A Look Back on New and Emerging Data in MDS

Dr. Guillermo Garcia-Manero
Guillermo Garcia-Manero, MD
Dr. Kenneth B. McCredie Chair in Clinical Leukemia Research
Chief, Section of Myelodysplastic Syndromes
Department of Leukemia 
The University of Texas MD Anderson Cancer Center
Houston, Texas

Dr. David A. Sallman
David A. Sallman, MD
Assistant Member
Malignant Hematology Department
Moffitt Cancer Center
Tampa, Florida

It is critical that healthcare providers in the community setting remain up to date in the management of MDS. In this activity, you will hear from Dr. Guillermo Garcia-Manero and Dr. David Sallman on the advances made this year in MDS. This newsletter will cover recent studies that will impact practice and what to look for in the future.

Recent studies have confirmed and extended our knowledge of TP53 mutations and how they impact prognosis in patients with myelodysplastic syndromes (MDS). Could you describe recent findings that may have clinical implications?

Dr. Garcia-Manero: TP53 is becoming a very important topic in MDS. Approximately 8% of MDS cases have a mutation on this particular gene, and there are now treatments under investigation that may have activity in this subset of poor-prognosis patients. We know that TP53 is one of the key genes involved in oncogenesis, and in patients with MDS, it is associated with an increased rate of transformation to AML and resistance to multiple therapies. There is some data that hypomethylating agents like decitabine or azacitidine may be more active compared to standard chemotherapy for patients with TP53-mutated disease, but prognosis remains very poor and responses are short-lived, even for these hypomethylating agents.

In that context, there have been studies that have extended our understanding of TP53 mutations in MDS, including the recently published analysis of 359 patients with MDS and a complex karyotype, which is defined as two or more cytogenetic abnormalities, and is a highly adverse prognostic indicator; this study showed the poor risk associated with complex karyotype was driven by presence of TP53 mutations.1 So I think a key message for the community reading this would be that, if you have complex karyotype, it is still worth looking for this particular mutation, due to risk and poor prognosis.

There was also a study, presented at ASCO 2019, that reviewed our experience at MD Anderson, looking at patterns of leukemic transformation in patients with TP53-mutant MDS.2 Predictors of AML transformation in this retrospective study included TP53 loss of heterozygosity, presence of three TP53 abnormalities, and complex cytogenetics, basically corroborating what we already know, which is that these mutations really confer poor prognosis, particularly for patients with MDS that transform to AML, such that these patients really are in need of more advanced therapies.

With that in mind, there is in fact a new compound under investigation called APR246 that is being tested on a randomized phase 3 trial that may have activity in this particular subset of patients.3 There is also a compound known as Hu5F9-G4, also called 5F9 and now magrolimab, that may have activity in patients with TP53-mutated MDS and AML. So while more study is needed, we may hopefully soon have some new treatment tools for these patients that right now have an extremely poor prognosis.

Could you please describe how magrolimab is thought to work, and some of the clinical data to date?

Dr. Sallman: We know that cancer cells can express what are called pro-“eat me” signals that can tell macrophages to induce phagocytosis and essentially eat the cancer cells. The challenge with that on cancer cells is that they express a marker called CD47 that is really a “don’t eat me” signal. And so really what Hu5F9-G4, or magrolimab, does is block the interaction of CD47 with the receptor SIRPα on macrophages. So magrolimab can lead to selective elimination of cancer cells by blocking this interaction again of CD47 with SIRPα. This has been shown in a lot of different tumor models, particularly in AML, while CD47 has been found to be significantly expressed both on leukemic stem cell and blast populations as well.4-5

Those findings ultimately led to the phase 1b clinical trial results presented at ASCO 2019, which included a safety run-in cohort of patients with relapsed/refractory AML or MDS, followed by an expansion cohort of untreated AML or MDS patients who received magrolimab in combination with azacitidine.6 For the MDS group specifically, all patients did have to have intermediate- or higher-risk MDS.

