Drug Design, Development and Therapy
`
`Open Access Full Text Article
`
`CELGENE 2125
`APOTEX v. CELGENE
`IPR2023-00512
`
`Dovepress
`open access to scientific and medical research
`
`R eVi e w
`
`Safety and efficacy of azacitidine in myelodysplastic
`syndromes
`
`Carlos e Vigil
`Taida Martin-Santos
`Guillermo Garcia-Manero
`Department of Leukemia, The
`University of Texas MD Anderson
`Cancer Center, Houston, TX, USA
`
`Correspondence: Carlos e Vigil
`Department of Leukemia, Unit 428,
`The University of Texas MD
`Anderson Cancer Center, Houston,
`TX 77030, USA
`Tel +1 713-745-2411
`Fax +1 713-745-4138
`Email cvigilgonzales@gmail.com
`
`Purpose: The clinical efficacy, different dosages, treatment schedules, and safety of azacitidine
`are reviewed.
`Summary: Azacitidine is the first drug FDA-approved for the treatment of myelodysplastic
` syndromes that has demonstrated improvements in overall survival and delaying time to
` progression to acute myelogenous leukemia. The recommended dosage of azacitidine is
`75 mg/m2 daily for 7 days, with different treatment schedules validated. It appears to be well
`tolerated, with the most common adverse effects being myelosuppression. Several other off-label
` recommendations were also analyzed.
`Conclusion: Azacitidine is the first DNA hypomethylating agent approved by FDA for the
`treatment of myelodysplastic syndromes with demonstrated efficacy.
`Keywords: Azacitidine, MDS, hypomethylating agents
`
`Hypomethylating agents are a group of chemotherapeutic drugs with the capacity to
`induce transient DNA hypomethylation, an important mechanism in the treatment of
`myelodysplastic syndromes (MDS). Two hypomethylating agents approved in the
`United States and widely used in Europe and the rest of the world are azacitidine
`(5-azacytidine) and decitabine. Azacitidine has been reported to prolong survival
`in MDS patients. Azacitidine has been studied in different dosing schedules and
` combination therapies with the objective of improving the response rates in patients
`with MDS and acute myelogenous leukemia (AML).
`Azacitidine is a nucleoside analog with a ribose structure that is incorporated
`into RNA and requires the activity of ribonucleotide reductase to be incorporated to
`DNA.1 Azacitidine is phosphorylated intracellularly to its active form, azacitidine
`triphosphate.2,3 Like most nucleoside analogs, azacitidine enters cells using the nucleo-
`side transporters hENT1 and hENT2, but unlike the nucleoside analog decitabine,
`azacitidine does not require deoxycytidine kinase for phosphorylation.
`Uridine-cytidine kinase phosphorylates azacitidine to its active form.4 Because
`hypermethylation of the promoters of certain tumor suppression genes is prevalent in
`MDS and secondary AML, it is postulated that the DNA hypomethylation induced
`by azacitidine, may result in the reactivation of silenced genes, restoring their cancer-
`suppressing functions, and inducing cellular differentiation.
`Efficacy
`Azacitidine as a front-line single agent
`In the late 1960s and early 1970s, azacitidine was tested in a series of phase I and II trials
`as a classic cytotoxic agent and was found to be effective for the treatment of myeloid
`
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`DOI: 10.2147/DDDT.S3143
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`Drug Design, Development and Therapy 2010:4 221–229
`© 2010 Vigil et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
`which permits unrestricted noncommercial use, provided the original work is properly cited.
