Therapy-related Myelodysplastic Syndrome Research Articles

Abstract CT060: Phase 1 study of azacitidine in combination with evorpacept for higher-risk myelodysplastic syndrome (MDS)

Abstract Background:Evorpacept (EVO) is a high affinity CD47-blocking fusion protein with an inactive human immunoglobulin Fc region designed to enhance the activity of other anti-neoplastic therapies with minimal additional toxicity. Here, we present final phase 1 results from the ASPEN-02 study. Methods:ASPEN-02 is an open-label, multicenter phase 1/2 study designed to evaluate the safety and activity of EVO in combination with azacitidine (AZA) in subjects with newly diagnosed (ND) higher-risk (HR) or relapsed/refractory (R/R) MDS. Adult subjects with ND HR (IPSS-R > 3.5) or R/R MDS were enrolled into phase 1 cohorts receiving escalating doses of EVO (20 mg/kg Q2W, 30 mg/kg Q2W, and 60 mg/kg Q4W) combined with AZA (75 mg/m2 IV/SC x 7d) in a 28-day treatment cycle. A phase 1 dose expansion portion enrolled adults with ND HR MDS into two dosing cohorts determined to be safe at EVO 40 mg/kg Q4W and 60 mg/kg Q4W. This clinical trial is registered at clinicaltrials.gov: NCT04417517. Results: As of June 2, 2023, 65 subjects were treated in the phase 1 portion, including 13 subjects with R/R MDS [EVO doses of 20 mg/kg Q2W (n=1) or 60 mg/kg Q4W (n=12)], and 52 subjects with ND HR MDS [EVO doses of 40 mg/kg Q4W (n=23) and 60 mg/kg Q4W (n=29)]. Of 52 ND HRMDS subjects, 9 (17.3%) had therapy-related MDS. Multi-hit TP53 mutations were present at baseline in 2/13 (15.4%) R/R MDS and 3/52 (5.8%) ND HR MDS patients. 13/13 (100%) R/R MDS patients had received prior hypomethylating agents or cytotoxic chemotherapy. Median age was 70 (range 24 - 88) years, and baseline ECOG scores were 0 (n=27, 41.5%), 1 (n=31, 47.7%), or 2 (n=7, 10.8%). No dose-limiting toxicity was observed, and a maximum tolerated dose (MTD) was not reached. Treatment-emergent AEs and treatment-related AEs for EVO were reported in 65/65 (100%) and 35/65 (53.8%) subjects respectively; discontinuation, however, was infrequent. Seven (10.8%) subjects experienced a serious adverse event related to EVO. There were no EVO-related deaths on study. Preliminary PK indicated dose-proportional pharmacokinetics consistent with prior studies. Objective response [complete remission (CR), partial remission (PR), marrow CR (mCR), hematologic improvement (HI)], per modified International Working Group 2006 criteria, was observed in 19/52 (36.5%) ND HR [CR=8, mCR=9, HI=2] and 2/13 (15.4%) R/R [mCR=2] MDS subjects. Conclusion:The myeloid checkpoint inhibitor EVO was well tolerated in combination with AZA with an initial safety and activity profile comparable to that of historical AZA monotherapy. Additional updated data will be provided at the time of presentation. Citation Format: Guillermo Garcia-Manero, Bart L. Scott, Ashwin Kishtagari, Srinivasa R. Sanikommu, Aref Al-Kali, Je-Hwan Lee, Juan M. Bergua Burgues, Maria Diez-Campelo, Harry P. Erba, Carmen Garcia-Hernandez, Guillermo Sanz Santillana, Casey O'Connell, Jun-Ho Jang, Dong-Yeop Shin, Hamid Sayar, Mayank Rao, Richard S. Schwartz, Grace An, Feng Jin, Alison J. Forgie, Athanasios C. Tsiatis, Jessica K. Altman. Phase 1 study of azacitidine in combination with evorpacept for higher-risk myelodysplastic syndrome (MDS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT060.

