears to require lower azacitidine doses than does cyto-
`toxicity, as the concentration of azacitidine required for
`maximum inhibition of DNA methylation in vitro does not
`suppress DNA synthesis [2].
`Upon uptake by cells, azacitidine is phosphorylated to
`5-azacytidine monophosphate by uridine-cytidine kinase and
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`then to diphosphate and triphosphate by pyrimidine mono-
`phosphate and diphosphate kinases, respectively. 5-Azaciti-
`dine triphosphate is incorporated into RNA, disrupting
`nuclear and cytoplasmic RNA metabolism and inhibiting pro-
`tein synthesis [2]. 5-Azacytidine diphosphate is reduced by
`ribonucleotide reductase to 5-aza-deoxycytidine diphosphate,
`which is then phosphorylated by nucleoside diphosphate
`kinases to 5-azadeoxycitidine triphosphate, which is incorpo-
`rated into DNA. As a result, DNA synthesis is inhibited.
`Azacitidine is most toxic during the S-phase of the cell cycle,
`but the predominant mechanism of cytotoxicity has not been
`established [3, 4].
`Azacitidine inhibits methylation of replicating DNA by
`stoichiometric binding with DNA methyltransferase 1,
`resulting in DNA hypomethylation [1, 5]. DNA hypermethy-
`lation at the CpG islands has been described in myelodys-
`plastic syndrome (MDS) [6], acute myelogenous leukemia
`(AML) [7], and other malignancies.
`Azacitidine is rapidly absorbed after s.c. administration.
`Maximum plasma concentrations occur 30 minutes after s.c.
`administration and 11 minutes after a 10-minute i.v. infusion.
`The mean plasma concentration following i.v. infusion is
`approximately fourfold higher than that following s.c.
`administration. The bioavailability after s.c. administration is
`89% of that after i.v. administration, as determined by the
`area under the concentration-time curve (AUC). The plasma
`half-life is approximately 22 minutes after i.v. infusion and
`about 41 minutes after s.c. administration. The drug is widely
`distributed in tissues; the mean volume of distribution after
`i.v. administration is about 76 liters, which is greater than the
`total body water volume (42 liters).
`Azacitidine undergoes spontaneous hydrolysis in aqueous
`solutions, as well as rapid deamination by cytidine deaminase
`and subsequent degradation [8]. Human pharmacokinetic data
`are derived from studies of [14C]-labeled drug, not from deter-
`minations of azacitidine metabolite concentrations. Urinary
`excretion is the main elimination route of azacitidine and its
`metabolites (85% after i.v. dosing and about 50% after s.c.
`administration). Less than 1% of the radiolabeled azacitidine
`
`NH2
`
`N
`
`y
`(
`
`N
`
`N
`
`HO
`
`O
`
`O
`
`OH
`
`OH
`
`Figure 1. Molecular structure of azacitidine (5-azacytidine).
`
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`Kaminskas, Farrell, Wang et al.
`
`178
`
`clinical infections with neutropenia requiring antibiotics) at
`prespecified crossover time points (after two or four 28-day
`cycles). About 55% of patients in the observation arm crossed
`over to the azacitidine treatment arm.