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`malignancies. In these studies, most of them involving
`patients with relapsed AML, azacitidine was mainly used
`in combinations and was administered at doses ranging
`from 100–750 mg/m2 with response rates ranging from 0%
`to 58%.4–8 In a phase I trial in which patients with relapsed
`leukemia received azacitidine intravenously at various sched-
`ules at doses ranging from 150–750 mg/m2, higher remission
`rates were observed in patients treated with the lower doses.5
`Later studies performed by Cancer and Leukemia Group B
`(CALGB) demonstrated that azacitidine had activity in MDS
`and AML when given at 75 mg/m2 by intravenous infusion
`(CALGB 8421) or subcutaneous injection (CALGB 8921
`and 9221) daily for 7 days in a 28-day cycle.9–11 The cross-
`over phase III CALGB 9221 trial10,11 showed a significant
`effect of azacitidine on response rates (P , 0.0001), with an
`overall response rate of 60% in patients receiving azacitidine
`compared with 5% in those receiving only supportive care.
`Patients who crossed over from supportive care to azacitidine
`had an overall response rate of 47%, confirming that azac-
`itidine improved overall response. Although the difference
`was not significant (due to the crossover design of the study),
`there was a marked improvement in overall survival times
`for patients receiving azacitidine (20 months) compared with
`patients receiving supportive care (14 months). These data
`are summarized in Table 1. The CALGB 9221study results
`led to the approval of azacitidine in the United States for
`patients with MDS.
`In a second randomized phase II study (AZA-001)
` performed to determine the effect of azacitidine on survival,
`Fenaux et al compared the efficacy of azacitidine to conven-
`tional care regimens in patients with high-risk MDS.12–14 The
`358 patients were randomized 1:1 to receive azacitidine or
`a conventional care regimen that could include supportive
`care, low-dose cytarabine, or induction-type chemotherapy.
`Azacitidine was administered subcutaneously at 75 mg/m2
`daily for 7 consecutive days every 28 days for at least
`six cycles. A median of nine cycles of azacitidine was admi-
`nistered (range 4–15 cycles). The primary endpoint in the
`
`Table 1 Phase III trials of azacitidine as a single agent
`AZA-001
`Study
`CALGB 9221
`Updated CALGB
`No. (%)
`No. (%)
`No. (%)
`179
`99
`99
`No. patients
`30 (17)
`7 (7)
`10 (10)
`CR
`21 (12)
`16 (16)
`1 (1)
`PR
`87 (49)
`37 (37)
`36 (36)
`Hi
`138 (78)
`60 (60)
`47 (47)
`OR
`Abbreviations: CR, complete remission; PR, partial remission; Hi, hematological
`improvement; OR, overall response.
`
` AZA-001study was overall survival. Patients treated with
`azacitidine had median overall survival of 24.5 months,
`while patients receiving conventional care had a median
`overall survival of 15.0 months. An analysis of the efficacy
`endpoints found significantly prolonged survival for patients
`in the azacitidine arm compared with the best supportive care
`or low-dose cytarabine subgroups but not compared with
`the intensive chemotherapy subgroup, reflecting the small
`number of patients preselected to receive intensive chemo-
`therapy. The estimated 2-year survival rates were 50.8%
`for patients receiving azacitidine and 26.2% for patients
` receiving conventional care; patients in the azacitidine
`group also had higher rates of complete response (CR)
`(17% versus 8%, P = 0.015) and partial response (PR)
`(12% versus 4%, P = 0.0094). Likewise, the median times
`to disease progression, relapse after CR or PR, and death
`were significantly longer in the azacitidine group than in the
`conventional care group (14.1 months versus 8.8 months,
`P = 0.047). The proportion of major erythroid improvements
`(40% versus 11%, P , 0.0001) and major platelet improve-
`ments (33% versus 14%, P = 0.0003) based in the Inter-
`national Working Group 2000 criteria, were higher in the
`azacitidine group than in the conventional care group, but no
`significant difference in major neutrophil improvements was
`observed. The median duration of hematological response
`(CR, PR, and hematological improvements) was significantly
`longer in the azacitidine group than in the conventional care
`group (13.6 months versus 5.2 months, P = 0.0002). The
`rate of transformation to AML was lower in the azacitidine
`group than in the conventional care group, and the median
`time to AML transformation was 17.8 months in the azaciti-
`dine group compared with 11.5 months in the conventional
`care group. In subgroup analysis, the time to progression
`for the azacitidine group was significantly lower than that of
`the best supportive care subgroup but did not differ signifi-
`cantly from that of either the low-dose cytarabine subgroup
`or the intensive chemotherapy subgroup. Results are sum-
`marized in Tables 1 and 2. In summary, the AZA-001study
`showed for the first time that a hypomethylating agent
`prolonged survival and decreased the risk of transformation
`to AML in patients with high-risk MDS compared with
`conventional therapies.
