Anti-CD47 Therapy and Other New Approaches to the Treatment of Myelodysplastic

Evolving ParadigmsAnti-CD47 in Myleodysplastic Syndrome

Myelodysplastic syndrome (MDS) is a heterogeneous group of hematologic malignancies characterized by bone marrow failure, peripheral blood cytopenia, oligoclonal hematopoiesis, cellular dysmorphology, and genomic instability.1 MDS can transform into acute myeloid leukemia (AML).

About 90% of MDS cases have no identifiable cause; however, exposure to tobacco smoke, ionizing radiation, organic chemicals, heavy metals, herbicides, pesticides, fertilizers, stone and cereal dusts, exhaust gases, nitro-organic explosives, and petroleum and diesel derivatives are risk factors associated with MDS.2

According to the National Cancer Institute’s Surveillance, Epidemiology, and End Results database, approximately 20,541 new cases of MDS were reported annually in the United States from 2007 through 2011.3 The incidence of MDS increases with age; most patients who are diagnosed with MDS are over the age of 65 years, and the median age at time of diagnosis is 71 years.1,3,4

MDS may be clinically asymptomatic and stable for years, in part because of immune-mediated suppression of hematopoiesis.1,3 Furthermore, aberrant bone marrow cells may overexpress immune checkpoint proteins, which allows them to escape detection by patients’ immune systems.1,5,6

MDS is diagnosed by a histopathologic evaluation of peripheral blood and bone marrow with a bone aspirate and biopsy.3 To be diagnosed with MDS, patients must meet the following criteria: at least 1 peripheral blood cytopenias that cannot be explained by other causes, defined as hemoglobin less than 10 g/dL (100 g/L), absolute neutrophil count less than 1.8 x 10/L (less than 1800/microL), and platelets less than 100 x 10/L (less than 100,000/microL), blasts that account for less than 20% of nucleated cells in the bone marrow and/or peripheral blood, and evidence for dysplasia in greater than 10% of cell lines.

Nearly 78% of patients with MDS have blasts containing at least 1 genemutation.7 The most common genes mutated in MDS are SF3B1, TET2, SRSF2, ASXL1, RUNX1, TP53, U2AF1, DNMT3A, and EZH2.8 Mutation can be correlated with specific clinical features such as the severity of cytopenia, blast percentage, overall survival (OS), and response to therapy.3 For example, TP53 is a tumor suppressor gene associated with complex cytogenetics, worse thrombocytopenia, and poor OS, whereas tumors that express TET2 mutations respond better to hypomethylating agents (HMAs).

Prognostic scoring systems are used by clinicians to stratify patients and inform treatment decisions.3 The International Prognostic Scoring System (IPSS) was developed in 1997 and is based on the percentage of blasts present in the bone marrow, the karyotype, and the number of cell lineages with cytopenia. The revised IPSS (IPSS-R) adds a separate score for absolute neutrophil count, hemoglobin value, and platelet value. The IPSS-R gives greater weight to the severity of cytopenia and cytogenetic abnormalities and has been shown to better predict survival and AML evolution than the original IPSS model.2,3

Patients with an IPSS-R score of greater than 3.5 (intermediate through very poor prognoses) are considered to have higher-risk disease.4 Median survival is considerably lower in patients categorized as having very high-risk disease than in patients having very low-risk disease: 0.8 years vs 8.8 years respectively.9 Approximately 40% of patients have higher-risk disease as defined by the IPSS-R. Furthermore, progression to AML can occur rapidly in untreated patients with higher-risk MDS.4

Median OS in patients with MDS is about 3 years; OS decreases as patient age increases.1,4 Because of the advanced age of and multiple comorbid conditions in patients with MDS, less than 5% of patients with MDS are eligible for allogeneic hematopoietic stem cell transplantation (HSCT), the only curative therapy available for MDS.1 Infections and hemorrhagic complications related to low blood cell counts caused by MDS are leading causes of death in most patients with MDS.

This article will discuss unmet needs in the current standard of care for MDS and explore novel therapeutics that are in development for MDS, with a particular focus on therapies that target CD47 immune checkpoint transmembrane proteins, the overexpression of which allows MDS blasts to evade immune system detection and which is correlated with disease pathogenesis in AML cells.5 Finally, this article will detail studies of approved cancer therapies in combination with HMAs in patients with MDS.


