MDS: BEYOND A ONE - SIZE - FITS - ALL APPROACH
`
` Oral hypomethylating agents: beyond
`con ve nience in MDS
`
` Elizabeth A. Griffi ths
` Roswell Park Comprehensive Cancer Center, Buffalo, NY
`
` Oral hypomethylating agents (HMAs) rep re sent a sub stan tial poten tial boon for patients with myelodysplastic syn drome
`(MDS) who have pre vi ously required between 5 and 7 vis its per month to an infu sion clinic to receive ther apy. For patients
`who respond to treat ment, ongo ing monthly main te nance vis its rep re sent a con sid er able bur den to qual ity of life, and
`for those who are early in ther apy, these sequen tial vis its may tax transportation and fi nan cial resources that would be
`opti mally dis trib uted over the treat ment cycle to facil i tate trans fu sion sup port. The avail abil ity of oral HMAs may sup port
`the opti mal appli ca tion of these agents by con trib ut ing to adher ence and less en ing the bur den of ther apy, poten tially
`encour ag ing patients to stay on lon ger - term treat ment. Distinct phar ma co ki netic pro fi les for the recently approved oral
`HMAs (oral azacitidine and decitabine - cedazuridine) result in dif fer en tial tox ic ity pro fi les and have prompted their clin i cal
`trial devel op ment in lower - and higher - risk MDS, respec tively.
`
` LEARNING OBJECTIVES
` • Describe the chal lenges of effec tive ther apy with HMAs for patients with MDS and the bar ri ers to this ther apy
` • Understand the PK pro fi les for HMAs given par en ter ally and con trast these with the PK pro fi les fol low ing oral
`admin is tra tion of unmod i fi ed oral azacitidine and decitabine / cedazuridine
` • Recognize how the PK for oral HMAs may dif fer from an established par en teral reg i men and antic i pate the chal-
`lenges asso ci ated with transitioning from one reg i men to another
`
`with par en teral azacitidine 75 mg / m 2 given sub cu ta ne-
` CLINICAL CASE 1
`ously (SQ ) 7 days of a 28 - day sched ule. The ini tial treat-
` A 78 - year - old woman presented to our clinic after rou tine
`ment was char ac ter ized by the devel op ment of red blood
`blood work dem on strated throm bo cy to pe nia and neutro-
`cell (RBC) and plate let trans fu sion depen dence in cycles
`penia. The patient was oth er wise in rea son able health for
`1 and 2. She presented prior to cycle 3 of ther apy, and the
`her age with comorbid med i cally man aged hyper ten sion.
`CBC showed a WBC count of 1.0 × 10 9 / µ L with absolute
`She was widowed but lived inde pen dently, with min i mal
`neutrophil count 0.2 × 10 9 / µ L, an Hg of 8 g / µ L, and plate-
`sup port from her local adult chil dren. A com plete blood
`lets, 105 k / µ L. She came to the clinic accom pa nied by
`count (CBC) at the ini tial eval u a tion dem on strated a white
`her chil dren. She stated that she was no lon ger will ing to
`blood cell (WBC) count of 1.4 × 10 9 / µ L, with an abso-
`con tinue ther apy. She reported intol er a ble loss of qual ity
`lute neu tro phil count of 0.5 × 10 9 / µ L, hemo glo bin (Hg)
`of life and inde pen dence due to the daily infu sion clinic
`of 11 g / µ L, and plate let count of 25 k / µ L. She was dem-
`vis its in the fi rst week of each cycle and the bur den of
`on strated to be nutri ent replete for B 12 , folate, iron, and
`trans fu sion depen dence. She was ada mant that she would
`cop per. A bone mar row (BM) aspi ra tion and biopsy were
`take no fur ther che mo ther apy despite an early response
`performed, show ing refrac tory ane mia with excess blast - 2
`to treat ment that suggested she was likely to derive a sur-
`(15 % blasts); cyto ge net ics were nor mal. Next - gen er a tion
`vival ben e fi t from con tin ued treat ment (early hema to logic
`sequenc ing (NGS) revealed muta tions in IDH2 and SRSF2 .