As far as safety, there was not any maximum tolerated dose, so all patients have been treated at the full dose. We only had one dose-limiting toxicity, which was a severe infusion-related reaction, all of the signs and symptoms of which resolved within 24 hours, but that was the one patient that has been discontinued from treatment. The side effects we do see with magrolimab include mild transaminitis, mild infusion reactions, and of note, an anemia that is typically transient and tends to normalize within four weeks. We see this anemia because old red blood cells also express “eat me” ligands, which is our body’s normal way to eliminate those cells; we try to account for that in the dosing regimen by using a priming dose intended to mitigate on-target anemia. Otherwise, we’ve really not seen any exacerbation of cytopenias, that is to say, neutropenia or thrombocytopenia, which definitely can occur with azacitidine.

In terms of efficacy, we had one responder in 10 relapsed/refractory patients, but where the data was quite exciting was with magrolimab in combination with azacitidine in untreated patients. This was clearly active, with a 100% overall response rate in untreated MDS, and a little more than half had complete remissions. The median time to response was 1.9 months, so that was more rapid than the three to four months we would expect with standard azacitidine. Additionally, we are seeing deeper responses, including a moderate percentage of complete cytogenetic responses, and a subset of patients who achieved minimal residual disease (MRD) negativity. A quarter of our patients were successfully bridged to transplant, which was higher than expected.

Based on these data, we have expanded enrollment, particularly with regard to MDS patients. And secondarily, I think we will want to know if there are molecular subsets or groups of patients that may best respond to this type of treatment. And I think longer follow-up will be quite critical, both to see the durability of responses, and to get a more complete picture of the type of responses that we’re seeing. If these responses are durable and hold up in a larger study, I could foresee this being a potential frontline treatment option for high-risk MDS patients. Given that we’ve really had a lack of new drugs for MDS since 2006, I think the whole field would be very excited to see another agent, and particularly one that improves response rates and may get more patients to transplant, and obviously having more durable remissions would be extremely welcome in the field.

What is APR246, and what do we know about its activity in TP53-mutated AML and MDS?

Dr. Sallman: APR246 is novel, first-in-class compound that really selectively targets mutant TP53 cancer cells. This agent selectively induces apoptosis in those cells via mutant p53 protein re-activation by restoring the wild-type conformation. In patients with mutant TP53 AML, APR246 had single-agent activity, and subsequently we looked at this agent combined with azacitidine in a phase 1b study of patients with mutant TP53 MDS/AML. In that study, we saw really high response rates, including an overall response rate of 100% (11 of 11 patients), of which nine were CR and two were marrow CR.7 That led to the opening of the full phase 2 portion of the trial, and there is also a randomized phase 3 trial open across the United States right now, looking at the combination of azacitidine with APR246 versus azacitidine alone, specifically in patients with TP53-mutated MDS.3 So I think this agent and this set of trials is quite exciting for this molecular subgroup of patients, which historically has done so poorly.

What is new in terms of hypomethylating agents under development, including guadecitabine, cedazuridine, and CC-486?

Dr. Garcia-Manero: There are several hypomethylating agents being developed in MDS, including guadecitabine (SGI-110), which is a potent next-generation hypomethylating agent that really has shown promising efficacy in MDS so far, with no apparent increase in toxicity compared to what we have seen with azacitidine or decitabine. In a phase 1/2 study, we saw results in treatment-naïve patients that compared favorably with what has been seen with first-generation hypomethylating agents, with a CR of 22% and median OS of 23.4 months, while in previously treated patients, the rate of CR plus mCR was 32% and median overall survival was 11.7 months. If you look at the mutational spectrum of these patients, for instance, for those who did not have a TP53 mutation, the median survival was close to 23 months.8,9

I would mention that there are two other hypomethylating agents that are being developed in MDS. One is an oral form of decitabine called cedazuridine (ASTX727), that had similar pharmacokinetics, safety profile, and clinical responses similar to intravenous decitabine in a phase 1 study.10 The other is oral azacitidine, or CC-486, which was generally well-tolerated and induced hematologic responses in early-phase studies in MDS, and recently it was announced that CC-486 met primary and secondary endpoints in a phase 3 AML trial.11,12

So I think the field now is going to be interesting in terms of how we move forward with hypomethylating agents in MDS. Guadecitabine is being evaluated in a ASTRAL-3, a phase 3 trial of relapsed/refractory patients with MDS or chronic myelomonocytic leukemia.13 If that trial is positive, then we would have a role for guadecitabine for patients with hypomethylating agent failure, but then even in that situation, the question is whether the community is going to use an oral hypomethylating agent like cedazuridine or a subcutaneous compound like guadecitabine. I don’t have an answer to this, but it may be that within the next year or two we may have two or even three new hypomethylating agents approved for patients with MDS, so this is going to be very interesting.