`Patient demographics and disease characteristics at study
`entry are summarized in Table 1. Patients in the azacitidine
`and the observation arms were well matched by gender, race,
`age, MDS subtype, and transfusion history. The study popu-
`lation was typical of MDS patients. The male:female patient
`
`Table 1. Patient demographics and disease characteristics
`
`Characteristic
`
`Azacitidine
`n = 99 (%)
`
`Observation
`n = 92 (%)
`
`36 (36)
`39 (39)
`24 (24)
`
`72 (73)
`27 (27)
`
`93 (94)
`1 (1)
`2 (2)
`3 (3)
`
`Age group
`18–64 years
`65–74 years
`75 years and older
`Sex
`Male
`Female
`Race
`Caucasian
`African American
`Asian
`Hispanic
`Performance status
`26 (28)
`35 (35)
`0 Normal
`39 (42)
`34 (34)
`1 Fatigue
`6 (7)
`8 (8)
`2 Impaired
`0
`1 (1)
`3 Bed rest
`21 (23)
`21 (21)
`4 Not recorded
`MDS subtypes and AML as adjudicated by the central laboratory
`RA
`21 (21)
`18 (20)
`RARS
`6 (6)
`5 (5)
`RAEB
`38 (38)
`39 (42)
`RAEB-T
`16 (16)
`14 (15)
`CMMoL
`8 (8)
`7 (8)
`AML
`10 (10)
`9 (10)
`Use of transfusion products during 3 months before study entry
`Any product
`70 (71)
`59 (64)
`RBC
`66 (67)
`55 (60)
`Platelets
`15 (15)
`12 (13)
`Plasma/hetastarch
`1 (1)
`1 (1)
`Unknown
`2 (2)
`2 (2)
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`33 (36)
`33 (36)
`25 (27)
`
`60 (65)
`32 (35)
`
`85 (92)
`1 (1)
`1 (1)
`5 (5)
`
`Abbreviations: AML = acute myelogenous leukemia; CMMoL =
`chronic myelomonocytic leukemia; MDS = myelodysplastic syndrome;
`RA = refractory anemia; RAEB = refractory anemia with excess blasts;
`RAEB-T = refractory anemia with excess blasts in transformation;
`RARS = refractory anemia with ringed sideroblasts.
`
`dose is excreted in the feces. The mean elimination half-life
`of radiolabeled azacitidine is about 4 hours after either i.v. or
`s.c. administration. Azacitidine, like other pyrimidine or
`purine nucleosides, is unlikely to be a substrate, an inhibitor,
`or an inducer of cytochrome P450 enzymes, but the available
`information is incomplete. Interactions with other drugs have
`not been tested.
`Azacitidine has been used primarily in the treatment of
`AML [9] and MDS through the National Cancer Institute
`(NCI) expanded-access program to investigational drugs and
`in studies sponsored by the NCI Cancer Therapy Evaluation
`Program.
`The submitted new drug application (NDA) sought
`approval of azacitidine for the treatment of patients with all
`five subtypes (French-American-British [FAB] classifica-
`tion) of MDS: refractory anemia (RA) or refractory anemia
`with ringed sideroblasts (RARS) (if accompanied by neu-
`tropenia or thrombocytopenia or requiring transfusions),
`refractory anemia with excess blasts (RAEB), refractory
`anemia with excess blasts in transformation (RAEB-T), and
`chronic myelomonocytic leukemia (CMMoL) [10]. No ther-
`apeutic agents were approved for MDS prior to azacitidine.
`
`CLINICAL STUDIES
`In the NDA, the sponsor submitted the results of three clini-
`cal studies, originally conducted by the Cancer and Leukemia
`Group B (CALGB) [11–13]. Two studies were single-arm tri-
`als; the third study had a control arm. The controlled study
`was a randomized, open-label, phase III, multicenter trial, in
`which 99 patients were randomized to azacitidine treatment
`and 92 were randomized to best supportive care (observa-
`tion). Azacitidine was administered s.c. at a starting dose of
`75 mg/m2/day for 7 days in each 28-day cycle. Dose adjust-
`ments were prespecified. The dose was to be decreased for
`hematological toxicities or decreased renal function and
`increased for lack of beneficial effect without toxicity. The
`protocol did not permit the use of growth factors.
`Study participants included patients with all five MDS
`subtypes, by the FAB classification listed above. Patients with
`RA or RARS were eligible for the trial only if they had neu-
`tropenia or thrombocytopenia or required transfusions.
`Randomization criteria included stratification by MDS sub-
`type. The initial diagnosis at the study site was adjudicated by
`the CALGB central laboratory. Patients with adjudicated
`diagnoses of AML at study entry were excluded from the
`analysis of efficacy end points, but they were included in the
`intent-to-treat (ITT) analyses of all patients randomized.
`Observation arm patients were permitted to cross over to
`treatment with azacitidine if they met prespecified criteria of
`disease progression (increasing cytopenias and transfusion
`needs, major hemorrhages requiring platelet transfusions,
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`179
`
`Table 2. Response criteria
`
`Complete response
`Peripheral blood: Normal CBC, absence of myeloblasts.
`Bone marrow: Less than 5% myeloblasts.
`Duration: At least 4 weeks.