`improve ment [HI] of the plate let lin e age). She requested
`A diag no sis of higher - risk myelodysplastic syn drome
`enroll ment in home hos pice care and passed away 1 month
`(MDS) was ren dered (International Prognostic Scoring
`after ther apy dis con tin u a tion. Today, the avail abil ity of oral
`System [IPSS] - Revised [R], 5.5 points [high risk]; IPSS 2.0
`agents might have con vinced this patient to con tinue
`points [in ter me di ate - 2]), and the patient started ther apy
`treat ment, opti miz ing her sur vival and improv ing her
`CELGENE 2086
`APOTEX v. CELGENE
`IPR2023-00512
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`Figure 1. Chemical structure of cytidine, azacitidine analogues, and the breakdown products of CDA.
`
`qual ity of life. As it stood, this patient accrued all the tox ic ity
`from the use of this agent, includ ing ini tial loss of qual ity of life,
`with out real iz ing the lon ger-term poten tial ben e fits of trans fu-
`sion inde pen dence (TI) and sur vival, which she might have been
`expected to achieve given her early evi dence of response.
`
`Introduction
`Hypomethylating agents (HMAs) have been the main stay of
`treat ment for patients with higher-risk MDS since the ini tial reg u-
`la tory approval of monthly treat ments with par en teral azacitidine
`and decitabine in the early 2000s.1 The shared active metab o lite
`of both agents (~15% of the admin is tered azacitidine dose, con-
`verted by the action of ribo nu cle o tide reduc tase) is decitabine
`tri phos phate, an ana logue of the nucle o side cyti dine (Figure 1).
`Although 85% of par en ter ally admin is tered azacitidine is incor-
`po rated into RNA, interrupting pro tein syn the sis and induc ing
`apo pto sis, the clin i cal impact of this incor po ra tion on its activ-
`ity remains an area of active inves ti ga tion.1 When decitabine tri-
`phos phate is incor po rated into DNA whose par ent strand bears
`a methyl group in the con text of a cyto sine-phospho-gua nine
`sequence, DNA methyltransferase enzymes (par tic u larly DNMT-1)
`
`bind it irre vers ibly, cre at ing an adduct that results in both DNA
`dam age and the deple tion of DNMT enzymes.2 With repeated
`cycles of DNA rep li ca tion, loss of the meth yl a tion enzymes re-
`sults in the pas sive demethylation of DNA at mul ti ple loci. At low
`doses that do not cause over whelm ing cyto tox ic ity, these drugs
`induce tran sient gene-spe cific and global hypomethylation that
`are hypoth e sized to medi ate their response. Historically, activ ity
`has been pos tu lated to result from the reexpression of epi ge-
`net i cally silenced tumor sup pres sor genes, but more recently,
`reexpression of endog e nous ret ro vi ral ele ments with enhanced
`immune rec og ni tion of MDS pro gen i tors has been hypoth e sized
`as another puta tive mech a nism.3 Despite ongo ing con tro versy
`over the defin i tive expla na tion for ther a peu tic effi cacy, opti mal
`patient out comes from HMA ther apy seem to require long-term
`treat ment on a reg u lar and unin ter rupted sched ule.4–7
`
`Dose, sched ule, and treat ment con tin u a tion are crit i cal
`to opti mal HMA response
`When given on a monthly basis for repeated cycles, these agents
`improve cytopenias, lower BM blasts, improve qual ity of life, de-
`crease trans for ma tion to acute mye loid leu ke mia (AML), and im-
`prove sur vival for select patients.8–10 Despite years of study, no
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`effec tive pre treat ment pre dic tors of response are clin i cally appli-
`ca ble.11 About half of HMA-treated patients will respond, most
`with improve ments in cytopenias (HI of the affected lin e age)
`and a minor ity (per haps 15%) with com plete response (CR), but
`responses can take sev eral months to develop (National Com-
`prehensive Cancer Center guide lines rec om mend a min i mum of
`6 cycles of treat ment before response assess ment) and are gen-
`er ally of lim ited dura bil ity.12,13 Critically, hema to log i cal improve-