`MDS patients with abnormalities in chromosome 7 (-7/
`del(7q)) typically have poor outcomes with traditional treat-
`ments. Follow up of the patients of the AZA-001 trial showed
`that patients in the azacitidine group with chromosome 7 abnor-
`malities had a longer median overall survival time than those in
`the conventional care group (13.1 months versus 4.6 months,
`
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`Azacitidine in myelodysplastic syndromes
`
`Table 2 Results of the AZA-001 trial of azacitidine versus
`conventional care in patients with myelodysplastic syndromes13
`
`28-day cycle (525 mg/m2 total). Because of the difficulty of
`continued administration for 7 days, in a randomized trial,16
`MDS patients were given azacitidine subcutaneously in one
`of three schedules every 4 weeks for six cycles: AZA 5-2-2
`(75 mg/m2 daily for 5 days, followed by 2 days of no treat-
`ment, and then 75 mg/m2 daily for 2 days for a total dose of
`525 mg/m2 per cycle), AZA 5-2-5 (50 mg/m2 daily for 5 days,
`followed by 2 days of no treatment, and then 50 mg/m2 daily
`for 5 days for a total dose of 500 mg/m2 per cycle), or AZA
`5 (75 mg/m2 for 5 days for a total dose of 375 mg/m2). Most
`patients were FAB criteria-defined (had refractory anemia
`with ringed sideroblasts/chronic myelomonocytic leukemia
`with less than 5% bone marrow blasts, 63%) or refractory
`anemia with excess blasts (30%). Seventy-nine patients (52%)
`completed six or more treatments cycles. After six cycles of
`treatment, hematological improvement was reported in 44%
`(22 of 50), 45% (23 of 51), and 56% (28 of 50) of the patients
`in the AZA 5-2-2, AZA 5-2-5, and AZA 5 arms, respectively.
`Proportions of red blood cell transfusion-dependent patients
`who achieved transfusion independence were 50% (12 of 24),
`55% (12 of 22), and 64% (16 of 25) in the AZA 5-2-2, AZA
`5-2-5, and AZA 5 arms, respectively. More than one grade
`3 or 4 adverse event occurred in 84% (42 of 50), 77% (37
`of 51), and 58% (29 of 50) of patients the AZA 5-2-2, AZA
`5-2-5, and AZA 5 arms, respectively. All three alternative
` dosing regimens produced hematological improvements, red
`blood cell transfusion independence, and safety responses
`consistent with the approved azacitidine regimen. However,
`results suggest that the AZA 5 dosing regimen may be better
`tolerated with a more convenient dosing schedule than the
`two alternative dosing regimens.
`
`Azacitidine in transplantation
`Immediate stem cell transplantation therapy has been rec-
`ommended for patients with intermediate-2 and high-risk
`MDS according to the International Prognostic Scoring
`System because of their poor outcomes and short survival
`times.17 A frequent type of treatment failure after stem cell
`transplant is disease relapse, which is very difficult to man-
`age. The graft-versus-leukemia effect can be magnified by
`weaning the patient from the immunosuppressive therapy
`and initiating a donor lymphocyte infusion, but this strategy
`is of very limited value, especially because of the risk of
`graft-versus-host disease.
