| MyetopysPLastic SYNDROMES: UNDERSTANDING THE CURRENT TREATMENT LANDSCAPE |
`
`CeTY OF
`%
`
`=
`
`Incorporating novel approachesin the management of MDS
`.
`.
`beyond conventional hypomethylating agents
`5 O:
`= @ Olatoyosi Odenike
`
`we
`
`@o
`
`Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, IL; and The
`University of Chicago Comprehensive Cancer Center, Chicago, IL
`
`In the last decade, the treatment of higher-risk myelodysplastic syndromes (MDS) has revolved around the azanu-
`cleosides, azacitidine and decitabine, which at lower doses are postulated to work predominantly via their effects on
`inhibition of DNA methyltransferases and consequent DNA hypomethylation. For patients whorelapse after, or do not
`respond to, hypomethylating agent therapy, the outcomeis dismal, and new agents and approachesthat have the
`potential to alter the natural history of these diseases are desperately needed. Allogeneic stem cell transplantis the only
`knownpotentially curative approach in MDS,butits applicability has been limited by the advanced age of patients and
`attendant comorbidities. There is now anincreasing array of new agents underclinical investigation in MDS that aim to
`exploit our expanding understanding of molecular pathways that are importantin the pathogenesis of MDS.This review
`focuses on a critical appraisal of novel agents being evaluated in higher-risk MDS that go beyond the conventional
`hypomethylating agent therapies approved by the US Food and Drug Administration.
`
` Limitations of treatment with HMAsare therefore obvious; namely,
`
`Learning Objectives
`
`e To understand the current treatment landscape in higher-risk
`MDSandthe limitations of conventional hypomethylating
`agent therapy
`e To gain an insightinto the novel agents and approaches under
`clinical investigation in higher-risk MDS
`
`manypatients have primary resistant disease, time to onset of response
`and achievement of best response can take several months, and
`myelosuppression before onset of response is nearly universal. Fur-
`thermore, despite the fact that a survival benefit has been demonstrated
`with azacitidine in higher-risk MDS,* these agents are not curative.
`The median duration of responseis in the 10- to 14-month range.***
`Outcomeafter failure of HMAsis particularly dismal, with a median
`survival of less than 6 months.’* Therefore, the development of new
`agents and strategies beyond the traditional HMAs approved by
`the FDA represents a significant area of unmet need at this time.
`This review will focus on novel agents and combinations under in-
`vestigation, including novel formulations of HMAs, novel epigenetic
`modulators, immunotherapeutic approaches, and therapies targeting
`specific molecular pathwaysin higher-risk myelodysplastic syndromes
`(Figure 1).
`
`Next-generation hypomethylating agents
`Because HMAsare S-phase-specific, a more prolonged exposure to
`the drug may allow greater incorporation into DNA.If used at rela-
`tively low doses, this would be hypothesized to lead to more sustained
`hypomethylation. A longer schedule of parenteral administration of
`decitabine and of azacitidine have been associated with significant
`activity in both acute myeloid leukemia (AML) and MDS,including
`poor prognosis subsets, lending somecredenceto that hypothesis.©?"!!
`These considerations, along with the very short half-lives (less than
`30 minutes) of conventional HMAs, coupled with the need for
`chronic administration to achieve or maintain a response, has spurred
`the developmentof the next generation of hypomethylating agents'”
`(Table 1). These include oral formulations of existing HMAsand/or
`
`Introduction
`The most notable development in the treatment of higher-risk myelo-
`dysplastic syndromes (MDS)in the last several years was the approval by
`the US Food and Drug Administration (FDA) of the hypomethylating
`agents (HMAs) 5-azacytidine (azacitidine) and 5-aza-2'deoxycytidine
`(decitabine) in 2004 and 2006,respectively. The use of these agents at
`lower doses, where their effects on DNA methyltransferase (DNMT)
`inhibition are postulated to predominate, results in objective responses
`including complete (CR) and partial (PR) responses in approximately
`15% to 20% ofpatients. An additional 20% to 30% achieve hematologic
`improvement (HI) in blood counts.’ Similar response rates have been
`demonstrated in clinical
`trials focused solely on higher-risk MDS
`(intermediate-2 or high-risk by International Prognostic scoring system
`[IPSS]). For example, in the landmark study by Fenaux etal, in which
`azacitidine was compared with conventional care regimens, the CR plus
`PRrate was 29%. The overall response rate (ORR) defined as CR, PR,
`and HI was 49%.* Responsesare gradual in onset, with a median onsetto
`response of 2 to 4 months and median time to best response of 5 to
`6 months. Responses can occur aslate as 12 months,although the majority
`of responses (>90%) would be expected to occur by 6 months™®)
`
`Conflict-of-interest disclosure: The authoris on the boardofdirectors or an advisory committee for Baxalta, CTI BioPharma, Celgene,Incyte, Pfizer, Jazz Pharmaceuticals,
`and ABIM, and hasreceived honoraria from AbbVie and Dava Oncology.