`ment (HI) in any lin e age is asso ci ated with sur vival ben e fit for
`patients who con tinue ther apy; with sustained treat ment some
`indi vid u als will have improved blood counts across more than
`one lin e age, even converting to CR.7,13,14 Unfortunately, when pa-
`tients discontinue ther apy, rapid pro gres sion and relapse with
`poor sur vival are likely.15–21 Good responses and improved sur vival
`are often accom pa nied by recov ery of the plate let count in the
`first 1 to 3 cycles of treat ment, an early bio marker for those who
`are likely benefit ing from treat ment.22,23
`As for the patient in our first case, early cycles of HMA ther apy
`are often char ac ter ized by the wors en ing of cytopenias and the
`devel op ment of trans fu sion depen dence. This has the poten tial
`to cre ate a sub stan tial bur den for patients and fam i lies, espe cially
`since each monthly cycle has his tor i cally required 5 to 7 con sec-
`u tive daily doses of intra ve nous (IV; decitabine, azacitidine) or SQ
`(azacitidine) treat ment at a des ig nated infu sion cen ter. Given the
`early wors en ing of cytopenias, opti mal sup port ive care requires
`weekly or even twice-weekly vis its dur ing the sub se quent 3 weeks
`to assess trans fu sion needs as well as the pro phy lac tic use of anti-
`mi cro bi als.24 The devel op ment of RBC and plate let trans fu sion
`depen dence and neutropenia early in the course of treat ment can
`trig ger cli ni cians to inap pro pri ately reduce doses, delay, or even
`discontinue ther apy; deci sions known to com pro mise effi cacy.25,26
`Such deci sions may explain the dif fer ence between the sur vival
`ben e fit documented in con trolled pop u la tions of patients treated
`with HMAs in the con text of clin i cal tri als com pared to out comes
`in unse lected pop u la tions of patients, where improved sur vival
`rates have been less con sis tent.10,21,27,28
`A set of recent ret ro spec tive ana ly ses using the sur veil lance,
`epi de mi ol ogy, and end results Medi care-linked data base in a large
`cohort of 644 patients with higher-risk MDS eval u ated between
`2011 and 2015 sought to inves ti gate the way in which patients
`treated in a real-world set ting rou tinely receive ther apy. This study
`dem on strated that almost 30% of patients discontinued HMAs
`before com plet ing 4 cycles—a major ity after com plet ing only
`1 cycle of treat ment.29 A more detailed anal y sis of this same cohort
`reveals that an addi tional 20% of patients had early dose delays of
`>90 days between cycles, which likely obvi ates response.30 Over-
`all, among the approx i ma tely 50% of patients with higher-risk
`MDS, those who did not receive their HMA on sched ule for at least
`4 cycles had sub stan tially higher rates of health care uti li za tion
`char ac ter ized by increased emer gency room vis its, higher rates
`of hos pi tal i za tion, and more admis sions to skilled nurs ing facil i ties
`and hos pice. Suboptimally treated patients in this cohort were
`more likely to be older and unpartnered.
`Real-world stud ies fur ther dem on strate the rel a tively lim ited
`ini ti a tion of HMA treat ment for high-risk patients, with only 12%
`to 30% of pre sum ably eli gi ble patients receiv ing ther apy at all ,
`depending upon the report.20,27,30 These data high light the fact
`that despite the avail abil ity of HMAs as pri mary ther apy for MDS
`for more than 15 years, many patients do not receive any ther apy
`at all , and among those who do, early dis con tin u a tion or inad e-
`
`quate dose inten sity dur ing early cycles prob a bly com pro mises
`response.30 Such treat ment deci sions are likely to have an adverse
`impact on qual ity of life and com pro mise sur vival for those MDS
`patients, who will accrue all the tox ic ity from HMA ther apy and
`none of the ben e fits (HI, CR, or sur vival) of sustained ther apy.24
`The impor tance of ade quate sup port and ther apy per sis tence for
`patients with higher-risk MDS can not, there fore, be overstated.