`Because induction chemotherapy is not suitable for some
`elderly patients or patients with other contraindications, and
`because modifications to conditioning regimens have not
`improved their tolerability, azacitidine has been considered
`
`Azacitidine
`N = [179]
`24.5
`
`Conventional
`care N = [179]
`15.0
`
`50.8
`
`17.8
`
`26.2
`
`11.5
`
`P
`
`P # 0.0001
`
`P , 0.0001
`
`P # 0.0001
`
`Median overall
`survival (mo)
`2-year overall
`survival (%)
`Median time to
`AML (mo)
`Cytogenetic overall
`survival (mo)
`-7/del (7q)
`Response (%)
`P = 0.015
`8 [14]
`17 [30]
` CR
`P = 0.0094
`4 [7]
`12 [21]
` PR
`P = 0.33
`36 [65]
`42 [75]
` Stable disease
`Notes: Definitions of hematological response and improvement were based on the
`international working Group 2000 criteria for MDS.
`Abbreviations: AML, acute myeloid leukemia; CR, complete remission; PR, partial
`remission.
`
`13.1
`
`4.6
`
`P = 0.0017
`
`P = 0.0017); for patients with chromosome 7 abnormalities
`alone, the median overall survival time did not significantly
`differ between the two treatment groups (18.4 months versus
`10.3 months); however, in patients with -7/del(7q) as part
`of complex karyotype there was a significant difference
`between the median overall survival times of the azacitidine
`and conventional care groups (8.3 months versus 4.2 months,
`P = 0.0024). Therefore, azacitidine is the only treatment, aside
`from hematopoietic stem cell transplantation, to confer a
`demonstrable survival benefit in patients with MDS, including
`those with -7/del(7q) cytogenetic abnormality.12–14
`Patients with high-risk MDS must undergo prolonged
`treatment with azacitidine to improve their outcomes, with
`a median of three cycles needed before the first evidence of
`response appears. In the AZA-001study, the survival advan-
`tage was observed after three cycles of azacytidine com-
`pared with the conventional care group, with separation of
`Kaplan–Meier survival curves. A total of 81% of patients had
`achieved an evidence of response by the sixth cycle of treat-
`ment and an additional 9% of patients eventually responded
`to azacitidine by the ninth cycle. Furthermore, although the
`first response to azacitidine was a good response for over
`half the patients treated, a median of four additional cycles
`of azacitidine improved response in an additional 43% of the
`patients, suggesting that prolonged treatment with azacitidine
`may maximize the response to the agent.12,13,15
`
`Alternative schedules and dosing
`The standard dosing schedule of azacitidine for the treatment
`of MDS is 75 mg/m2 daily subcutaneously for 7 days in a
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`as an alternative. In a Nordic MDS study, 23 patients in
`CR after induction chemotherapy who were not eligible for
`allogenic transplantation received azacitidine at 60 mg/m2
`daily subcutaneously for 5 days in a 28-day cycle until
`relapse or unacceptable toxicity occurred. Unfortunately,
`the median duration of response was only 13.5 months
`(range 2–49 months) with just 30% of the cases remaining
`in CR beyond 20 months.18 A similar study by the Groupe
`Francophone des myélodysplasies (GFM) is currently under
`way. Patients with greater than 10% blasts in the bone marrow,
`or greater than 5% if a nonmyeloablative transplantation is
`planned, may require treatment aimed at reducing the tumor
`burden to decrease the risk of relapse. Azacitidine has been
`observed to produce better responses in patients with unfa-
`vorable cytogenetics.19 In a retrospective study the outcomes
`of 34 MDS patients who underwent stem cell transplanta-
`tion were analyzed, 14 of whom had received azacitidine at
`standard doses before transplantation. The Kaplan–Meier
`estimates for overall survival and progression-free sur-
`vival between the two groups did not show clear evidence
`of a favorable outcome for either group, nor were there
`marked differences in toxic effects and other complications
`between the two groups. These results indicate that these
`two treatment options are still valid approaches but deserve
`further analysis.20
`As mentioned, outcomes for patients with early recur-
`rence of AML are dismal. Maintenance therapy with azaciti-
`dine may aid as an adjuvant for decreasing the recurrence rate