`Off-label drug use:| will be discussinginvestigational drugs in the treatment of MDSincluding novel formulations of azanuclesoides, novel epigenomic modulators,
`combinationsinvolving immune checkpointinhibitors, agents targeting specific genotypic subsets,kinase inhibitors, and BCL2inhibitors.
`
`460
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`CELGENE 2102
`APOTEXv. CELGENE
`IPR2023-00512
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`American Society of Hematology
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`[= ——— —
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`Transcription
`
`Immune
`Checkpoint
`Inhibition
`
`
`
`Figure 1. Novel agents and pathways underinvestigation in MDS. Epigenetic modulators including HMA, HDACis, BETinhibitors, and LSD1i affect
`chromatin structure and transcription; immune checkpointinhibition with a variety of monoclonal antibodies targeting the PD-1/PDL1 interaction, or
`CTLA-4 andits correspondingligand facilitate antigen (MHC) recognition by T-cell receptors; IDH1/2 inhibition affects the mutant enzyme within
`mitochondria, splicing modulation acts preferentially on cells harboring mutationsin splicing factors (splice mut); kinase inhibitors downregulate key
`signaling pathways including the RAS/MAPKand the PI3-K/AKT/m-TOR pathway.
`
`novel compounds,rationally designed, with a view to increasing or
`prolonging cellular exposure to HMAtherapy and ultimately im-
`proving therapeutic outcome.
`
`Oral azanucleosides
`In the last few years we have witnessed the introduction of oral
`azanucleosidesinto clinical trials. These agents may improvepatient
`convenience,eliminate injection site reactions, and facilitate chronic
`administration, including alternative dosing schedules, designed to
`lead to a more sustained cellular exposure.
`
`Oral azacitidine (CC-486) wasinitially studied in an open-label pilot
`trial. The agent was demonstrated to have 17% bioavailability, when
`compared with historical experience with parenteral azacitidine, after
`single-dose administration at 60 or 80 mg.'* A subsequentdose-finding
`study conducted in patients with MDS, chronic myelomonocytic
`leukemia (CMML), and AML, evaluating a 7 consecutive day oral
`administration schedule, established the maximum tolerated dose
`(MTD) of CC-486 as 480 mg daily for 7 days, with cycles being
`repeated every 28 days. Diarrhea was the dose-limiting toxicity. The
`most commonadverse events (AEs)included gastrointestinal toxicities,
`febrile neutropenia, and fatigue. ORR in patients with MDS or CMML,
`and without prior HMA exposure, was 73% (11 of 15 responded,
`including 6 CR and 5 HI). ORR in those whohadreceivedprior therapy
`was 35%.'* Extended dosing schedules of CC-486, 300 mgdaily for
`14 or 21 days, were investigated in lower-risk MDS.'* Accordingto
`the results of this early-phase trial, CC-486 is now being inves-
`tigated in a phase 3 trial (NCT01566695) in IPSS lower-risk MDS,
`with red cell transfusion dependency and thrombocytopenia. A recent
`analysis that focused on the experience of CC-486 across trials in
`
`patients who were previously exposed to HMA therapy showed that
`of 20 patients who had received 6 or more cycles of prior HMA
`therapy, 7 (35%) responded.'© Thus,there is an ongoingeffort evaluating
`CC-486 in the HMAfailure space, in combination with other novel
`approaches (Table 2).
`
`A majorhurdle in the clinical developmentoforal azanucleosidesis the
`fact that both azacitidine and decitabine are rapidly cleared by cytidine
`deaminase present in the gut and the liver, thus limiting their bio-
`availability. ASTX727, a novel formulation of oral decitabine paired
`with an oral cytidine deaminase inhibitor-E7727, is being studied in
`MDS,with a view to improvingthe bioavailability of the oral decitabine.