`Oral agents, which might limit the need for treat ment-related
`infu sion clinic vis its and allow patients a sched ule based solely on
`trans fu sion needs, have the poten tial to decrease rates of early
`dis con tin u a tion due to treat ment bur den and thereby result in
`improved qual ity of life, effi cacy, and sur vival for patients with
`MDS. Furthermore, although most responses to HMAs have been
`shown to occur within 4 to 6 cycles of treat ment, con tin u a tion
`of ther apy beyond the first HI results in fur ther improve ment
`in response cat e gory for about half of those on treat ment.7,18
`Indeed, the best documented response seems to man i fest at
`least 2 to 3 cycles after the first documented HI response, with
`opti mal responses in 1 study manifesting as late as cycle 12 for a
`major ity of patients.13,18
`Given the ongo ing bur den of treat ment, con tin ued ther-
`apy on sched ule must be empha sized to patients and should
`not be underrecognized. Early on, trans fu sion depen dence may
`increase patient will ing ness to come to the office for treat ment,
`but in the long term, these vis its can become oner ous. Ongo-
`ing stud ies are test ing whether patients on an established par-
`en teral HMA reg i men can be switched to a lower-inten sity oral
`reg i men to max i mize adher ence with out com pro mis ing effi cacy
`(eg, NCT04806906). Such changes to our ther a peu tic approach
`may also improve the real-world out comes asso ci ated with HMA
`treat ment when com pared with those seen in clin i cal tri als. If
`pre ma ture dis con tin u a tion in responding patients is driven by
`doc tors and patients unwill ing to con tinue ther apy, at least in
`part due to the bur den of infu sion clinic appoint ments, I believe
`oral ther a pies may help us max i mize HMA ben e fit for patients.
`
`CLINICAL CASE 2
`A 69-year-old man with a med i cal his tory nota ble for obe sity,
`dia be tes, and bilat eral knee oste o ar thri tis was referred to our
`prac tice after a pre op er a tive CBC performed for a planned knee
`replace ment sur gery dem on strated throm bo cy to pe nia. The CBC
`showed a nor mal WBC count, plate lets of 40 000/µL, and ane mia
`with an Hb of 10 g; the mean cor pus cu lar vol ume was 106 fL. The
`remain der of the CBC and a com pre hen sive pro file were nor mal,
`and nutri tional workup dem on strated a suf fi ciency of vita min B12,
`folate, and iron; fer ri tin was 600 (min i mally ele vated), and the
`serum erythropoietin level was 580 IU (ele vated). The periph eral
`blood smear was nota ble for pelgeroid neu tro phils, throm bo cy-
`to pe nia, and RBC anisocytosis. A BM aspi rate and biopsy were
`hypercellular and ery throid pre dom i nant with 6% blasts and trilin-
`eage dyspoeisis. Cytogenetics were 47 XY, + 8 in 21 meta phases.
`NGS was nota ble for muta tions in TET2 and ASXL1. A diag no sis
`of inter me di ate-risk MDS (IPSS score, inter me di ate-1; IPSS-R,
`5 points [high risk]) was ren dered. After dis cus sion of prog no-
`sis and options, he elected to enroll in a phase 1b phar ma co-
`ki netic (PK) study of oral decitabine-cedazuridine fixed-dose
`tab let 35 mg/100 mg. Initial cycles were char ac ter ized by grade
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`Table 1. PK char ac ter is tics of the HMAs
`
`Agent
`
`Azacitidine IV34,40
`
`Azacitidine SQ34,40
`
`CC-48640,52
`
`Decitabine IV35
`
`Decitabine PO41
`
`C-DEC43
`
`Bioavailability of sin gle oral
`dose (% of par en teral)
`
`100%
`
`89%
`
`11%
`
`100%
`
`3.9%-14.1%
`
`60% (55–65) D1; 106% (98–114) D5
`
`4 throm bo cy to pe nia and neutropenia and plate let trans fu sion
`depen dence. After cycle 5 the patient had recov ery of the plate let
`count. A BM biopsy after cycle 4 dem on strated a blast per cent age
`of 4% with ongo ing dys pla sia. Referral for trans plant was made,
`and a fully matched sib ling donor was iden ti fied. The patient cur-
`rently remains on pro to col cycle 12 of oral decitabine-cedazuridine,
`given 4 days of a 28-day cycle (the dose was reduced after cycle
`8 for neutropenia last ing more than 2 weeks and BM show ing
`ongo ing ther a peu tic response). He has declined to pro ceed with
`trans plant due to con cerns about trans plant-related mor tal ity. He
`enjoys an excel lent qual ity of life and remains trans fu sion inde-
`pen dent (TI) and nonneutropenic with a plate let count above
`100 k/µL. These counts allow him to use non ste roi dal agents for
`man age ment of his knee pain with out bleed ing risk.