`after transplantation. Azacitidine appears to induce leukemic
`cell differentiation and to increase the expression of human
`leukemia antigen DR1 and several other tumor-associated
` antigens, which can increase the graft-versus-leukemia
`effect.21–23 Moreover, in recent studies several mechanisms
`have been demonstrated through which azacitidine com-
`promises the proliferation and activation of regulatory
`T lymphocytes, mainly by blocking the cell cycle.24–26
`In another study,27 40 patients with high-risk MDS or
`AML in CR without grade 3 or 4 graft-versus-host disease
`were assigned, on the basis of their toxicity profiles, to receive
`maintenance doses of azacitidine at 8 mg/m2, 16 mg/m2, or
`24 mg/m2 daily for 5 days, starting on day 42 after stem cell
`transplantation and given in 28-day cycles. Eleven patients
`relapsed; two of these relapses occurred during maintenance
`therapy. The day 30 and day 100 nonrelapse mortality
`rates were 5% and 12%, respectively, with no increase
`in the graft-versus-host disease rates. Twelve patients
`received the 24 mg/m2 dose with no toxic effects for at least
`four cycles, suggesting that higher doses and longer periods
`
`of administration could be further investigated. In a later
`study including a higher dose of 32 mg/m2, thrombocytopenia
`limited further dose escalation, though it was reversible.
`A randomized controlled trial of azacitidine for 1 year versus
`best standard care is ongoing.28
`Few treatment options are available for patients whose dis-
`ease relapses after transplantation. Moreover, less than 30%
`of patients with relapsed MDS achieve a complete response
`with donor lymphocyte infusion, which has a recurrence rate
`close to 33%.29 Because azacitidine is able to induce response
`in pretransplant MDS patients, it also has been proposed as a
`treatment for relapse after unrelated donor peripheral stem cell
`transplantation.30 This recommendation came from a study of
`six patients with high-risk myeloid malignancies and cytoge-
`netic relapse after transplantation who received azacitidine
`at a minimum dose of 25 mg/m2 for 5 days. A reduction of
`cytogenetic abnormalities was observed in 83% of the patients
`shortly after one cycle of therapy, with one patient remaining
`in CR 4 months after the completion of therapy. The remain-
`ing patients relapsed 30 days after the completion of therapy,
`reflecting activity but a short-lived response. Further investi-
`gation may be necessary to evaluate azacitidine’s activity as
`pre-donor lymphocyte infusion regimen.
`
`Azacitidine in elderly patients
`As previously discussed, azacitidine was the first treatment
`to significantly extend overall survival times in patients with
`high-risk MDS. It is also known that the incidence of MDS
`increases with age, resulting in limited treatment options –
`particularly for fragile patients and those older than 75 years,
`who cannot adequately tolerate cytotoxic therapies. Therefore,
`an important goal of therapy is to reduce the transfusion
`dependence and delay the progression of disease while
`maintaining a basically favorable toxicity profile. A subset
`analysis of the AZA-001 trial in patients older than 75 years
`demonstrated higher overall survival rates at 2 years in the
`azacitidine group (55%) than in the conventional care group
`(15%).31 Moreover, azacitidine generally was well tolerated in
`patients older than 75 years and produced transfusion indepen-
`dence in 44% of the patients who received it, compared with
`22% in the conventional care group. Similar results have been
`reported elsewhere.32 It is of interest that most patients older
`than 75 years randomized to the conventional care regimen
`group received basic support only, suggesting that clinicians
`are generally unlikely to administer more aggressive treat-
`ments to elderly patients. Although these studies may have
`included a selected, relatively fit subpopulation of patients,
`the results of both studies clearly demonstrate azacitidine’s
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`Azacitidine in myelodysplastic syndromes
`
`better response rates compared with conventional care and
`its acceptable safety profile for elderly patients.
