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Cracking the Code of Myelodysplastic Syndromes and Myeloproliferative Neoplasms

December 13, 2022

The genetic and phenotypic heterogeneity of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) make these conditions particularly difficult to understand, classify, and treat. Gauging the tempo of disease with risk stratification systems helps us determine higher-risk patients who may benefit from clinical trials, targeted therapy, or hematopoietic stem cell transplantation (HSCT); however, there are currently many unanswered questions, particularly as we learn more about the molecular landscape of these diseases. At this year’s meeting, there were endless abstracts presented to address current dilemmas in MDS and MPN, and we highlight a few key studies here.

During the MDS – Clinical and Epidemiological sessions, much of the focus was on novel drug — including immunotherapy — trials, updates in risk classification systems, demographics and outcomes of patients with MDS/MPN, and targeted therapies based on mutational profiles.

Results of the phase II STIMULUS-MDS1 trial were presented by Dr. Amer Zeidan. This study evaluated sabatolimab, a novel immunotherapy targeting TIM-3 (T cell immunoglobulin and mucin-domain containing-3), an immunoregulatory receptor expressed on immune and myeloid leukemic cells but not on normal hematopoietic stem cells, used in combination with a hypomethylating agent (HMA) in untreated patients with revised international prognostic scoring system (IPSS-R) intermediate and high-risk MDS . Compared to HMA single-agent therapy, improvements in complete response and progression-free survival with sabatolimab were not statistically significant. However, there was a signal for improved duration of response and preferential effect in patients with a lower disease burden that received sabatolimab. Updates in prognostication were also addressed this year, particularly in the STIMULUS-MDS1 and -MDS2 trials. The molecular IPSS score (IPSS-M) demonstrated improved risk stratification compared to the IPSS-R. While most current clinical trials use IPSS-R, we expect to see the IPSS-M increasingly incorporated in the coming years with its more widespread use.

Treatment for lower-risk MDS was also highlighted, as many of our patients wish to actively participate in their care and hope to prevent disease progression. Results from IMerge, the phase II trial of telomerase inhibitor imetelstat in non-del(5q) lower-risk MDS relapsed/refractory to erythropoiesis-stimulating agents, were presented. These showed prolonged, continuous transfusion independence in 29 percent of treated patients. Results from a phase I study of lower dose oral decitabine/cedazuridine (ASTX727) in lower-risk MDS were also presented, demonstrating favorable drug tolerability and representing the future of an oral treatment regimen that can be given at home. However, the safety profile of these myelosuppressive agents, particularly therapy-related cytopenias, are likely to present an ongoing challenge.

In addition to new drugs and classification systems in MDS, Dr. Victoria Vardell presented a national analysis of overall survival and demographic features in MDS/MPN overlap syndromes (session 637, abstract 562). She reported “survival disparities in Black patients and those who are underinsured or treated at nonacademic centers,” emphasizing how lack of access to care is a significant barrier to survival. This is truly devastating for our patients and absolutely deserves to be highlighted.

It would not be an ASH annual meeting without someone addressing the infamous challenge of TP53-mutated disease, as these patients have inferior outcomes across the board. The ASCERTAIN trial evaluated oral decitabine/cedzuridine in subjects with MDS and chronic myelomonocytic leukemia (CMML). Importantly, an oral session by Dr. Michael Savona delivered a preliminary analysis of mutation profiles of subjects enrolled in ASCERTAIN. Overall, 35% of the study population harbored TP53 mutations. These patients displayed worse overall survival (OS) rates than those wild-type for TP53 – and even worse still if the alteration was biallelic. While this may not be surprising, the estimated survival of patients with biallelic TP53 mutations was 13 months, which compares favorably with historical results.

And how does TP53 play into the ongoing debate on the blurred lines between MDS and acute myeloid leukemia? Dr. Anna Stengel from Munich Leukemia Laboratory presented an analysis of TP53 mutations (single or double hit) and their correlation with blast count in MDS. As anticipated, TP53 single-hit events were found in those with <5% blasts and associated with better outcomes compared to those with double-hit events.  

Sometimes it may be hard just to determine if your patient has a biallelic TP53 mutation, and Dr. Waled Bahaj addressed this critical topic. Dr. Bahaj’s group used conventional methods to define single and double hit mutations, with variant allele frequency and 17p clonality to further characterize. Interestingly, they were able to discriminate OS differences using this algorithm. 

During the “MDS—Basic and Translational” session, spliceosome mutations, which typically confer a favorable prognosis in MDS but still can accompany high-risk MDS and/or eventually AML, were discussed separately by Drs. Martina Sarchi, Michaela Fontenay, and Sayantani Sinha. Their presentations enabled us to better understand this molecularly-defined subgroup's transformation potential and risk for drug resistance, as well as potential novel therapeutic approaches.

Circling back to TP53 – in MPN, now, Dr. Bridget Marcellino presented a unique approach to this crucial driver of disease progression at the “Myeloproliferative Syndromes and Chronic Myeloid Leukemia – Basic and Translation” session. Her group built on the premise that protein phosphatase Mg2+/Mn2+ dependent 1D (PPM1D) and double minute protein 2 (HDM2) are vital to the regulation of the TP53 pathway. They showed that inhibitors of PPM1D, a key negative regulator of the TP53 pathway, sensitized MPN, specifically myelofibrosis (MF) cells to targeting by HDM2 inhibitors, with subsequent reduction of MF stem cells, proving to be a potentially promising therapeutic strategy in this disease group.

We know that TP53 mutations have been associated with poor outcomes in myeloid malignancies, however, the impact of these mutations in MF, particularly in those undergoing HSCT, is not well defined. Dr. Nico Gagelmann attempted to shed light on this topic. His group evaluated outcomes of patients with TP53-mutated MF having undergone HSCT. In sum, TP53 mutations, in addition to complex karyotype, portended much poorer survival and higher rates of relapse post-HSCT, further underscoring, from a prognostic and therapeutic standpoint, just how revolutionary cracking the TP53 code would be.

But the future is now. The speakers at these sessions are ushering us into the next era of cancer care. We are that much closer to tailoring our therapies to patient-specific genetic alterations with increasingly precise actionable targets. What an exciting time to be caring for patients with myeloid diseases.


Dr. Amanam and Dr. Blackmon indicated no relevant conflicts of interest.

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