`Theresults ofa first-in-human phase 1 dose escalation trial of ASTX727
`demonstrated that the combination of the cytidine deaminase inhibitor
`E7727and oral decitabine, administered concurrently, successfully
`emulated the pharmacokinetic profile of intravenous (IV) decitabine.
`ASTX727 exhibited similar area under the curve parameters and a
`similar safety profile to IV decitabine, given at the standard dose and
`schedule.'’ The most common AEswere hematologic, including grade
`3 or greater thrombocytopenia, neutropenia, and febrile neutropenia.
`Nosignificant gastrointestinal-related AEs were reported. Preliminary
`report ofefficacy revealed a numberofresponses, including 5 CR and
`5 HI (n = 43). Four additional patients experienced a marrow CR.
`These results occurred in a patient population in which almosthalf had
`received prior HMA.
`
`A phase 2 fixed-dose confirmation stage of the study has just been
`completed, in whichpatients with intermediate- or high-risk MDS were
`randomly assigned in a crossoverdesignto receive the dose ofASTX727
`(35 mg decitabine plus 100 mg E7227)selected from the dose-escalation
`
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`Table 1. Next-generation HMAsandinhibitors of other posttranscriptional/posttranslational marks
`
`Mechanism of action
`
`Phase of development
`
`Comments
`
`Intermediate 2/high-risk MDS-HMAfailure in
`phase 1, HMA-naive in phase 2
`Intermediate 2/high-risk MDS-HMAfailure
`
`MDS-HMAnaive; high orvery high-risk; stage 1,
`openlabel; stage 2, randomized, placebo
`controlled
`
`MDSexcludes low orvery low-risk disease,
`MDS/MPN, AML, myelofibrosis
`MDS-HMAfailure, AML-R/R
`MDS-HMAfailure; single-agent cohort or
`combination with azacitidine cohort
`
`+ATRA in MDS-R/R and AML-R/R
`
`+ATRA and L-DAC in MDS-HMAfailure and
`AML-R/R
`MDS or CMML HMAnaive with high or very
`high-risk and/or excess blasts
`Randomized, openlabel
`
`Reference
`
`NCT02103478
`
`NCT02907359
`
`_NCT03151304
`
`NCT02158858
`
`NCT02308761
`NCT02929498
`
`NCT02273102
`NCT02717884
`
`NCT02610777
`
`Agents
`
`ASTX727
`
`DNMTinhibition
`
`Phase 1/2
`
`Guadecitabine
`(SGI-1 10)
`Pracinostat azacitidine
`
`DNMTinhibition
`
`HDACinhibition DNMT
`inhibition
`
`CPI-0610
`
`BETinhibition
`
`RO6870810/TEN-010
`GSK2879552*
`
`BETinhibition
`LSD1 inhibition
`
`Tranylcypromine
`
`LSD1 inhibition
`
`Pevonedistat
`azacitidinet
`
`NAEinhibition
`
`DNMTinhibition
`
`L-DAC,low-dosecytarabine; R/R,relapsed and/orrefractory.
`*Notyet recruiting at time of manuscript submission.
`tAccrual is complete.
`
`Phase 3
`
`Phase 2
`
`Phase 1
`
`Phase 1
`Phase 2
`
`Phase 1
`Phase 1/2
`
`Phase 2
`
`phase of the study, versus IV decitabine at the standard dose and
`schedule. The phase 2 results confirm that the area underthe curve
`of oral ASTX727at this dose and schedule, as well as its effect on
`demethylation of repetitive (LINE-1) sequences, is similar to that
`observed with IV decitabine. Future plans for the development of
`this agent will likely involve further evaluation as an alternative to
`IV decitabine. Ideally, the clinical development of this agent and
`other oral azanucleosides should also include evaluation ofalternative
`
`doses and schedules targeted to induce more sustained hypomethylation
`and lower myelosuppression when compared with parenteral
`azanucleoside therapy.
`
`Preliminary evidence of promisingactivity in a phase 2 trial conducted
`exclusively in higher-risk previously untreated MDS or CMML was
`also recently reported.” Almosthalf the subjects enrolled (45%) had
`a complex karyotype, with 38% having TP53 mutations. Preliminary
`results indicate promising activity in this setting, with an ORR of
`61% (n = 36), including 28% with CR. Myelosuppression, requiring
`dose reduction, occurred in a third of patients. The most common
`nonhematologic AEs were grade1/2 nausea, fatigue, and dyspnea.