`
`Azacitidine in lower-risk MDS
`It is known that 90% of patients with an initial diagnosis of
`MDS present with anemia and eventually become transfu-
`sion dependent. The erythropoiesis-stimulating agents, with
`or without granulocyte-colony stimulating factors, can be
`effectively used in the initial management in low-risk MDS to
`reduce the need for transfusions; however, some patients with
`lower-risk disease may need treatments other than growth
`factors. The best score to predict MDS natural history is the
`International Prognostic Scoring System, but this system has
`several limitations, the most important of which is the iden-
`tification of patients who may face a poor prognosis despite
`having lower-risk disease (low and intermediate-1 risk).
`A new scoring system, the MDACC score, was developed
`at The University of Texas MD Anderson Cancer Center to
`provide insight into which patients may benefit from more
`aggressive treatment. This was done by dividing a subset
`of patients into three categories depending on cytogenetics,
`hemoglobin levels, thrombocytopenia, age, and number of
`blasts in the bone marrow.33
`To date, few data have been made available regarding
`the specific use of azacitidine in patients with lower-risk
`disease. The CALGB 9221 trial included 44 patients with
`low-risk disease in its analysis. The overall response observed
`in patients with low-risk MDS receiving azacitidine was
`
`59% (9% CR, 18% PR, and 32% hematological improve-
`ment), with an overall survival of 44 months compared with
`27 months for the control group. Recently, a multicenter
`prospective community-based study (AVIDA)34 reported
`a series of 52 transfusion-dependent patients. In total 42%
`achieved transfusion independence while on azacitidine;
`67% of the patients who achieved transfusion independence
`did so after the second cycle of treatment. A significant
`62% of patients were able to reach platelet transfusion
`independence; 88% of the patients who achieved platelet
`transfusion independence did so after the second treatment
`course, with minimal side effects. A more recent retrospective
`Italian study35 evaluated 74 patients with low-risk MDS who
`received azacitidine at 75 mg/m2 or 100 mg/m2 in monthly
`schedules subcutaneously. The overall response in these
`patients was 45.0% (10.0% complete response, 9.5% partial
`response, and 20.3% hematological response). Hematological
` improvements were not as strong as those reported in higher-
`risk populations. We believe that the MDACC score could be
`used to better identify the subset of patients with lower-risk
`disease who would benefit from early therapeutic regimens,
`which may help improve their overall survival times. Further
`analyses are warranted.
`
`Oral azacitidine
`An oral formulation of azacitidine could facilitate dosing,
`reduce side effects, and favor compliance. It is postulated
`that oral formulations of the hypomethylating agents fail
`
`Diagnosis
`
`IPSS
`
`MDACC
`
`MDS
`
`Lower risk IPSS
`
`Higher risk IPSS
`
`MDACC category 1
`
`MDACC category 2–3
`
`Cytogenetics
`Age
`Performance status
`
`Figure 1 Classification of myelodysplastic syndromes based on the MD Anderson Cancer Center scoring classification.
`Abbreviations: iPSS, international Prognostic Scoring System; MDACC, MD Anderson Cancer Center scoring system; MDS, myelodysplastic syndromes.
`
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`MDACC score 1
`
`Supportive care
`
`MDACC score 2–3
`
`Hypomethylating agents
`
`Clinical trials
`
`High risk MDS
`
`Highly intensive treatment
`Hypomethylating agents
`
`Clinical trial
`
`Figure 2 Treatment algorithms of myelodysplastic syndromes at MD Anderson Cancer Center.
`Abbreviations: MDACC, MD Anderson Cancer Center scoring system; MDS, myelodysplastic syndromes.