`
`Azacitidine for MDS
`
`Partial response
`Peripheral blood: Greater than 50% restoration in the deficits from normal levels of baseline hemoglobin, WBC, and platelets, and absence of
`myeloblasts. For CMMoL, if WBC was elevated at baseline, a 75% reduction in the excess count above normal.
`Bone marrow: Greater than 50% decrease in myeloblasts from baseline in patients with RAEB, RAEB-T, and CMMoL. Decrease in myeloblasts is not
`applicable for patients with RA and RARS.
`Duration: At least 4 weeks.
`
`Abbreviations: CMMoL = chronic myelomonocytic leukemia; RA = refractory anemia; RAEB = refractory anemia with excess blasts; RAEB-T = refractory
`anemia with excess blasts in transformation; RARS = refractory anemia with ringed sideroblasts.
`
`ratio was about 3:1, and the average age was >67 years.
`Patients who were adjudicated by the central laboratory to
`have had AML at study entry were equally distributed
`between the two arms.
`The primary efficacy end point was the overall response
`rate (complete response [CR] plus partial response [PR]
`rates). The response criteria are shown in Table 2. The over-
`all response rate for all randomized patients in the azacitidine
`treatment arm, excluding those adjudicated to have AML,
`was 15.7%; no patient had a response in the observation arm.
`The overall response rate for all patients randomized to azac-
`itidine (ITT population), including those adjudicated to have
`had AML at study entry, was 16.2%. The overall response
`rate in patients randomized to azacitidine, excluding patients
`with adjudicated diagnoses of AML at study entry and
`patients with major protocol violations (hematopoietic
`growth factor or corticosteroid use), was 20.4%. Each of
`
`Table 3. Response rates to azacitidine in the randomized trial
`
`these differences between the azacitidine treatment group
`and the observation group was highly statistically significant.
`In the crossover from the observation to the azacitidine treat-
`ment group, excluding patients with adjudicated diagnoses of
`AML, the overall response rate to azacitidine treatment was
`12.8%; 11.8% in the ITT population had responses. These
`response data are summarized in Table 3.
`Similar response rates were reported in the two single-
`arm trials. In one trial, 72 patients with RAEB, RAEB-T, and
`CMMoL were treated with the above azacitidine dosage reg-
`imen administered s.c. On review, 17 of those patients were
`adjudicated to have had AML at study entry. The response
`rate was 12.7% excluding patients with adjudicated diag-
`noses of AML and 13.9% including all patients. In the sec-
`ond study, 48 patients with RAEB and RAEB-T were treated
`with the above azacitidine dosage regimen, administered i.v.
`instead of s.c. The response rate was 19.1% excluding patients
`
`Response
`
`Azacitidine
`
`Observation before crossover
`
`Observation without crossover
`
`Azacitidine after crossover
`
`All randomized patients (ITT population)
`CR + PR
`16/99 (16.2%)
`CR
`6 (6.1%)
`PR
`10 (10.1%)
`
`0/92 (0%)
`0
`0
`
`Excluding patients with adjudicated diagnoses of AML at study entry
`CR + PR
`14/89 (15.7%)
`0/83 (0%)
`CR
`5 (5.6%)
`0
`PR
`9 (10.1%)
`0
`
`0/41 (0%)
`0
`0
`
`0/36 (0%)
`0
`0
`
`Excluding patients with adjudicated diagnoses of AML at study entry or with major protocol violations
`CR + PR
`11/54 (20.4%)
`0/48 (0%)
`0/22 (0%)
`CR
`5 (9.3%)
`0
`0
`PR
`6 (11.1%)
`0
`0
`
`Abbreviations: AML = acute myelogenous leukemia; CR = complete response; ITT = intent-to-treat; PR = partial response.
`
`6/51 (11.8%)
`3 (5.9%)
`3 (5.9%)
`
`6/47 (12.8%)
`3 (6.4%)
`3 (6.4%)
`
`5/26 (19.2%)
`3 (11.5%)
`2 (7.7%)
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`Kaminskas, Farrell, Wang et al.
