mutations are found in 5%-10% of de novo myelodysplastic syndrome (MDS) and AML cases. By contrast, in therapy related MDS and AML, mutations in
are found in up to 30%-40% of patients. The majority ...of inactivating mutations observed in MDS and AML are missense mutations localized in a few prevalent hotspots.
missense mutations together with truncating mutations or chromosomal loss of
determine a loss-of-function effect on normal p53 function. Clonal expansion of
-mutant clones is observed under the selection pressure of chemotherapy or MDM2 inhibitor therapy.
-mutant clones are resistant to current chemotherapy, and when responses to treatment have been observed, they have correlated poorly with overall survival. The most heavily investigated and targeted agent for patients with
mutant MDS and AML has been APR-246 (eprenetapopt) a p53 reactivator, in combination with azacitidine, but also in triplets with venetoclax. Despite positive results in phase II trials, a phase III trial did not confirm superior response or improved survival. Other agents, like magrolimab (anti-CD47 antibody), failed to demonstrate improved activity in
-mutant MDS and AML. Agents whose activity is not dependent on a functional apoptosis system like anti-CD123 antibodies or cellular therapies are in development and may hold promises. Delivering prognostic information in a dismal disease like
-mutated MDS and AML is particularly challenging. The physician should balance hope and realism, describing the trajectory of possible treatments and at the same time indicating the poor outcome, together with promoting adaptive coping in patients and elaborating on the nature of the disease.
Mutations in TP53 are observed in ∼20% of patients with myelodysplastic syndromes (MDS), with increased frequency seen in patients with a complex karyotype and cases of therapy-related MDS. TP53 ...mutations represent perhaps the single greatest negative prognostic indicator in MDS. Inferior outcomes are demonstrated with all approved treatment approaches, although hypomethylating agents remain the standard frontline treatment option. Although outcomes with allogeneic hematopoietic stem cell transplant are poor, it remains the only potentially curative therapy. Novel agents are required to improve outcomes in this molecular subgroup, with therapies that directly target the mutant protein and immunotherapies demonstrating greatest potential.
Myelodysplastic syndromes (MDS) form a clinically and molecularly heterogeneous disease group. Precise risk stratification remains crucial for choosing optimal management strategies. Several ...conventional prognostic scoring systems have been developed and validated in the MDS population. These risk models divide patients into prognostic subgroups based on clinical and cytogenetic characteristics. Lack of dynamicity, variable risk estimate across models, and heterogeneity within intermediate-risk group are the limitations of traditional models like IPSS-R, with questionable relevance of these scoring systems in treated MDS patients. Recent progress in next-generation sequencing techniques has improved understanding of the distribution and prognostic importance of recurrent genetic mutations in MDS. Early studies have suggested that incorporating mutations in risk stratification could supplement IPSS-R in further refining the model's performance in predicting overall survival and risk of transformation to acute myeloid leukemia and should translate into a molecularly driven prognostication approach in the near future.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
34.