Any take-home messages regarding MDS research in and clinical care in 2020 and beyond?

Dr. Garcia-Manero: I think it’s really critical for the community to understand the important role of mutation analysis in MDS because now we’re starting to discover patients with TP53 mutations that may have distinct prognoses, and may have distinct therapies in the future. We have discussed APR246, magrolimab, guadecitabine, the two new oral hypomethylating agents, and of course there are others, such as luspatercept, which will be reviewed for a potential indication in MDS, and immune checkpoint inhibitors may also be quite interesting for our patients. So all of a sudden, the therapeutic armamentarium for our patients may become quite positive.


  1. Haase D, Stevenson KE, Neuberg D, et al. TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups. Leukemia. 2019;33(7):1747-1758. doi:10.1038/s41375-018-0351-2
  2. Chien KS, Benton CB, Class CA, et al. Patterns of leukemic transformation in patients with TP53-mutant myelodysplastic syndromes. J Clin Oncol. 2019;37(15_suppl):7054-7054. doi:10.1200/JCO.2019.37.15_suppl.7054
  3. APR-246 & Azacitidine for the Treatment of TP53 Mutant Myelodysplastic Syndromes (MDS) - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03745716. Accessed October 31, 2019.
  4. Majeti R, Chao MP, Alizadeh AA, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138(2):286-299. doi:10.1016/j.cell.2009.05.045
  5. Feng D, Gip P, McKenna KM, et al. Combination Treatment with 5F9 and Azacitidine Enhances Phagocytic Elimination of Acute Myeloid Leukemia. Blood. 2018;132(Supplement 1):2729-2729. doi:10.1182/blood-2018-99-120170
  6. Sallman DA, Donnellan WB, Asch AS, et al. The first-in-class anti-CD47 antibody Hu5F9-G4 is active and well tolerated alone or with azacitidine in AML and MDS patients: Initial phase 1b results. J Clin Oncol. 2019;37(15_suppl):7009-7009. doi:10.1200/JCO.2019.37.15_suppl.7009
  7. Sallman DA, DeZern AE, Steensma DP, et al. Phase 1b/2 Combination Study of APR-246 and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML). Blood. 2018;132(Supplement 1):3091-3091. doi:10.1182/blood-2018-99-119990
  8. Garcia-Manero G, Ritchie EK, Walsh KJ, et al. Long Term Results of a Randomized Phase 2 Dose-Response Study of Guadecitabine, a Novel Subcutaneous (SC) Hypomethylating Agent (HMA), in 102 Patients with Intermediate or High Risk Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML). Blood. 2018;132(Supplement 1):231-231. doi:10.1182/blood-2018-99-110465
  9. Garcia-Manero G, Roboz G, Walsh K, et al. Guadecitabine (SGI-110) in patients with intermediate or high-risk myelodysplastic syndromes: Phase 2 results from a multicentre, open-label, randomised, phase 1/2 trial. Lancet Haematol. 2019;6(6):e317-e327. doi:10.1016/S2352-3026(19)30029-8
  10. Savona MR, Odenike O, Amrein PC, et al. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: A multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol. 2019;6(4):e194-e203. doi:10.1016/S2352-3026(19)30030-4
  11. Celgene Announces Phase 3 QUAZAR® AML-001 Study of CC-486 as Maintenance Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia Met Primary and Key Secondary Endpoints. https://ir.celgene.com/press-releases/press-release-details/2019/Celgene-Announces-Phase-3-QUAZAR-AML-001-Study-of-CC-486-as-Maintenance-Therapy-in-Patients-With-Newly-Diagnosed-Acute-Myeloid-Leukemia-Met-Primary-and-Key-Secondary-Endpoints/default.aspx. Accessed October 31, 2019.
  12. Garcia-Manero G, Scott BL, Cogle CR, et al. CC-486 (oral azacitidine) in patients with myelodysplastic syndromes with pretreatment thrombocytopenia. Leuk Res. 2018;72:79-85. doi:10.1016/j.leukres.2018.08.001
  13. Guadecitabine (SGI-110) vs Treatment Choice in Adults With MDS or CMML Previously Treated With HMAs - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02907359. Accessed October 31, 2019.