`These results suggest guadecitabine is worthy of further investigation
`in larger randomized trials in the frontline setting in MDS.
`
`Histone deacetylase inhibition
`Histone acetylation is a dynamic process, catalyzed by histone
`acetyltransferases, and is associated with an open chromatinstructure
`and recruitment to chromatin of factors involved in transcriptional
`regulation, DNArepair, and DNA replication. Histone deacetylases
`(HDACs) removeacetyl groups from thelysinetails of histones and
`lead to transcriptional repression and a closed chromatin configu-
`ration. HDACinhibitors (HDACis) were investigated on the premise
`that transcriptional de-repression associated with their use would
`result in upregulation of a variety of genes aberrantly silenced in
`cancercells, including tumor suppressor genes.” These agents have,
`however, been shownto affect both histone and nonhistoneproteins,
`and have beenassociated with pleiotropic effects on various genes
`involvedin cell cycle regulation, apoptosis, and angiogenesis. They
`have limited single-agent activity in myeloid malignancies.
`
`Rationally designed HMA formulations
`Anotherstrategy that has been employed to try to circumvent the rapid
`degradation of azanucleosides by cytidine deaminase is to develop
`anovelformulation that is chemically modified to berelatively resistant to
`deamination. Guadecitabine (SGI-110) is a novel dinucleotide of deci-
`tabine and deoxyguanosine,linked by a phosphodiester bond. Gradual
`cleavage of the phosphodiester bond is purported to lead to a slower
`release of the active decitabine moiety, thus prolonging cellular exposure
`to the drug. In a phase 1 study in patients with MDSand relapsed/
`refractory AML, myelosuppression was the dose-limiting toxicity.
`The MTD in MDSwasestablished to be 90 mg/m? administered
`daily (90 mg/m?/d) for 5 consecutive days. The biologically effective
`dose wassignificantly lower, and was determined to be 60 mg/m*/
`d for 5 consecutive days, based on the achievement of maximum DNA
`hypomethylationat this dose level.'* This dose/schedule (60 mg/m*/
`HDACishavebeeninvestigated extensively in combinationtrials with
`d) is now underfurther investigation in a variety of trials in AML,
`DNMTinhibitors (DNMTis), based on the hypothesis that therapeutic
`MDS, and CMML.In MDS or CMML,ongoing studies (Tables 1
`targeting of 2 pathwaysof epigenetic silencing in myeloid neoplasia
`and 2) have focused on the HMA failure space, evaluating single-agent
`would be synergistic. This hypothesized synergy between DNMTis
`guadecitabine in the phase 3 setting, or in combination with other
`and HDACis has been repeatedly demonstrated in vitro,”* but has
`novel agents in early-phase trials. These trials in the HMA failure
`been challenging to duplicate in vivo. Early-phase trials combining
`setting are based on preliminary results of encouraging activity seen
`HDACis and DNMTis confirmedthefeasibility of these combinations
`with guadecitabinein a phase2 trial, including patients with MDS who
`and yielded encouraging*”® results. This promise has, however, not
`have had prior exposure ttHMAs. '? Other groupsevaluating the agent
`
`in patients with disease that has relapsed after, or is refractory to, yetbeenrealized in the contextof a series of randomized phase2trials
`azacitidine therapy have reported more modestresults.”°
`in higher-risk MDSevaluating HDACi/DNMTi combinations®?””? vs
`
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`Table 2. Combination therapy with immune checkpoint inhibitors
`Phase of
`development
`
`Agents
`
`Mechanism ofaction
`
`Comments
`
`Reference
`
`Nivolumab
`ipilimumab
`azacitidine
`
`Immune checkpointinhibitors plus DNMT
`inhibition
`
`Phase 2
`
`Cohorts include single-agent immune