`
`PKs of par en teral vs oral HMAs
`Parenteral daily HMA treat ment with azacitidine and decitabine
`results in blood drug lev els that peak between 15 and 30 min-
`utes after admin is tra tion and an elim i na tion half-life between
`1 to 2 hours for azacitidine and 35 to 40 min utes for decitabine
`(Table 1).31–35 The short half-life of par en ter ally admin is tered HMAs
`is medi ated largely by the ubiq ui tous expres sion of the enzyme
`cyti dine deam i nase (CDA), which is highly expressed in a vari ety
`of human tis sues, includ ing the liver, the BM, and the gas tro in-
`tes ti nal (GI) tract. CDA rap idly degrades these agents into the
`inac tive metab o lites of uri dine (Figure 1).32,36
`The early devel op ment of oral HMAs was char ac ter ized by
`the rec og ni tion that when given alone oral admin is tra tion results
`in mark edly lower peak plasma con cen tra tions with a wide
`range of bio avail abil ity when com pared with IV or SQ dos ing
`strat e gies.33,37–41 Table 1 pro vi des a com par i son of half-life, sin gle-
`dose bio avail abil ity (based upon area under the con cen tra tion
`time curve), time to max i mal blood drug level (Tmax), and max-
`i mal blood con cen tra tion achieved after the admin is tered dose
`(Cmax) for each drug depending upon the route of admin is tra-
`tion. Differences in bio avail abil ity are medi ated by wide inter-
`and intraindividual ranges of CDA expres sion, with higher lev els
`in men, in those with spe cific sin gle-nucle o tide poly mor phisms,
`and in the con text of inflam ma tory driv ers.32,36,42
`
`Oral decitabine/cedazuridine
`Based upon the dem on stra tion of phar ma co log i cal equiv a-
`lence to IV decitabine, in July 2020 the US reg u la tory author i-
`ties approved the first oral HMA, decitaine-cedazuridine (C-DEC;
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`T1/2
`4 h
`
`4 h
`
`0.5 h
`
`0.5 h
`
`0.36–0.93 h
`
`1.5 h
`
`Tmax (range)
`0.5 h
`
`0.5 h (0.2–1.1)
`
`1 h (0.47–2)
`
`1 h
`
`0.5 h
`
`1 h (0.3–3.0)
`
`Cmax in ng/mL (%
`coef fi cient of var i a tion)
`
`Similar to SQ
`
`750 (54%)
`
`145 (64%)
`
`147 (49%)
`
`—
`
`145 (55%)
`
`35/100 mg), for patients with higher-risk MDS (inter me di ate/high
`risk by IPSS).43 In con trast with another recently approved agent,
`unmod i fied oral azacitidine (CC-486), which will be discussed
`sub se quently, C-DEC has been shown in a ran dom ized phase 3
`study to reli ably reca pit u late the blood drug lev els over time
`(cumu la tive area under the con cen tra tion-time curve; AUC∞; Fig-
`ure 2) resulting from daily treat ment for 5 days with IV decit-
`abine, and the 2 can there fore be treated inter change ably for
`the pur poses of clin i cal man age ment.44,45
`As expected, based upon the ubiq ui tous expres sion of CDA
`in the liver and GI tract, there is sub stan tial first-pass metab o-
`lism of oral decitabine. Single-agent oral decitabine was shown
`in a phase 1 study to result in low bio avail abil ity with sub stan-
`tial var i a tion across indi vid u als when com pared with IV decit-
`abine.41 To over come the var i able PKs resulting from dif fer en tial
`CDA lev els within and across indi vid u als, a novel inhib i tor of CDA
`(CDAi) given the des ig na tion E7727 (sub se quently cedazuridine)
`was devel oped and exten sively tested in ani mals.46 This agent
`dem on strated excel lent bio avail abil ity and a wide safety mar gin
`in non hu man pri ma tes.46,47 In a series of early-phase stud ies, the
`com bi na tion of cedazuridine with oral decitabine (devel oped
`ini tially as ASTX 727 and sub se quently des ig nated decitabine-
`cedazuridine) was tested to develop a com bi na tion pill designed
`to reca pit u late the PK and phar ma co dy namic (PD) admin is tra tion