`
`because they undergo rapid catabolism by cytidine deami-
`nase and hydrolysis in aqueous environments. A phase 0 pilot
`study demonstrated plasma concentrations of azacitidine
`that were comparable to those achieved by subcutaneous
`injection.36 A subsequent phase I study of 40 patients
`receiving the first 75 mg/m2 dose of azacitidine subcutane-
`ously and then escalating doses (from 120 mg to 600 mg)
`of azacitidine orally over the next 7 days demonstrated
`that oral azacitidine was well tolerated with low toxicity.37
`The maximum tolerated dose was 480 mg, with grade 3
`and 4 diarrhea observed in two of the three patients in
`the 600 mg cohort. The plasma concentration range was
`5% to 35% for the first and 15% to 74% in the last group.
`Twenty-nine percent of the patients had a complete response
`and 43% had stable disease after six cycles of therapy.
`Nevertheless, the exposures for the oral dosing regimens
`were lower than the historical data for subcutaneous dos-
`ing, providing the rationale for an extended schedule and
`twice-daily dosing in a future trial.38
`
`Azacitidine in combination therapy
`The goals of combining azacitidine with other agents are to
`increase the response rates and to prolong the duration of
`response while maintaining low rates of toxic effects. Based
`on models of epigenetic biology and utilizing azacitidine’s
`synergistic effects, several combinations of azacitidine with
`histone deacetylase (HDAC) inhibitors have been assessed.
`The concept is based on the reactivation of suppressed anti-
`cancer genes.39 Valproic acid is a short-chain fatty acid HDAC
`inhibitor with modest activity as a single agent, but it has
`shown activity in combination with other hypomethylating
`agents.40,41 The median overall survival for patients receiving
`
`valproic acid plus azacitidine was 14.4 months, and the
` disease progressed in 32% of the patients. Other investigators
`have sought to improve this result by looking to all-trans
`retinoic acid, a cell differentiation agent that releases co-
`repressors and HDACs and induces the expression of target
`genes.42 This activity suggests the possibility that adding
`all-trans retinoic acid to the combination of azacitidine and
`valproic acid could potentiate the combination’s effects. Of
`the four patients with MDS receiving the three-drug combi-
`nation, two achieved a complete response and the other two
`a bone marrow response.43 Another phase I study combining
`azacitidine with the HDAC inhibitor MS-275, showed a
`44% overall response rate, with 7 of 13 patients with MDS
`achieving a response.44
`MGCD0103 is a selective HDAC inhibitor that demon-
`strated promising activity as a single agent in MDS patients.
`In a phase I/II study, patients with relapsed/refractory MDS
`or AML received a standard dose of subcutaneous azacitidine
`plus MGCD0103 in escalating doses from 35 mg to 135 mg
`three times per week commencing on day five of azacitidine.45
`Eleven (30%) of the patients responded, with four achieving
`a complete response, five achieving an incomplete response,
`and two achieving a partial response. The maximum tolerated
`dose of MGCD0103 was fixed at 90 mg because of severe
`nausea, vomiting, and dehydration at higher doses. Additional
`combination trials with other broad and more specific HDAC
`inhibitors are underway.
`Empiric combinations of drugs with demonstrated indi-
`vidual activity have been evaluated in several other clinical
`trials. Thalidomide, an effective modulator of immune
`response with anti-angiogenic activity, was administered
`in escalating doses with a standard dose of azacitidine for
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`Azacitidine in myelodysplastic syndromes
`
`5 days.46 Of the 40 patients enrolled, 15% experienced a
`complete response and a hematological improvement was
`observed in 42%. In a phase I study with 18 patients, azaciti-
`dine was tested in combination with lenalidomide, which had
`demonstrated activity in MDS patients with 5q chromosome
`abnormalities.47 The treatment regimen was well tolerated,
`and the overall response rate for the 17 evaluable patients was
`71%, with 41% of patients achieving a complete response.