`checkpointinhibitors and combination
`with azacitidine; MDS-HMAfailure and
`naive
`
`NCT02530463
`
`Nivolumab
`azacitidine others*
`
`Immune checkpointinhibitors plus DNMT
`inhibition
`
`Phase 2/3
`
`Randomized phase 2, multiple experimental NCT03092674
`group study, selected exptal group in
`phase 2 proceeds to phase 3,
`azacitidine is the control group in both
`phase 2 and 3
`
`
`inhibition
`
`Durvalumab CC-486—Immune checkpoint inhibitors plus DNMT Phase 2 MDS-HMAfailure NCT02281084
`
`
`
`Durvalumab
`azacitidine
`
`Immune checkpointinhibitors plus DNMT
`inhibition
`
`Phase 2
`
`Pembrolizumab
`azacitidine*
`Nivolumab lirilumab
`azacitidine
`
`Immune checkpointinhibitors plus DNMT
`inhibition
`Anti-KIR MABplus immune checkpoint
`inhibitors + DNMTinhibition
`
`Phase 2
`
`Phase 2
`
`Randomized phase 2, MDS, HMAnaive-
`high or very highrisk or intermediate risk
`with excess blasts or poorrisk
`karyotype; AML = 65y old
`MDS-HMAfailure and naive cohorts,
`intermediate 1 or higherrisk
`Lirilumab + nivolumab in lower-risk MDS
`lirilumab + nivolumab + azacitidine in
`
`NCT02775903
`
`NCT03094637
`
`NCT02599649
`
`intermediate-2/high-risk MDS, HMAnaive
`Atezolizumab Single-agent immune checkpoint inhibitors|NCT02508870Immune checkpointinhibitors plus DNMT Phase 1
`
`
`azacitidine
`inhibition
`or combination with azacitidine. MDS-
`HMAfailure and HMA-naive cohorts
`
`
`
`Atezolizumab
`guadecitabine
`Ipilimumab
`decitabine
`
`Immune checkpointinhibitors plus DNMT
`inhibition
`Immune checkpointinhibitors plus DNMT
`inhibition
`
`Phase 1/2
`
`Phase 1
`
`NCT02935361
`
`NCT02890329
`
`MDS-HMAfailure, intermediate-1 or
`higher-risk
`MDS-HMAfailure and with excess blasts
`or MDS-relapsedafter allo-HCT, AML
`R/R, or =75 y old; allo-HCT naive and
`allo-HCTfailure cohorts
`
`
`inhibition
`
`Ipilimumab entinostat—Immune checkpoint inhibitors plus HDAC Phase 1b MDS-HMAfailure NCT02936752
`
`
`
`KIR, killer cell immunoglobulin-like receptor; MAB, monoclonal antibody.
`*Notyet recruiting at time of manuscript submission.
`
`single-agent DNMTi. A higher incidence of adverse events and/or
`early treatment discontinuation in the combination groups has been
`cited as an explanation for some of the recent disappointing results
`obtained in the context of these randomized trials.7*?? Pharmaco-
`dynamic antagonism has been cited as another potential explanation
`for failure of HDACi/DNMTi combinations to show benefit in the
`
`far. Ultimately, further developmentofthis class of drugs in MDSis
`predicated on being able to develop more tolerable combinationsthat
`are amenable to chronic administration and onthe ability to demonstrate
`a relative clinical advantage of the HDACi to these combination
`regimens.
`
`Lenalidomide-based combinations
`randomized setting. For example, the addition of entinostat did not
`Lenalidomide is FDA-approved for lower-risk MDSwith deletion 5q
`translate into clinical benefit, and less demethylation was observed in
`[del(5q)] MDS whoare transfusion dependent. The agent has more
`the combination group in the E1905 Intergroup randomized phase 2
`modestactivity in non-del (5q) lower-risk MDS (reviewed extensively
`trial, evaluating the HDACientinostat combined with azacitidine vs
`in an accompanying article by Giagounidis*’). In higher-risk MDS,
`single-agent azacitidine.® The possibility that this issue is schedule-
`lenalidomide was combined with azacitidine in a phase 1/2 trial in 36
`dependenthas been raised, with an overlapping schedule of admin-
`patients, with an ORR of 72%,including CR in 44% and HIin 28%.*!
`istration of the HDACi and DNMTileading to less incorporation of
`These promising results led to investigation of this combination in
`the azanucleoside into DNA,and consequently less hypomethylation.