`of IV decitabine dosed at 20 mg/m2 for 5 days.47 Serial blood col-
`lec tion was performed, and changes in global meth yl a tion using
`the repet i tive DNA sequence long inter spersed nuclear ele ment
`1 (a sur ro gate for global DNA meth yl a tion) was used as a tool for
`com par ing phar ma co dy namic (PD) effi cacy.48 Given the sub stan-
`tial intra- and inter in di vid ual var i abil ity in CDA lev els, the devel-
`op ment pro gram for this agent used each patient as their own
`con trol and com pared the PK/PD for IV decitabine against the
`PK/PD for the oral com bi na tion.47–49 Early stud ies used PK/PD
`read outs to titrate the oral doses of E7727 and decitabine in
`order to cre ate a near iden tity with IV decitabine admin is tra tion
`(Figure 2a). Ultimately, the 2 were com bined into a fixed-dose
`com bi na tion tab let containing 35 mg of decitabine and 100 mg
`of cedazuridine.43–45
`The phase 3 study of C-DEC, upon which approval was based,
`ran dom ized and treated 133 patients in a cross over design to
`receive either sequence A: C-DEC orally for 5 out of 28 days
`in cycle 1 followed by IV decitabine 20 mg/m2 × 5 out of 28 days in
`cycle 2 and sub se quently C-DEC for cycles 3 onward or sequence
`B: IV decitabine 20 mg/m2 × 5 out of 28 days in cycle 1 followed
`by C-DEC orally daily for 5/28 days in cycle 2 and sub se quently
`
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`

`Figure 2. Concentration time curves for (a) IV decitabine vs oral C-DEC and (b) SQ azacitidine vs CC-486.40,46 Figure 2a was re-
`produced from Future Oncol. 2021;17(16):2077–2087 and was modified only by renumbering for the purpose of this article. Figure
`2b was reproduced from Leukemia 2016;30(4):889–896 and was also modified only by renumbering. Both works are licensed under
`the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. http: / /creativecommons .org /licenses
`/by -nc -nd /4 .0 /
`
`C-DEC for cycles 3 onward; cycles were to be repeated every
`28 days (Figure 3). The pri mary end point for this phase 3 study was
`PK for cumu la tive AUC equiv a lence between IV and oral dos ing of
`decitabine. Eligible patients had MDS by French-Amer i can- Brit ish
`clas si fi ca tion, includ ing chronic myelomonocytic leu ke mia, or
`MDS deemed inter me di ate 1, 2, or high risk by the IPSS. The clin-
`i cal response to ther apy was assessed according to International
`Working Group 2006 cri te ria by an inde pen dent review com mit-
`
`tee. Enrolled patients were of median age 71 years (range, 44–88),
`65% were male, 12% had chronic myelomonocytic leu ke mia, the
`remain der had MDS, and 42% had >5% mar row blasts. Transfu-
`sion depen dence for either RBCs or plate lets was pres ent in 43%.
`After a median fol low-up of 12.6 months, com plete remis sion was
`reported in 28 (21%) and HI in 30 (23%) patients for an over all
`response rate of 43%. An addi tional 23 patients dem on strated
`mar row CR with out HI, although blast clear ance with out blood
`
`Figure 3. Summary comparison of the 2 completed phase 3 studies of C-DEC and CC-486 in MDS. Data abstracted from Garcia-Manero
`et al40,49,55 and Savona et al.45 AZA, azacitidine; DAC, decitabine.
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`count improve ment is an end point of unclear clin i cal sig nifi -
`cance. Adverse events (AEs) asso ci ated with C-DEC were con-
`sis tent with the famil iar toxicities from early cycles of par en teral
`HMA ther apy, nota bly cytopenias (≥grade 3: neutropenia, 52%;
`throm bo cy to pe nia, 50%; ane mia, 40%; leu ko pe nia, 21%) and
`infec tions (febrile neutropenia, 26%; pneu mo nia, 12%; sep sis, 7%);
`in con trast to CC-486, GI toxicities were not prominent.