`This combination was well tolerated, with a significant clini-
`cal activity encouraging for further analysis. A clinical trial
`is planned in which patients will receive a 75-mg/m2 dose
`of azacitidine from days 1 through 5 and a 10-mg dose of
`lenalidomide from days 1 through 21.
`Preliminary data from preclinical studies of the mecha-
`nisms that may cause MDS have implicated tumor necrosis
`factor-α2 receptors. Therefore, a combination of etanercept,
`a tumor necrosis factor-α blocker, and azacitidine was
` evaluated in a phase II study of 23 patients. Azacitidine was
`given in the standard 7-day dose, while etanercept was admin-
`istered at 25 mg subcutaneously twice a week for 2 weeks in
`a 28-day cycle. It is notable that 14 patients responded, with
`28% achieving CR and 44% achieving PR.48
`Targeting cell surface markers has also been studied for
`the treatment of MDS. CD33 is a surface marker known
`to be present in early hematopoietic stem cell precursors.
`Gemtuzumab ozogamicin, an antibody attached to a toxin
`that targets CD33-expressing cells, has produced good
`responses in hematological malignancies. Its combination
`with azacitidine has been assessed in early clinical trials in
`patients with refractory or relapsed AML or MDS.49 Median
`overall survival was 21 weeks, and 27% of patients achieved
`a complete response. Notably, 26% of patients with refractory
`disease had a documented complete response, and the median
`overall survival was 40 weeks. A prospective clinical trial is
`underway.
`
`Failure of treatment
`Hypomethylating agents are currently the standard
`therapy for the treatment of MDS, but the prognosis
`after a failure of the treatment, although thought to be
`poor, has not been well documented. Recently, a single
`institution retrospective study of 87 patients, had deter-
`mined an expected median survival of 4.3 months, with
`no difference in the outcome noted between patients
`who progressed to AML or who did not. An important
`validation of MDACC risk model was done, demonstrat-
`ing the utility of the model for advice in prognosis and
`treatment alternatives.50
`
`Safety
`Azacitidine appears to be well tolerated, with the most com-
`mon grade 3 or 4 events being peripheral blood cytopenias.6
`Injection site complications are the most common treatment-
`related non-hematological complications in subcutaneous
`azacitidine dosing, followed by nausea and vomiting.
`Although sometimes severe, myelosuppression is usually tran-
`sient, with most patients recovering before their next treatment
`or usually managed with dosing delays (23%–29%).51
`The highest proportion of adverse events occurs during
`the first two cycles, and the drug’s tolerability improves sub-
`sequently. The infection rates were not statistically different
`when comparing with basic support (RR = 1.00 [95% CI: 0.81,
`1.22], P = 1.00]. The administration-related events such as
`nausea and vomiting occurred typically in the first week of
`drug delivery, resolved with antiemetics during the studies.
`The majority of injection site complications are typically mild
`erythema, and most improve after the application of warm or
`cold compresses to the affected area for a couple of hours.
`This drug is mainly renally excreted (50%–85%), and
`some renal complications have been reported, although these
`are rare. These have included serum creatinine elevation,
`renal failure, renal acidosis, and death, and occurred more
`often when azacitidine was given in combinations with other
`drugs and at higher doses for non-MDS conditions.52 Azaciti-
`dine has not been studied in patients with renal impairment
`and MDS. In patients with decreased levels of serum bicar-
`bonate (, 20 mEq/L) or unexplained elevations of creatinine,
`dose reductions may be warranted. Caution should also be
`used in patients with hepatic impairment. Early studies asso-
`ciated hepatic toxicity, including coma, with subcutaneous
`injections of azacitidine.6,53 All of these patients who became
`comatose had liver metastasis at the time of treatment. Based
`on these reports, azacitidine is contraindicated in patients
`with advanced hepatic tumors, and caution is needed when
`administering azacitidine to patients with other liver condi-
`tions. Also unknown are the interactions be