`
`There is an ongoing randomized early-phasetrial in AML (NCT01305499) a larger groupofpatients with higher-risk MDS or CMMLinarecent
`designed to test this hypothesis by evaluating an overlapping vs
`North American Intergroup trial, $1117. This was a randomized
`a sequential schedule of administration of the azacitidine/entinostat
`phase 2 trial in which 277 patients were randomly assigned in a
`1:1:1 fashion to azacitidine combined with lenalidomide or with the
`combination.Atthis time, ongoing trials in MDSsuchas the azacitidine/
`pracinostat combination trial (Table 1) are focused on exploring al-
`ternative doses and/or schedules of HDACi/DNMTi combinations,
`with a view to improvingtolerability and outcome. In addition, beyond
`HDACi/DNMTitrials, other combinations involving HDACi and
`other novel agents such as immune checkpoint inhibitors are now
`underway in MDSin the HMA failure space (Table 2). At the moment,
`the future of HDACi-containing regimens in MDSis uncertain, given
`the multiple negative randomized trials that have been conducted thus
`
`HDACi vorinostat vs azacitidine monotherapy. The primary end-
`point was response rate. ORR wassimilar, at 38% for azacitidine
`monotherapy, 49% for azacitidine plus lenalidomide, and 27% for
`azacitidine plus vorinostat. Response duration and overall survival
`(OS) were also similar across treatment groups. There was a higher
`incidence of dose modifications and reductions in the combination
`
`groups compared with azacitidine monotherapy, implying poorer
`tolerability of the combination regimens.7®
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`In patients with CMML,the ORR washigherin the azacitidine plus
`lenalidomide group, with 68% (13 of 19 patients) responding vs
`28% (5 of 18 patients) in the azacitidine monotherapy group.”
`Theseresults suggest the azacitidine plus lenalidomide combination
`may bebeneficial in patients with CMML. The numberofpatients
`with CMMLenrolled in the $1117 is too small, however, to be able
`to draw definitive conclusions. These results require validation in
`larger trials, focused on the CMMLpatient population.
`
`Novelinhibitors of other posttranslational or
`positranscriptional modifications
`Epigenomic dysregulation is a critical aspect of MDS pathogene-
`sis.** Beyondtargeting DNA methylation and HDACrecruitmentin
`MDS, however, there has been an increasing focus, in recent times,
`onthe clinical investigation of other inhibitors of posttranslational or
`posttranscriptional modifications that have the potential to affect the
`expression of key genes and pathways that are important in ma-
`lignant myeloid transformation.
`
`NEDD8-activating enzymeinhibition
`Pevonedistat is a NEDD8-activating enzyme (NAE) small molecule
`inhibitor. NAE regulates neddylation, which is a process by which
`Cullin-RING E3 ubiquitin ligases (CRLs) are activated and involves
`conjugation of the ubiquitin-like protein NEDD8to the Cullin protein
`scaffold. Activation of CRLsis, in turn, critical for proteasome-
`mediated protein degradation and proteasomal destruction of CRL
`substrates. Pevonedistat forms a covalent adduct with NAE, which
`leads to impaired CRL activation and accumulation of downstream
`CRL-dependentsubstrates. Several of these substrates are relevant to
`pathogenesis of myeloid malignancies, including cell cycle regulation,
`DNAdamage,andsignal transduction pathways. Preclinical work in
`AML demonstrated activity in cell lines, primary patient material, and
`murine xenograft models of AML.**
`
`Ina phase1 study of pevonedistatin relapsed refractory AML or MDS,
`modest single-agent clinical activity was observed: 17% ORR for
`schedule A (days 1, 3, and 5; n = 27) and 10% for schedule B (days1,
`4,8, and 11; n = 19). A subsequentdoseescalation trial was conducted
`investigating the combination of pevonedistat with azacitidine in
`treatment-naive AML. The MTD ofthe combination was pevonedistat
`20 mg/m? administered on days 1, 3, and 5 plus azacitidine 75 mg/m?
`administered on days 1 to 5, 8, and 9 on 28-day cycles. Grade 3
`hyperbilirubinemia and grade 4 aspartate aminotransferase (AST) were
`doselimiting. In the dose expansion phase ofthe study, of 55 patients
`enrolled, ORR was 60%, including 18 CR. Myelosuppression was
`common,with a febrile neutropenia rate of 25%. The median OS was
`7 months, with survival tending to be longer in patients with lowerblast
`burden below 30%.** A randomized trial is required to assess the
`relative contribution of pevonedistat to the combination. This is on-
`going in high-risk MDSandlow blast count AML(Table 1). Accrual to
`this trial was recently complete, and the results are eagerly awaited and
`are likely to determine the future developmentof this agent in MDS.