Therapy-related chronic myelomonocytic leukemia does not have the high-risk features of a therapy-related neoplasm

AbstractTherapy-related myeloid neoplasms (t-MNs) arise after exposure to cytotoxic therapies and are associated with high-risk genetic features and poor outcomes. We analyzed a cohort of patients with therapy-related chronic myelomonocytic leukemia (tCMML; n = 71) and compared its features to that of de novo CMML (dnCMML; n = 461). Median time from cytotoxic therapy to tCMML diagnosis was 6.5 years. Compared with dnCMML, chromosome-7 abnormalities (4% vs 13%; P = .005) but not complex karyotype (3% vs 7%; P = .15), were more frequent in tCMML. tCMML was characterized by higher TP53 mutation frequency (4% vs 12%; P = .04) and lower NRAS (6% vs 22%, P = .007) and CBL (4% vs 12%, P = .04) mutation frequency. Prior therapy with antimetabolites (odd ratio [OR], 1.22; 95% confidence interval [CI], 1.05-1.42; P = .01) and mitotic inhibitors (OR, 1.24; 95% CI, 1.06-1.44; P = .009) was associated with NF1 and SETBP1 mutations whereas prior mitotic inhibitor therapy was associated with lower TET2 mutation frequency (OR, 0.71; 95% CI, 0.55-0.92; P = .01). Although no differences in median overall survival (OS) were observed among tCMML and dnCMML (34.7 months vs 35.9 months, P = .26), multivariate analysis for OS revealed that prior chemotherapy was associated with increased risk of death (hazard ratio, 1.76; 95% CI, 1.07-2.89; P = .026). Compared with a cohort of therapy-related myelodysplastic syndrome, tCMML had lower TP53 mutation frequency (12% vs 44.4%, P < .001) and less unfavorable outcomes. In summary, tCMML does not exhibit the high-risk features and poor outcomes of t-MNs.

A case of Bloom syndrome manifesting with therapy-related myelodysplastic syndromes harboring a novel BLM gene variant.

Bloom syndrome (BS) is an autosomal recessive genetic disorder caused by variants in the BLM gene. BS is characterized by distinct facial features, elongated limbs, and various dermatological complications including photosensitivity, poikiloderma, and telangiectatic erythema. The BLM gene encodes a RecQ helicase critical for genome maintenance, stability, and repair, and a deficiency in functional BLM protein leads to genomic instability and high predisposition to various types of cancers, particularly hematological and gastrointestinal malignancies. Here, we report a case of BS with a previously unreported variant in the BLM gene. The patient was a 34-year-old woman who presented with short stature, prominent facial features, and a history of malignancies, including lymphoma, breast cancer, and myelodysplastic syndromes (MDS). She was initially treated with azacitidine for MDS and showed transient improvement, but eventually died at age of 35 due to progression of MDS. Genetic screening revealed compound heterozygous variants in the BLM gene, with a recurrent variant previously reported in BS in one allele and a previously unreported variant in the other allele. Based on her characteristic clinical features and the presence of heterozygous variants in the BLM gene, she was diagnosed with BS harboring compound heterozygous BLM variants.

The clinical outcomes of haploidentical stem cell transplantation (haplo-HSCT) for patients with therapy-related myelodysplastic syndrome: comparable to de novo myelodysplastic syndrome

Therapy-related myelodysplastic syndrome (t-MDS) is defined as a complication in patients with cancer following exposure to chemotherapy and/or radiotherapy and has an inferior outcome compared with de novo myelodysplastic syndrome (de novo MDS). This study aimed to estimate and compare the clinical outcomes of haploidentical stem cell transplantation (haplo-HSCT) for t-MDS and de novo MDS. We retrospectively analyzed 96 patients with MDS who received haplo-HSCT between January 2015 and December 2021. Eleven patients with t-MDS and 85 patients with de novo MDS were matched using the case-pair method in a 1:8 ratio with the following pairing criteria: (1) sex, (2) age (± 5 years), (3) year of haplo-HSCT (± 2 years), and (4) blast cell counts (≥ 5% or not). The 3-year overall survival and disease-free survival after haplo-HSCT for t-MDS versus de novo MDS patients were 72.7% versus 75.1% (P = 0.99) and 54.5% versus 67.0% (P = 0.50), respectively. The 3-year cumulative incidence of relapse was 36.4% versus 15.5% (P = 0.08), respectively. In multivariate analysis, there was no difference in relapse between t-MDS and de novo MDS. The 3-year cumulative non-relapse mortality rates were 9.1% versus 17.6% (P = 0.45), respectively. This study confirmed the comparable clinical outcomes of haplo-HSCT on the prognosis of t-MDS and de novo MDS.