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`180
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`Table 4. Response rates in azacitidine-treated patients in all three studies
`
`Response
`
`CALGB 9221
`Azacitidine arm
`
`CALGB 9221
`Azacitidine after crossover
`
`All randomized patients (ITT population)
`CR + PR
`16/99 (16.2%)
`CR
`6
`PR
`10
`
`6/51 (11.8%)
`3
`3
`
`Excluding patients with adjudicated diagnoses of AML at study entry
`CR + PR
`14/89 (15.7%)
`6/47 (12.8%)
`CR
`5
`3
`PR
`9
`3
`
`CALGB 8921
`
`CALGB 8421
`
`Total
`
`10/72 (13.9%)
`4
`6
`
`7/55 (12.7%)
`3
`4
`
`9/48 (18.8%)
`3
`6
`
`9/47 (19.1%)
`3
`6
`
`41/270 (15.2%)
`16 (5.9%)
`25 (9.3%)
`
`36/238 (15.1%)
`14 (5.9%)
`22 (9.2%)
`
`Abbreviations: AML = acute myelogenous leukemia; CALGB = Cancer and Leukemia Group B; CR = complete response; ITT = intent-to-treat;
`PR = partial response.
`
`with adjudicated diagnoses of AML at study entry and 18.8%
`including all patients. Response rates from all three trials are
`summarized in Table 4.
`Exploratory analyses showed that response rates were sim-
`ilar in males and females, all age groups, and all MDS sub-
`types. Patients adjudicated to have had AML at study entry
`had about the same response rate as MDS patients (17.9%).
`The most evident benefit of a response (CR or PR) was in
`transfusion-dependent patients. The patients who were
`dependent on RBC and/or platelet transfusions at study entry
`lost the need for transfusions during the duration of CR or
`PR. The responses were long lasting. The median response
`duration could only be estimated as >330 days, since most
`(75%) of the responding patients were still in response at
`treatment completion. Likewise, the mean response duration
`could only be estimated as >512 days.
`Delay in progression to AML could not be established
`as a treatment benefit, despite the persistence of decreased
`bone marrow blast percentages during CRs and PRs in the
`azacitidine treatment arm, because crossover of observation
`arm patients to the azacitidine treatment arm rendered the
`two arms no longer comparable with respect to percentages
`of patients with each MDS subtype.
`A survival benefit of azacitidine treatment could not be
`established because of crossover of observation arm patients
`and because the trial was insufficiently powered to detect a
`survival benefit.
`Initial changes indicating the beginning of a CR or PR to
`azacitidine treatment, such as a decrease in blast count or an
`increase in platelet count, hemoglobin, or WBC were observed
`by the fifth treatment cycle in greater than 90% of patients.
`Maximal responses (CR or PR) took longer to develop.
`In addition to CRs and PRs, lesser responses not meeting
`the CR or PR criteria, termed improvement (less than 50%
`restoration of normal blood counts and less than 50%
`
`decreases in RBC or platelet transfusion requirements),
`occurred in about 24% of azacitidine-treated patients, and
`two-thirds of them became transfusion independent. About
`6% of observation arm patients achieved the criteria for
`improvement by increased platelet or neutrophil counts; none
`of them became RBC transfusion independent. In the three
`studies, about 19% of azacitidine-treated patients met the cri-
`teria for improvement. The median duration of improvement
`(195 days) was shorter than that of CR or PR.
`The treatment strategy of starting azacitidine at dose of 75
`mg/m2 and adjusting it during subsequent cycles was effective.
`About 46% of the patients with best responses of CRs or PRs
`received 75 mg/m2 for the majority of cycles before achieving
`a response, 37% received less than 75 mg/m2, and 17%
`received more than 100 mg/m2.
`
`SAFETY
`Safety evaluation of azacitidine was confounded by the patho-
`physiology of MDS, which overlaps, to a great extent, the
`most common toxicities of azacitidine. Serious adverse events
`(SAEs) occurred in about 60% of azacitidine-treated patients
`and in about 36% of observation-arm patients. The most com-
`mon SAEs resulting in hospitalization in both arms were
`thrombocytopenia, febrile neutropenia, fever, and pneumonia.