Historically, treatment options have been very limited for patients with MDS because of the extreme genetic and clinical heterogeneity of MDS disease subsets as well as the advanced age and comorbidities of this patient population.10-12

Therapeutic choice—observation, supportive measures, systemic agents, or HSCT—for patients with MDS is based on the IPSS-R–defined risk level of their disease.12 The aim of therapy for patients with low-risk disease is to relieve symptoms caused by anemia and thrombocytopenia. Delaying the progression to AML is the goal for patients with intermediate- to very high-risk disease.


Lenalidomide, an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties, is approved by the FDA for the treatment of adult patients with transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with a deletion 5q [del(5q)] cytogenetic abnormality with or without additional cytogenetic abnormalities.13 In patients with del(5q) MDS, lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells.

This indication was granted based on the results of an international, multicenter study (NCT00065156) to determine the frequency of erythroid and cytogenetic responses to lenalidomide therapy in patients with transfusion-dependent, del(5q) MDS.14

Of the 148 patients who received 10 mg of lenalidomide for 21 days every 4 weeks or daily, 112 (76%) had a reduced need for transfusions and 99 (67%) no longer required transfusions, regardless of karyotype complexity.14

The median time to response was 4.6 weeks and the median duration of transfusion independence was not reached after a median follow-up of 104 weeks.14 The maximum hemoglobin concentration reached a median of 13.4 g/dL, with a corresponding median increase of 5.4 g/dL. Cytogenetic improvement was evaluated in 85 patients; 62 experienced improvement, and 38 obtained complete cytogenetic remission. Of the 106 patients whose serial bone marrow samples could be evaluated, 38 patients experienced complete resolution of cytologic abnormalities.

The most common adverse events (AEs) leading to treatment interruption and dose adjustments were neutropenia (55%) and thrombocytopenia (44%).14

As shown by this study, lenalidomide could provide rapid, durable response in patients to reduce transfusion requirements and reverse cytologic and cytogenetic abnormalities in patients with MDS; however, this therapy is limited to patients with low- to intermediate-risk MDS with del(5q).13,14


HSCT is a procedure in which a patient receives donated stem cells to replace their own stem cells that have been destroyed by treatment with radiation or high doses of chemotherapy.15 These donated stem cells may come from the blood or bone marrow of a related donor who is not an identical twin of the patient or from an unrelated donor who is genetically similar to the patient. Although the optimal timing of deploying HSCT has not been defined, it is generally used in second-line settings.16

According to consensus recommendations by an expert international panel, patient characteristics (eg, age, performance status, frailty, and comorbidities) and disease related risk factors need to be considered to determine a patient’s eligibility for HSCT.16

The outcomes of patients registered in the European Society for Blood and Marrow Transplantation database who received HSCT between 2000 and 2011 (N = 286) was reported in a retrospective analysis that aimed to identify risk factors in recipients of HSCT.17 The primary end points were progression-free survival (PFS) and OS. All patients included in the analysis were classified as low or intermediate-1 risk as defined by the IPSS.

OS at 3 years was 58%, and PFS was 54%.17 Although the results of this study showed positive responses to HSCT, as previously stated, the majority of patients with MDS are of advanced age and have multiple comorbidities; therefore, few of these patients are eligible for HSCT.11

HMA Therapies

Drugs in the HMA class inhibit DNA methylation in MDS cells.18,19 There are currently 2 FDA-approved HMAs: azacytidine and decitabine.

Both drugs require prolonged administration before patients respond to treatment. The median number of cycles required before first hematologic response in patients treated with azacytidine is 3, with 90% responding by cycle 6.20 Patients treated with decitabine require a median of 2.2 cycles of treatment before first response.

For patients who are not transplant candidates, HMAs are their only therapeutic option.10 If HMA therapy fails, there are no second-line therapies available; consequently, OS for these patients is less than 6 months.


Azacitidine is indicated for continued treatment of adult patients with AML who achieved first complete remission or complete remission with incomplete blood count recovery following intensive induction chemotherapy and are not able to complete intensive curative therapy.18

Azacitidine is a pyrimidine nucleoside analogue of cytidine that inhibits DNA/RNA methyltransferases.18 Following cellular uptake and enzymatic biotransformation to nucleotide triphosphates, azacitidine is incorporated into the DNA and RNA of AML cells, which inhibits DNA methyltransferases, reduces DNA methylation, and alters gene expression, including re-expression of genes that regulate tumor suppression and cell differentiation. Incorporation of azacitidine into the RNA of malignant cells inhibits RNA methyltransferases, reduces RNA methylation, decreases RNA stability, and decreases protein synthesis. The antileukemic activity of azacitidine was demonstrated by reduction of cell viability and induction of apoptosis in AML cell lines in vitro. Azacitidine decreased tumor burden and increased survival in leukemic tumor models in vivo.