`
`Bromodomaininhibition
`Bromodomain and extraterminal (BET)proteins are epigenetic readers
`that recognize acetylatedlysinetails of histones, and thus areas of open
`chromatin structure or transcriptionally active sites. BET proteins
`possess conserved bromodomain modules that bind acetylated lysine
`tails and also interact with a numberofother proteins and function
`as scaffolds for molecules involved in gene transcription. BET
`proteins have been implicated in various cancers including myeloid
`
`malignancies. Inhibition of BET proteins leads to a significant re-
`duction of a numberof genes in a cell- and context-specific-dependent
`manner.*> Thefirst selective BET inhibitor, JQ1, was demonstrated to
`be active in vitro and in vivo in preclinical models of NUT midline
`carcinoma, a rare aggressive intrathoracic squamouscell carcinoma
`characterized by a rearrangement of the BET proteins BRD4 or
`BRD3, thusestablishing proof of concept for the therapeutic targeting
`ofBETproteins.*° In preclinical studies in AML,the use ofJQ] in AML
`cell lines and primary patient samples was associated with down-
`regulation of MYC and MYC-driven gene signatures specific to the
`leukemia stem cell population.*”°° There are a numberofclinical
`trials ongoing with BET inhibitors in various malignancies including
`MDS(Table 1). These trials are based largely on the potential
`promise of this class of drugs based on the experiencein preclinical
`models. It is too early at this juncture, however, to make definitive
`statements aboutclinical activity (andtolerability) of BETi in myeloid
`malignancies, including MDS.
`
`LSD1 inhibition
`Overexpression of the mono and dimethyl lysine demethylase, LSD1
`(also known as KDM1A)has been implicated in a variety of tumors
`including myeloid malignancies. LSD1 is important in maintaining
`embryonic stem cell pluripotency and regulates hematopoietic differ-
`entiation by keeping key differentiation genes and programssilenced.
`Inhibition of LSD1 or knockdownof the gene enhancesdifferentiation.
`LSD1 inhibition sensitized non-APL AML to all trans-retinoic acid
`
`(ATRA), and this was associated with an increase in histone 3 lysine 4
`dimethylation (H3K4me2), a marker of active transcription, and
`expression of myeloid differentiation genes. Furthermore, treatment
`with ATRA and a pharmacologic inhibitor of LSD1, tranylcypromine,
`resulted in a significant decrease in engraftment of primary AMLcells
`in nonobese diabetic-severe combined immunodeficient mice, sug-
`gesting this combination may target leukemia-initiating cells.*? Other
`novel LSD1 inhibitors have demonstrated activity in preclinical studies
`in AML and MDS“?Clinical trials are in progress evaluating LSD1
`inhibitors in combination with prodifferentiating agents such as ATRA
`or HMAsinpreviously treated patients with AML and MDS(Table 1).
`Theresults of these early-phase trials will determine thelikelihood for
`future developmentof these combinationsin larger groups of patients
`with higher-risk MDS.
`
`Immune checkpointinhibition
`Allogeneic stem cell transplant validates immunotherapy as a viable
`therapeutic strategy in MDS,but its applicability has been limited by
`the older age of patients at presentation and attendant comorbidities.
`The success of immune checkpoint inhibitors in solid tumors and
`Hodgkin lymphomahasled to the rapid introduction of these agents
`into clinical trials in other settings. These agents are based on the
`premise that a wide variety of tumors upregulate molecules such as
`PD-1/PDL-1 and CTLA4,which serve under normal circumstancesas
`“checkpoints” to recognize self and prevent autoimmunity.*! Cancer
`cells hijack these checkpoints as a meansto evade the immunesystem.
`Preclinical studies in myeloid malignancies have demonstrated that
`blockade of the PD-1/PDL1 pathway overcomes immuneevasion and
`prolongs survival in a murine model of AML.** Single-agentipili-
`mumab therapy has been investigated in a phase | trial in patients who
`relapsed after an allogeneic stem cell transplant and was associated
`with a CRin all 4 patients with extramedullary AML andin 1 patient
`with MDSthat had evolved to AML.*? These observations serve as
`proof of concept for immune checkpoint inhibition in AML/MDSin
`the postallogeneic stem cell transplant space.