`No deaths were attributed to azacitidine. Virtually all (99%)
`azacitidine-treated patients and over 96% of the observation-
`arm patients reported adverse events. Gastrointestinal events
`(nausea, vomiting, diarrhea, constipation, and anorexia),
`hematologic events (neutropenia, fever, rigors, ecchymoses,
`and petechiae), injection site events, arthralgia, cough, dysp-
`nea, headache, weakness, dizziness, and insomnia were more
`commonly reported by patients treated with azacitidine than
`by patients in the observation arm. However, the duration of
`exposure was almost twice as long in the azacitidine-treatment
`arm as in the observation arm in the controlled trial (mean
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`181
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`Azacitidine for MDS
`
`duration of 11.4 months in the azacitidine arm versus 6.1
`months in the observation arm).
`The highest proportion of patients reporting adverse
`events occurred in the first two cycles of therapy; this pro-
`portion decreased in subsequent cycles with the use of
`appropriate concomitant medications. The most common
`reasons for azacitidine discontinuation, dose reduction, or
`therapy interruption (besides the main reason of lack of
`effectiveness) were neutropenia, leukopenia, and thrombo-
`cytopenia. The main indications for concomitant medica-
`tions to treat adverse events were gastrointestinal
`symptoms and fever in the azacitidine-treated patients and
`fever, hypokalemia, and nausea in observation-arm patients.
`Blood cell counts were low at baseline in all patients and
`decreased further in patients treated with azacitidine. Blood
`cell counts increased in patients who showed responses or
`improvements. Patients with hepatic or renal impairment
`were excluded from the clinical trials. Liver function abnor-
`malities occurred, for the most part, in patients with inter-
`current illnesses, including hepatobiliary disorders. More
`severe abnormalities developed in patients with previously
`diagnosed liver cirrhosis. In previous literature reports,
`hepatic coma occurred in patients with extensive metas-
`tases to the liver [9]. Renal failure was reported in patients
`during periods of sepsis and hypotension.
`Some adverse events, such as vomiting, diarrhea,
`headache, injection site erythema, arthralgia, tachycardia,
`and postprocedural hemorrhage, were reported more fre-
`quently by females than males. The proportion of patients
`with adverse events was not greater in older age groups.
`
`COMMENTS AND CONCLUSIONS
`Most MDS patients die from bleeding or infection and from
`progression to AML. Prior to this approval, no single agent
`was approved for the treatment of MDS. The mainstay of
`therapy has been supportive care, including RBC and platelet
`
`REFERENCES
`
`transfusions and treatment with hematopoietic growth fac-
`tors, if serum erythropoietin levels were decreased. Because
`of their advanced age, most MDS patients are not candidates
`for more aggressive therapy, such as hematopoietic stem cell
`transplantation or high-dose chemotherapy.
`As described in the clinical trials in this NDA, treatment
`with azacitidine resulted in consistent responses in about
`16% (11.8%–18.8%) of patients. There were no responses in
`patients who received only supportive care. The statistical
`significance of the response rate in the controlled trial per-
`sisted after patients with adjudicated diagnoses of AML and
`patients with major protocol violations (which consisted
`mainly of pretransfusion steroid injections) were excluded.
`The response rate was reproducible among the three trials
`and is consistent with other published reports [14–18].
`The responses (CRs and PRs) had the direct clinical ben-
`efit of transfusion-dependent patients losing the need for
`RBC and/or platelet transfusions for the duration of the
`response. In addition, about 19% of patients in the three stud-
`ies whose responses did not meet the CR or PR response
`criteria also had clinical benefit.
`Clinical benefits of the decreased incidence of bleeding
`or infections requiring antibiotics could not be established
`because of low incidences of these events during the trial
`period. Likewise, survival benefit or delay in progression to
`AML could not be established because crossover of control
`patients to the active treatment arm confounded these time-
`to-event end points.
`In summary, azacitidine is an active agent that provides
`a benefit to patients with MDS. Its use is accompanied by
`adverse events that appear to be relatively easily controlled
`in most patients by appropriate medications. It is a rela-
`tively safe drug for a malignant or premalignant condition
`such as MDS for which there previously were no approved
`drugs. Azacitidine was approved because the benefits of its
`use clearly outweigh the accompanying risks.
`
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`2 Glover AB, Leyland-Jones B. Biochemistry of azacitidine: a
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