The efficacy of azacitidine was compared to conventional care regimens (best supportive care, low-dose cytarabine, or intensive chemotherapy) in NCT00071799, a phase 3, international, multicenter, controlled, parallel-group openlabel clinical trial in patients with higher-risk MDS.21 Between February 13, 2004, and August 7, 2006, 358 patients were randomized to receive azacytidine (n = 179) or conventional care (n = 179). The primary end point was OS; a key secondary end point was time to transformation to AML.

After a median follow-up of 21.1 months, median OS for patients treated with azacitidine was 24.5 months vs 15.0 months for patients treated with conventional care.21 At last follow-up, over half of all patients who participated in the study died; 82 of these patients were treated with azacitidine and 113 were treated with conventional care. Based on Kaplan-Meier estimates, 2-year OS was 50.8% for azacitidine vs 26.2% in the conventional care group.

The median time to AML transformation for patients treated with azacitidine was 17.8 months vs 11.5 months for patients treated with conventional care.21 Peripheral cytopenias were the most common grade 3 or higher AEs for both groups.

Although azacitidine treatment demonstrated improved OS and extended time to AML transformation compared with conventional care regimens in this study, clinicians who have used the study’s dose schedule for azacytidine (75 mg/m2 per day for 7 consecutive days) have reported that it is inconvenient.2 The impact of modified dosing schedules on survival is not yet known. Furthermore, “real world” clinical experience with azacitidine has not reproduced the survival outcomes observed in randomized trials.10


Decitabine is indicated for treatment of adult patients with MDS.19 Decitabine exerts its antineoplastic effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis.19 Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated into DNA. Nonproliferating cells are relatively insensitive to decitabine.

A phase 3, randomized study compared decitabine to supportive care in 170 patients with intermediate- to high-risk MDS. The primary end points were overall response rate (ORR) and time to AML transformation or death.

Among the 89 patients treated with decitabine, the ORR was 17%, which included 8 patients (9%) who obtained complete response (CR).20 No responses were reported in patients who received supportive care. Twelve patients (13%) in the decitabine group experienced hematologic improvement vs none in the supportive care group. The median time to AML progression or death was numerically longer for patients treated with decitabine than for patients who received supportive care (12.1 vs 7.8 months), but the results were not significant (P < .16).


Because of the high failure rate of HMA therapies in patients with higher-risk MDS and the limited treatment options available, there is a considerable unmet need for safe and effective treatment options in MDS for patients with higher-risk disease who are ineligible for HSCT.10,20,21

New therapies are currently under investigation that aim to improve rates of response and duration of response (DOR), delay transformation to AML, and prolong survival.12 Magrolimab, pevonedistat, and eprenetapopt are among several novel therapeutics currently being investigated with ongoing clinical trials listed in the Table.22-35


CD47 has been a potential target of interest in therapeutic development for MDS and other hematologic malignancies.36 CD47 is a transmembrane protein and represents the ligand for the signal regulatory protein alpha (SIRPα).37-39 SIRPα activation triggers a signal transduction cascade, which leads to the inhibition of phagocytosis. Thus, CD47/SIRPα is a macrophage inhibitory checkpoint that is essential in allowing cancer progenitor cells to escape phagocytosis. CD47 overexpression plays a key role in mediating cancer cell evasion of phagocytosis from the innate immune system.

Overexpression of CD47 has been found on tumor cells in patients with MDS, which indicates that malignancies can co-opt CD47 to evade recognition and attacks by a patient’s immune system.36-39 The goal of anti-CD47 targeted therapies is to inhibit CD47 expression in tumor cells, which would allow the immune system to properly identify and destroy malignant cells.