`While phase 3 data have been reported only in abstract form,
`they largely reca pit u late the recently published results from a
`phase 2 mul ti cen ter ran dom ized cross over study of sim i lar design
`that enrolled and treated 80 patients. In this phase 2 study,
`responses (CR + HI) were observed in 44% of patients, with a
`major ity of first responses seen by cycle 3 and best responses by
`cycles 5 or beyond. Among base line trans fu sion-depen dent (TD)
`patients, about 50% became TI. Overall responses and tox ic ity
`from C-DEC appear com men su rate with those from par en ter ally
`admin is tered HMAs, and this is not sur pris ing given the iden ti cal
`blood drug lev els (AUC) achieved with this drug. Many patients,
`like our patient in Case 2, will have increased trans fu sion needs
`dur ing early cycles of ther apy. The same aggres sive sup port-
` ive care, includ ing pro phy lac tic anti mi cro bi als (a mold-active
`anti fun gal, an oral agent that cov ers gram neg a tives, and an
`anti-herpes simplex virus agent) for those with prolonged neu-
`tropenia and reg u lar eval u a tion of blood work for deter mi na tion
`of trans fu sion needs (man dated weekly dur ing cycles 1–3 by the
`clin i cal trial and gen er ally performed at least 1–2 times per week
`in my own prac tice as a stan dard of care), par tic u larly dur ing
`early ther apy cycles, is crit i cal to opti mize responses from this
`agent, as for all HMAs.4,24,25
`Oral C-DEC is cur rently the only oral HMA approved for MDS.
`This agent was approved only for higher-risk MDS dis ease cate-
`gories, but alter nate dos ing strat e gies with this agent are cur-
`rently under inves ti ga tion to deter mine the poten tial ben e fit
`for those with lower-risk dis ease (NCT03502668). Preliminary
`reports of effi cacy in higher-risk MDS from the phase 2 and 3
`tri als dem on strate clin i cal activ ity and response that are at least
`com pa ra ble with (and pos si bly supe rior to) the response to IV
`decitabine. Although cur rent guide lines favor SQ azacitidine as
`the first-choice HMA for patients with MDS given the sur vival
`ben e fit reported for this agent, decitabine and C-DEC are both
`con sid ered accept able alter na tives.10,50 Despite this caveat, sub-
`se quent reports from clin i cal tri als of azacitidine and decitabine
`sug gest that sur vival dif fer ences in the ini tial clin i cal tri als may
`stem from issues of trial design rather than true dif fer ences in
`effi cacy, and a major ity of prac tic ing MDS experts would con-
`sider these agents largely inter change able.25
`
`Unmodified oral azacitidine
`In Sep tem ber 2020 unmod i fied oral azacitidine (sub se quently
`des ig nated CC-486) at a dose of 300 mg daily for 14 out of 28
`days (not 21 days, as tested in the MDS study) per month was
`approved by the US Food and Drug Administration as main te-
`nance ther apy for inter me di ate- and poor-cyto ge netic-risk AML
`patients in com plete remis sion fol low ing an inten sive induc tion
`reg i men; this agent is not cur rently approved for patients with
`MDS.51,52 Although this agent shares its name with par en ter ally
`admin is tered azacitidine, the dis tinct PK pro files resulting from
`oral admin is tra tion of this agent ren der it a dif fer ent drug (Figure
`2b). Substitution of CC-486 for IV or SQ azacitidine is not accept-
`able for patients with MDS.
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`| Hematology 2021
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`| ASH Education Program
`
`As shown pre vi ously for sin gle-agent decitabine, the exten-
`sive expres sion of CDA results in low bio avail abil ity of unmod i-
`fied oral azacitidine. The pilot study of CC-486 ini tially dosed it
`daily for 7 days in an attempt to reca pit u late the stan dard par-
`en teral dos ing sched ule. In this study the max i mum tol er ated
`dose was iden ti fied to be 480 mg, with a mean oral bio avail-
`abil ity between 6% and 20%. Relatively poor oral bio avail abil ity
`could not be over come due to dose-lim it ing grades 3 and 4 GI
`tox ic ity (diar rhea [12.2%], nau sea [7.3%], vomiting [7.3%]) at the
`highest doses; other grade 3/4 AEs included febrile neutropenia
`(19.5%) and fatigue (9.8%).53 With this reg i men, hypomethylation
`was low est at day 15 and recov ered to base line by the end of
`the cycle.53,54 While some responses (mostly HI) were observed
`in this early study, decreases in meth yl a tion across a range of
`tested loci (the PD bio marker for activ ity) were less robust with
`CC-486 com pared with the par en teral azacitidine for mu la tion.