`
`464
`
`American Society of Hematology
`
`

`

`Table 3. Other novel targeted agents and kinase inhibitors
`Phase of
`development
`
`Comments
`
`Reference
`
`Agents
`
`Mechanism of action
`
`Enasidenib (AG-
`221)*
`Ivosidenib (AG-
`120)*
`
`H3B8800 MDS-HMAfailure/intolerant, intermediate-2 or high-|NCT02841540Splicing modulator Phase 1
`risk; AML-R/R/U; CMML previously treated
`MDS- HMAfailure, intermediate-2 or high-risk, single- NCT02966782
`agent venetoclax and azacitidine+venetoclax
`combination cohorts
`
`IDH2 inhibition
`
`IDH1 inhibition
`
`
`
`Venetoclax
`azacitidine
`
`BCL2inhibition DNMT
`inhibition
`
`IDH2 mutant advanced and/or high-risk AML, MDS- NCT01915498
`RAEB1/2, or high-risk or R/R
`IDH1 R132 mutant advanced heme malignancy
`
`NCT02074839
`
`Phase 1/2
`
`Phase 1/2
`
`
`
`Phase 1
`
`Venetoclax
`azacitidine
`
`Rigosertib
`
`Ibrutinib
`azacitidine
`
`BCL2inhibition DNMT
`inhibition
`
`Phase 2
`
`Multitargeted kinase inhibition
`
`Phase 3
`
`BTKinhibition DNMTinhibition
`
`Phase 1b
`
`Selumetinib
`azacitidinet
`
`MEKinhibition DNMT
`inhibition
`
`Phase 1
`
`MDS- HMAnaive, intermediate-2/high-risk and > 5% NCT02942290
`blasts, randomized
`HMAfailure MDS-EB,includes RAEB-t; phase 3vs
`physician’s choice (includes best supportive care;
`azacitidine or DEC use also permitted)
`Intermediate or higher-risk MDS, HMAfailure (dose
`escalation stage only), HMAnaiveincluded in both
`stages of study
`Advanced myeloid malignancies including MDS-
`relapsed/refractory
`
`NCT02562443
`
`=NCT02553941
`
`BTK, Bruton tyrosine kinase; DEC, decitabine; MEK, mitogen-activated protein/extracellular signal-regulated kinase; RAEB,refractory anemia with excessblasts.
`*No longerrecruiting.
`tNotyet recruiting, clinicaltrials.org listing pending at the time of manuscript submission,
`
`Upregulation of PD-1 and PDL-1 expression has been demon-
`strated in primary MDS and AMLcells obtained from patients
`undergoing hypomethylating agent therapy, and has been linked to
`resistance to these agents.** Immune checkpoint inhibitor plus
`HMAcombinations in MDSare basedin part on the premise that
`HMAsmayact as an immunesensitizer*> and augmentthe activity
`of immune checkpoint blockade in MDSbyfacilitating recognition
`of malignant cells by cytotoxic CD8* T cells. Immune checkpoint
`blockade may also help overcome a potential mechanism ofre-
`sistance to azanucleoside therapy. The preliminary experience thus
`far suggests limited activity when immune checkpointinhibitors
`are used as single agents after HMAfailure.*° There are several
`combinationtrials of immune checkpoint inhibitors plus HMAsor
`HDACisthat are now ongoing in MDS, in both the HMA-naive and
`failure settings (Table 2). These trials are heterogeneous in design
`and patient population enrolled, and are largely predicated on the
`success of immune checkpoint inhibitors in solid tumors and
`Hodgkin lymphoma. Randomizedtrials will be required to decipher
`the relative contribution of immune checkpoint inhibition to these
`combinations.
`
`Therapies targeting specific genotypic subsets
`IDH1/2 inhibition
`Mutationsin isocitrate dehydrogenase enzymes (IDH1 and IDH2),are
`presentin approximately 15% to 20% ofpatients with AML. In MDS,
`these mutations are less common,being present in approximately 6%
`of cases, with the incidence rising with leukemic transformation.*7**
`Under physiologic conditions, IDH enzymescatalyze the conversion
`of isocitrate to a-ketoglutarate. IDH1/2 mutations confer a neomorphic
`enzymatic activity, resulting in isocitrate being converted to the
`oncometabolite R-2-hydroxyglutarate (2-HG). Elevated levels of
`2-HG result in competitive inhibition of a-ketoglutarate-dependent
`enzymesincluding TET2 and Jumonji-C enzymatic activity, leading
`to DNA andhistone hypermethylation, changes in chromatin con-
`figuration, and differentiation block.*? Small molecule inhibitors of
`mutant IDH1 or IDH2bindto the catalytically active site, preventing
`
`conversion of a-ketoglutarate to 2-HG andresulting in progressive
`reversal of histon