Potential mechanisms of antitumor control via CD47 inhibitors are enhanced phagocytosis, increased antibody-dependent cell-mediated cytotoxicity, increased complement dependent cytotoxicity, induction of apoptosis, and increased cytokine production.36-38

On September 15, 2020, magrolimab (5F9)—a first-in-class, investigational, anti-CD47 monoclonal antibody—was granted FDA approval for a Breakthrough Therapy designation (BTD) to treat patients with newly diagnosed higher-risk MDS.40 The BTD was granted on the basis of positive preliminary results observed in an ongoing phase 1b trial (NCT03248479) that evaluated magrolimab in combination with azacitidine in patients with previously untreated intermediate-, high-, and very high-risk MDS.40,41

Magrolimab targets CD47, a macrophage immune checkpoint, to inhibit its “don’t eat me” signal on cancers.40 Magrolimab works synergistically with azacitidine to enhance tumor phagocytosis in AML with CD47 blockade.

NCT03248479 assessed the efficacy and safety of magrolimab in combination with azacitidine in patients with intermediate- to very high-risk MDS (as defined by the IPSS-R) as well as patients with untreated AML who were not eligible for induction chemotherapy.41 The median age of the patients (N = 43) was 73 years; 18 patients had MDS and 25 had AML. Among these patients, 28% harbored a TP53 mutation.

The primary end points were to evaluate AEs, the rate and duration of complete response (CR), and rate of red blood cell transfusion.41 Secondary end points included ORR, DOR, and PFS. Responses were assessed by using International Working Group 2006 and European LeukemiaNet 2017 criteria for MDS and AML patients, respectively.

An initial and dose escalation regimen of magrolimab 1-30 mg/kg weekly was used in combination with azacitidine 75 mg/m2 on days 1 to 7 in a 28-day cycle.41

The combination of magrolimab with azacitidine was well tolerated, with a safety profile similar to that of azacitidine alone.41 Treatment-emergent AEs (TEAEs) that occurred in at least 15% of patients were anemia (37%), neutropenia (26%), and thrombocytopenia (5%). Treatment-related febrile neutropenia was observed in only 1 patient (2%), and 1 patient discontinued treatment due to a TEAE.

Of the 29 patients evaluable for efficacy at the time of data cutoff, 13 were in the MDS group and 16 were in the AML group.41 All patients with untreated MDS responded to treatment; 7 patients (54%) obtained CR. Of these, 5 patients (39%) obtained marrow CR, which was accompanied by hematologic improvement in 3 patients. One patient did not obtain CR but experienced hematologic improvement. In the AML group, 11 patients (69%) responded to treatment; 8 patients obtained CR or CR with incomplete blood count recovery (50%), 2 patients obtained partial response (PR) (13%), 1 patient (6%) obtained morphologic leukemia-free state, and 5 patients (31%) obtained stable disease. The expansion cohort of the trial reports data on 29 evaluable patients, with objective response in 13 of 13 patients (100%) with untreated MDS, including 54% who achieved a CR and 39% with marrow CR.

Median time to response was more rapid with magrolimab combined with azacitidine (1.9 months) than previously observed in studies of azacitidine monotherapy.41 No median DOR or OS was reached for any of the treated patients, with a median follow-up of 4.9 months for patients with MDS and 5.8 months for patients with AML.

Notably, 7 of 8 evaluable patients (88%) with TP53 mutations obtained an objective response; of these, 5 were patients with AML who obtained CR or CR with incomplete blood count recovery and 2 were patients with MDS (1 obtained CR and 1 obtained marrow CR).41 This highlights the potential efficacy of the magrolimab-azacitidine regimen in a patient population with poor prognosis and difficult-to-treat disease.

The success of the phase 1b trial supported the launch of ENHANCE (NCT04313881), a phase 3, randomized, double-blind, placebo-controlled, international multicenter trial, which will evaluate the efficacy of magrolimab in previously untreated patients with higher-risk MDS.22 The participants are randomized to receive magrolimab in combination with azacitidine or azacitidine with placebo. Patients in the magrolimab combination arm will receive the same magrolimab dose as used in NCT03248479.

The primary end point is CR, which will be measured by the percentage of participants who obtain CR within 24 months and OS within 5 years.22 Also, the study will measure time to transformation to AML within 5 years.

The ENHANCE trial, which is still actively recruiting, will determine whether adding magrolimab to azacitidine will improve patient outcomes and fulfill an unmet need for newly diagnosed high-risk MDS, including patients with TP53 mutation.22 The anticipated study completion date is February 2025.