A Phase II Study of Clinical Efficacy of Venetoclax in Combination with Azacitidine in Patients with Therapy Related Myelodysplastic Syndrome (t-MDS)

Background: The occurrence of therapy-related myelodysplastic syndrome (t-MDS) is a well-recognized sequelae of cytotoxic treatments for prior neoplasms, including other hematologic malignancies, sarcomas, and ovarian and testicular cancer. t-MDS accounts for 10% to 20% of newly diagnosed MDS, with a median time to development of 3 to 5 years. The prognosis of t-MDS is often poor, as the genetic abnormalities that characterize multiple subtypes can lead to rapid progression to AML and confer resistance to conventional therapies. In general, treatment with conventional anti-leukemic chemotherapy has uniformly poor outcomes, with median survivals of 8.6 months for t-MDS.In patients with high-risk t-MDS, hypomethylating treatment is associated with objective response rates (ORR) of 38% to 42%, among which only 14%-15% achieve complete remission (CR). Innovative strategies using targeted agents provide a unique opportunity to combat the dismal outcomes experienced by this t-MDS patient population. The combination of azacitidine and venetoclax has been a large area of interest in the clinical research field for the MDS and AML population. Whether the combination of azacitidine and venetoclax can similarly benefit a high-risk t-MDS population has yet to be addressed. We hypothesize that the combination therapy of azacitidine and venetoclax will result in improved outcomes for treatment-naïve t-MDS compared to azacitidine alone. Study Design and Methods: This is a multi-center, open-label, phase II study of clinical efficacy of venetoclax in combination of azacitidine in patients with treatment-naïve t-MDS (NCT05379166) being led by The Ohio State University Comprehensive Cancer Center with active sub-site University of Texas Southwestern. Our primary endpoint is rate of complete remission. Up to 53 participants will be enrolled to this study (Figure 1). Patients must be untreated with IPSS intermediate, high, or very high risk. Prior venetoclax is allowed if not utilized for MDS or AML. Prior transplant is allowed if received greater than 2 years prior to initiation of study treatment. Participants will receive the combination of azacitidine and venetoclax according to the recommended dosing parameter determined by Wei et al. Participants will initiate first cycle with Venetoclax 400 mg for Days 1 to 14 and Azacitidine 75 mg/m 2 days 1 through 7 of each 28-day treatment cycle. Participants will continue to receive the study combination until disease progression (per 2006 International Working Group [IWG] response criteria for myelodysplasia), unacceptable toxicity, death, or discontinuation of study treatment for any other reason (e.g., withdrawal, start of an off-protocol therapy, or at the discretion of study investigator). This study is active and open accrual and has enrolled 9 patients to date (Table 1). A sample size of 53 participants will provide 80% power to detect a CR of 30% (desired response rate) vs. 15% (poor response rate) based on Simon's 2-stage minimax design with a 5% false positive rate and accounting 10% over accrual. The trial will stop early after stage 1 if there are ≤3 CRs among 23 evaluable participants. If, after 25 additional participants are evaluated up to 4 cycles, there are ≥12 CRs among a total of 48 evaluable participants, the combination of azacitidine and venetoclax will be considered promising for t-MDS and will warrant further investigation. All eligible patients who receive at least one dose of any study drug will be considered evaluable for the primary endpoint analysis and included in the efficacy-evaluable set.

Burden of Chemotherapy-Related Myelodysplastic Syndrome/Acute Myeloid Leukemia in the Chemotherapeutic Armamentarium

Introduction: Therapy related Myelodysplastic Syndrome and Acute Myeloid Leukemia (t-MDS/AML) is a well-established adverse event (AE) associated with conventional chemotherapy drugs and has historically carried a poorer prognosis when compared to de novo disease. Newer chemo medicines like PARP inhibitors have also been implicated in developing this complication. However, comprehensive real-world data is lacking pertaining to the AE burden relative to individual drug classes. Methods: We used the FDA Adverse Events Report System (FAERS) public dashboard to obtain the data. Data was available for the years 1970 - 2023. We retrieved the number of events that were reported as “Myelodysplastic Syndrome” or “Acute Myeloid Leukemia” for individual chemotherapy classes that have historically been known to cause t-MDS/AML. Disproportionality analysis was performed by calculating the reporting odds ratio (ROR) with its 95% confidence interval (CI). Results: The drug class with the highest ROR of MDS/AML was the topoisomerase inhibitors - ROR 2.38 (95% CI 2.27-2.49). Intercalating agents like anthracyclines and mitoxantrone had the next highest ROR of 2.12 (95% CI 2.04 - 2.21). The novel drug class PARP inhibitors had the third most burden of t-MDS/AML with an ROR of 1.57 (95% CI 1.46 - 1.69). Table 1. depicts the individual drug classes and their ROR for associated MDS/AML. Table 1 depicts the individual drug classes and their ROR for associated MDS/AML. Conclusions: From this retrospective analysis, we identified that among all the chemotherapy drug classes, the topoisomerase II inhibitors were associated with the highest burden of t-MDS/AML, followed by intercalating agents and PARP inhibitors. Further data is essential to identify the patient characteristics associated with higher risk of developing this dreaded complication. This could improve patient-counseling prior to treatment initiation, assist with alternate drug choices when applicable, and perhaps also aid in developing strategies for closer monitoring in high-risk patients.