`Given the prevailing hypoth e sis that the opti mal hypometh-
`ylating activ ity of HMAs requires incor po ra tion dur ing S phase as
`well as the rel a tively slow pro lif er a tive rate of MDS pro gen i tors,
`sub se quent drug devel op ment focused on extending the dos ing
`sched ule to 14 or 21 days to allow opti mal drug incor po ra tion.38
`Lower peak blood drug lev els, with the sustained low-level expo-
`sure asso ci ated with this dos ing strat egy, would be expected to
`improve response rates. Indeed, exten sion of the dos ing sched ule
`in this man ner in a PK/PD study dem on strated effec tive induc-
`tion of hypomethylation using doses of 200 mg twice daily for 14
`days or 300 mg daily for 14 or 21 days that were low est at day 22
`of treat ment; hypomethylation of selected loci persisted at day
`28.33 This dose sched ule was tol er a ble, and although a major ity of
`patients expe ri enced GI (84%) and hema to log i cal (81%) toxicities,
`these were not dose lim it ing.38 The oral admin is tra tion of CC-486
`results in rapid absorp tion from the GI tract, with food con sump-
`tion and gas tric pH hav ing lim ited impacts on blood drug lev els.37
`Subset ana ly ses of early CC-486 stud ies have suggested that low-
`er-risk patients, par tic u larly those with throm bo cy to pe nia, might
`derive par tic u lar ben e fit from such a low-dose oral reg i men.39
`Recently, a phase 3 study of CC-486 in TD lower-risk MDS
`patients (by IPSS cri te ria) reported results on 216 patients ran-
`dom ized 1:1 between pla cebo and CC-486 dosed at 300 mg daily
`for 21 days of a 28-day sched ule (Figure 3).55 Eligibility required
`an Eastern Cooperative Oncology Group per for mance sta tus of
`at least 2, throm bo cy to pe nia (plate let count ≤75 × 109/L), and
`RBC trans fu sion depen dence of at least 2 units per month for at
`least 2 months (International Working Group 2006 cri te ria).12 The
`pri mary end point for this study was RBC TI; the use of exog e-
`nous growth fac tors was not per mit ted.
`Enrolled and treated patients in this study were of median
`age 74 years (range, 30–89), with IPSS-defined inter me di ate-1 risk
`dis ease (by IPSS-R, 28% had high or very high-risk MDS). They
`were heavily RBC TD (requir ing about 3 units/month) and base-
`line throm bo cy to pe nic (median 25 × 109/L; ~30% plate let TD; 40%
`with base line plate let count <20 × 109/L). The study met its pri mary
`end point of RBC TI in 30% of the CC-486 patients vs 11% of pla-
`cebo-treated patients; HI of the plate let count was also higher
`for CC-486-treated patients—24% vs 4.6%. Responses took on
`aver age 2.4 months, and decreased trans fu sion needs for both
`RBCs and plate lets were sustained with CC-486 treat ment (for a
`median of 10 months for RBCs and 12 months for plate lets); bilin-
`eage improve ments (in both Hb and plate let counts) were seen
`in about a quar ter of the CC-486-treated patients. With a median
`
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`fol low-up of about 13 months, an under pow ered over all sur vival
`esti mate was the same in both arms, although the rate of AML pro-
`gres sion was lower in the CC-486 arm. Toxicities were as expected
`with an HMA-based ther apy and were worst in the first cycles of
`treat ment. Most patients reported low-grade GI tox ic ity asso ci-
`ated with tak ing CC-486. Grades 3 and 4 cytopenias (neutropenia,
`47% vs 12%; throm bo cy to pe nia, 29% vs 16%) and infec tions (febrile
`neutropenia, 28% vs 10%) were more com mon in the CC-486-
`treated patients vs those who got pla cebo. A higher rate of early
`death was reported in the CC-486 arm (16 vs 6 patients), pre dom-
`i nantly asso ci ated with bac te rial infec tions as well as neutropenia.
`The phase 3 data reviewed above sug gest sub stan tial activ-
`ity in TD lower-risk MDS patients, likely supporting an expan sion
`of the labeled indi ca tion in the near future.55 High rates of early
`infec tious death in this lower-risk pop u la tion should at least war-
`rant the rou tine use of pro phy lac tic anti-infec tives in order to
`mit i gate risk and may give the Food and Drug Administration
`pause in the deci sion to approve this agent.24 Since CC-486 has
`a mark edly dis tinct PK/PD pro file from par en teral azacitidine,
`the two agents are not inter change able (Figure 2b); addi tional
`stud ies are needed to deter mine whether CC-486 is appro pri-
`ate for indi vid u als with higher-risk MDS. Pr