Another investigational drug that was recently granted BTD by the FDA was pevonedistat (previously TAK-924/MLN4924), a first-in-class NEDD8-activating enzyme inhibitor.42 The approval, which was issued July 30, 2020, was based on results of the phase 2, open-label, international pevonedistat-2001 study (NCT02610777), which evaluated the combination of pevonedistat with azacitidine in patients with rare leukemias, including higher-risk MDS.

Pevonedistat is a small-molecule inhibitor of the NEDD8- activating enzyme (NAE), which processes NEDD8 for binding to target substrates.43 The best-characterized NAE targets in cells are the cullin-RING E3 ubiquitin ligases, which direct the degradation of specific substrates (eg, p27, CDT1, and Nrf-2) through the proteasome. Pevonedistat impairs NAE activity, which leads to accumulation of the cullin- RING E3 ubiquitin ligase substrate and causes antiproliferative effects in AML. Among the mechanisms that have been implicated as drivers of these effects are disruption of cellular redox via stabilization of pIKB (a critical mediator of cell killing), DNA replication, and cell cycle arrest.

To be eligible for inclusion in phase 2 of pevonedistat-2001, patients had to have morphologically confirmed higher-risk MDS, nonproliferative chronic myelomonocytic leukemia (CMML), or low-blast AML (LB-AML; 20% to 30% myeloblasts in bone marrow).44 Overall, 120 patients were enrolled and randomized 1:1 to receive either pevonedistat in combination with azacitidine or azacitidine monotherapy.

The primary end points were OS and event-free survival (EFS), defined as time from randomization to death or transformation to AML, higher-risk MDS, CMML, or death from LB-AML.44

The median follow-up was 21.4 months for patients in the pevonedistat-azacitidine combination group and 19.0 months for patients in the azacitidine monotherapy group.44 In the intent-to-treat (ITT) population, patients in the pevonedistatazacitidine combination group experienced improved OS compared with patients in the azacitidine monotherapy group (21.8 vs 19.0 months). Also, patients treated with the pevonedistat-azacitidine combination had longer median EFS than patients treated with azacitidine alone (21.0 vs 16.0 months). Among 108 response-evaluable patients, ORR was 70.9% for patients in the pevonedistat-azacitidine combination group compared with 60.4% for patients in the azacitidine monotherapy group. Median DOR was longer in patients treated with the pevonedistat-azacitidine combination than patients treated with azacitidine monotherapy (20.6 vs 13.1 months).

In particular, patients with higher-risk MDS responded well to pevonedistat-azacitidine combination therapy.44 In this subgroup, median OS among patients treated with pevonedistat- azacitidine combination was 23.9 months compared with 19.1 months in patients treated with azacitidine monotherapy. Also, patients in the higher-risk MDS subgroup treated with pevonedistat-azacitidine combination experienced longer median EFS than patients treated with azacitidine monotherapy (20.2 vs 14.8 months). ORR among patients with higher-risk MDS who were treated with the pevonedistat-azacitidine combination was 79.3% compared with 56.7% in patients treated with azacitidine monotherapy. Also, 56.7% of patients with higher-risk MDS treated with pevonedistat-azacitidine obtained CR, nearly double the number of patients treated with azacitidine monotherapy who obtained CR (26.7%). The median DOR was also considerably higher in this subgroup among patients treated with the pevonedistatazacitidine combination than in patients treated with azacitidine monotherapy (34.6 vs 13.1 months, respectively).

The safety profile of the pevonedistat-azacitidine combination was comparable to that of azacitidine alone.44 TEAEs of grade 3 or higher were experienced by 90% of patients treated with the pevonedistat-azacitidine combination compared to 87% of patients treated with azacitidine monotherapy. The most frequent grade 3 or higher TEAEs experienced by patients treated with the pevonedistat-azacitidine combination or azacitidine monotherapy were neutropenia (33% vs 27%), febrile neutropenia (26% vs 29%), anemia (19% vs 27%), and thrombocytopenia (19% vs 23%), respectively.

Because patients with MDS frequently have age-related and disease-related comorbidities, it is important to note that treat-ment with the pevonedistat-azacitidine combination did not result in additional myelosuppression, which meant patients could remain on treatment longer with the pevonedistat-azacit-idine combination than they could on azacitidine alone.44 This contrasts with prior studies, in which the addition of a second agent to azacitidine led to increased toxicity, resulting in azacit-idine dose reductions or shorter dosing schedules.