TP53 and therapy-related myeloid neoplasms Chung, Jae; Sallman, David A.; Padron, Eric
Best practice & research. Clinical haematology,
March 2019, 2019-03-00, 20190301, Volume:
32, Issue:
1
Journal Article
Peer reviewed
Therapy-related myeloid neoplasms (t-MNs) are the most serious late complications in patients treated with traditional cytotoxic chemotherapy and/or radiation. T-MNs are aggressive and ...chemorefractory hematologic malignancies, with a median survival of less than 6 months. TP53 mutations are highly enriched in t-MN patients, though the mechanism for this selective enrichment has only come to light over the past several years. In this review, we discuss the history and function of p53, and the role of TP53 mutations in the origin and progression of t-MNs. Emerging data has begun to elucidate who may be at highest risk of developing t-MNs, which ideally will enable us to develop preventative strategies for this devastating disease. As t-MNs may not be avoidable, novel therapies are urgently needed for this patient group and are underway as exemplified by recent investigation in restoring wild-type p53 function as well as directly targeting TP53 mutant variants. With better prevention and treatment, outcomes will hopefully begin to improve in the near future.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Komrokji et al examined the proposed international working group proposal to designate SF3B1-mutant myelodysplastic syndrome (MDS) as a unique disease entity, using a single-institution validation ...cohort of 1779 MDS patients, of whom 320 harbored SF3B1 mutations. They confirmed the demographics of older age, low-risk disease, ring sideroblasts, and low blast percentage. They further confirmed better overall survival that is negatively impacted in those patients with concomitant mutations, high variant allele fraction, and increased blast percentage.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Handbook of Hematologic Malignanciesprovides a unique, practical, and concise guide focused on the must-know points of diagnosis, prognosis, therapeutic management, and cutting edge clinicaltrial ...opportunities for each hematologic malignancy. With an ever-increasing growth of evidence and a significant expansion of available treatment optionsfor patients with hematologic disease, remaining current and up to date can be extremely challenging for practicing clinicians. This comprehensivesubspecialty handbook is designed and organized for the busy hematologist, hematologic oncologist, hematopathologist, and trainee in mind. Every chapter is richly illustrated with color figures and flow diagrams, and contains helpful tables on differential diagnosis, prognostic scoring systemsand therapeutic options. A concise case-based review for testing pathologic diagnosis and clinical knowledge for each chapter is included near the end ofthe book as well as provided in an online compendium. Written by experienced clinicians at the world-renowned Moffitt Cancer Center in Tampa, Florida, aswell as contributions from leading academicians throughout the country, this handbook is an essential resource for anyone diagnosing, treating, or managingpatients with hematologic malignancy. Key Features: Contains clear prognostic and diagnostic tools (e.g. tables/flow diagrams/pathology images) with emphasis on key differential diagnoses and diagnostic dilemmas Easy to use treatment recommendations with bullet point format and key references. Discusses the future of patient management based on practice changing clinical trials Online compendium of clinical scenarios/questions with high resolution pathology images linked to each individual chapter
Magrolimab is a monoclonal antibody that blocks cluster of differentiation 47, a don't-eat-me signal overexpressed on cancer cells. Cluster of differentiation 47 blockade by magrolimab promotes ...macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine, which increases expression of eat-me signals. We report final phase Ib data in patients with untreated higher-risk myelodysplastic syndromes (MDS) treated with magrolimab and azacitidine (ClinicalTrials.gov identifier: NCT03248479).
Patients with previously untreated Revised International Prognostic Scoring System intermediate-/high-/very high-risk MDS received magrolimab intravenously as a priming dose (1 mg/kg) followed by ramp-up to a 30 mg/kg once-weekly or once-every-2-week maintenance dose. Azacitidine 75 mg/m
was administered intravenously/subcutaneously once daily on days 1-7 of each 28-day cycle. Primary end points were safety/tolerability and complete remission (CR) rate.
Ninety-five patients were treated. Revised International Prognostic Scoring System risk was intermediate/high/very high in 27%, 52%, and 21%, respectively. Fifty-nine (62%) had poor-risk cytogenetics and 25 (26%) had
mutation. The most common treatment-emergent adverse effects included constipation (68%), thrombocytopenia (55%), and anemia (52%). Median hemoglobin change from baseline to first postdose assessment was -0.7 g/dL (range, -3.1 to +2.4). CR rate and overall response rate were 33% and 75%, respectively. Median time to response, duration of CR, duration of overall response, and progression-free survival were 1.9, 11.1, 9.8, and 11.6 months, respectively. Median overall survival (OS) was not reached with 17.1-month follow-up. In
-mutant patients, 40% achieved CR with median OS of 16.3 months. Thirty-four patients (36%) had allogeneic stem-cell transplant with 77% 2-year OS.
Magrolimab + azacitidine was well tolerated with promising efficacy in patients with untreated higher-risk MDS, including those with
mutations. A phase III trial of magrolimab/placebo + azacitidine is ongoing (ClinicalTrials.gov identifier: NCT04313881 ENHANCE).