The TP53 mutation is present in about 10% to 20% of patients with MDS or AML, and it is associated with a high rate of relapse following HSCT relapse and failure with HMA thera-pies.45,46 Eprenetapopt (APR-246) is a novel, first-in-class, small molecule that restores wild-type p53 function and selectively induces apoptosis in mutant TP53 cancer cells.45

In January 2020, eprenetapopt received BTD approval by the FDA as a combination therapy with azacitidine to treat TP53-mutant MDS. It also received an orphan drug designation for the treatment of AML.45

NCT03072043, a phase 1b/2 open-label, multicenter, dose-escalation, dose-expansion study, evaluated the safety and efficacy of eprenetapopt in combination with azacitidine in patients with TP53-mutated (as determined by next generation sequencing [NGS]) higher-risk MDS and AML.45

Fifty-five patients were in the ITT population: 40 in the MDS group, 11 in the AML group, and 4 in the MDS/myeloproliferative neoplasms group.45 Along with 75 mg/m2 of azacitidine, eprenetapopt was intravenously administered through dose escalation on days 1 to 4 in each 28-day cycle. Dose-limiting toxicities were evaluated to establish the treatment dose administered in phase 2.

The primary end point of the phase 2 study was CR (as defined by International Working Group 2006), and key secondary end points included ORR and OS.45

ORR was 71%, which included 44% of patients obtaining CR.45 Among patients with MDS, ORR was 73% (n = 29), including 20 patients (50%) obtaining CR and 23 patients (58%) obtaining a cytogenetic response. ORR was 64% among patients with AML, which included 4 patients obtaining CR (26%). Median OS was 10.8 months.

AEs were similar to those reported for azacitidine or eprenetapopt monotherapy.45 The most common grade 3 or higher AEs were febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%).

The results of this study demonstrated treatment with eprenetapopt in combination with azacitidine provided a higher rate of CR for patients with MDS than HMA monotherapy, especially in patients whose tumors have TP53 mutations.45


Several anticancer agents that are already approved by the FDA for cancer treatment are being studied in combination with HMAs as potential therapies for MDS; among these are venetoclax and ivosidenib.46-50


Venetoclax, a selective BCL2 inhibitor, is indicated in com-bination with azacitidine, decitabine, or low-dose cytarabine for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.46 On July 21, 2021, venetoclax was granted BTD by the FDA for the treatment of newly diagnosed higher-risk MDS.47

In a study published in 2020, Bell et al reviewed medical records of 44 patients with MDS who received venetoclax in combination with HMAs at 5 major medical centers in the United States.48 Among the patients included in the study, 41% were classified by IPSS-R as very high risk, 43% had poor- or very poor-risk cytogenetics, and 28% had TP53 mutations.

For the total cohort, ORR was 59%.57 CR was obtained in 14% of patients, 27% obtained bone marrow CR with hematologic improvement, and 18% obtained bone marrow CR without hematologic improvement.48 Median time to initial response was 1.6 months. At the time of data cutoff, 17 patients (39%) had died, and 27 patients (61%) were still alive. Both the median follow-up and OS were 7.6 months.


Ivosidenib is a selective inhibitor of mutant IDH1, which is reported in up to 10% of patients with AML.49 Ivosidenib is indicated for the treatment of adult patients with relapsed or refractory AML with a susceptible IDH1 mutation, as detected by an FDA-approved test.

In the phase 1b study NCT02677922, 23 newly diagnosed patients with mutant IDH1 were treated in a 28-day schedule of ivosidenib 500 mg once daily in combination with azacitidine 75 mg/m2 for 7 days.50 The ORR was 78.3% in 18 patients, 14 of whom (60.9%) obtained CR. Median time to response was 1.8 months and median time to CR was 3.7 months. OS probability at 1 year was 82%.


After 15 years of stagnation, the treatment landscape for MDS is now expanding. Patients with historically poor prog-noses and few agents from which to choose could have access to more therapeutic options, which were specifically de-signed for their particular disease subtype. This expansion has been driven, in large part, by increased knowledge of tumor genomics, which has allowed identification of common gene mutations and overexpression in MDS, some of which are correlated with specific clinical features associated with patient poor outcomes.3,7,8 This information has provided re-searchers with new targets, such as CD47, for which novel therapeutics can be developed. Finally, NGS provides clinicians with a valuable tool to test patients’ tumors and determine which therapies are most likely to provide patients with deep and enduring therapeutic responses.


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