Clinical Characteristics of Patients with TP53 Multihit MDS and AML. a Single-Center Experience

Introduction TP53 is a tumor suppressor protein encoded by the TP53 gene that plays a pivotal role in maintaining genomic stability in response to DNA damage, activates DNA repair programs and triggers cell-cycle arrest. Mutations in TP53 (TP53-mut) are present in approximately 5-10% of de novo myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML), and confer an extremely poor prognosis, irrespectively of the treatment administered. The frequency of TP53 abnormalities increases up to 25-40% in therapy-related MDS and AML, up to 70%-80% in patients with complex karyotype and in patients with loss of chromosome 17/17p, 5/5q, or 7/7q. “Multihit” TP53-mut present with the loss of both wildtype TP53-alleles, either through point mutations or larger aberrations to chromosome 17, in complex monosomal karyotypes. Recent data strongly support the concept that TP53mut, particularly multi-hit TP53, results in similarly poor clinical outcomes, regardless of its classification as MDS or AML, arguing for a revised TP53 mutant myeloid entity that includes both MDS and AML. The aim of our analysis is to assess the impact of the multihit TP53-mut on clinical outcomes according to the type of treatment received. We will particularly focus on the presence of mono or biallelic mutation status of TP53 mutation. Methods We retrospectively evaluated 42 patients with TP53 mutated MDS or AML diagnosed from October 2016 to June 2023 in our department at the Catalan Institute of Oncology-L'Hospitalet in Spain. We analyze the prognosis of these two diseases, focusing on single-hit or multi-hit status of TP53 mutation and treatments received. Results Median age at diagnosis was 71 years (range, 44-87 years) with a male predominance (67%). Thirty-five (84%) patients were diagnosed of AML and 7 (16%) of MDS. Among AML patients, 17% had a prior diagnosis of dysplasia, 78% were diagnosed of AML with dysplasia-related changes, 13% with therapy-related neoplasms, and 9% were AML with maturation and/or AML with mutated NPM1. Regarding MDS patients, 57% had an excess of blast-2 (EB2) MDS, 43% MDS multilineage dysplasia (MLD) and MDS with excess of blast-1(EB1). Complex karyotype was present in 79% of the patients. The median variant allele frequency (VAF) of TP53mut was 36%. Multi-hit TP53 status was observed in 24 patients (57%). In this group of multi-hit TP53mut median age was 72 years (range,44-81 years) with a male predominance (67%), the median VAF of TP53mut was 40%. Twenty (83%) patients had MDS diagnosis and 4 (17%) had AML diagnosis; all of them presented complex karyotype. In the whole group the most concurrent mutations associated with TP53 were TET2 in 17%, ASXL1 in 14% and DNMT3A, NRAS y CREBBP in 12% of patients. Intensive chemotherapy (IC) was administrated as first-line treatment in 17% of patients, 45% received hypomethylating agents (HMA) monotherapy, 24% venetoclax-based combination with HMA, and 14% exclusively supportive treatment. 16 patients (38%) achieved a complete response (CR), 44%, 31% and 25% with HMA+venetoclax, IC and with HMA monotherapy, respectively. Eight patients (19%) achieved a partial response (PR), 88% with HMA and 12% with IC, 7 patients (17%) stable disease, 86% with HMA monotherapy and 14% with HMA+venetoclax and 2 patients (5%) were refractory to IC. In 2 patients (5%), disease was not evaluable. The treatment related mortality was 4.2%. Median overall survival (OS) was 12.5 months [IC 95 % (0.0, 23.54)] and median progression free survival (PFS) was 9, 2 months [IC 95% (3.2, 32.6)]. Median OS of patients with multihit TP53 was 9.8 months, vs 25.7 months in patients with single-hit TP53-mut (P=0.026) (Figure1). Median PFS of the patients with multi-hit and single-hit TP53 was 9.1 and 11.6 months (P=0.07), respectively. The impact of multi-hit TP53 on OS and PFS according to the treatment received (HMA monotherapy vs HMA + venetoclax vs IC) was not statistically significant, just like in the single-hit TP53 (Figure1). Conclusions The presence of multihit TP53 -mut is a prognostic variable for survival in our group of patients analyzed with TP53-Mut. Survival is poor, around one year, in this group of patients independently on the treatment strategy received; this fact would call into question the benefit of IC with the toxicity it entails, in this group of patients. Further development of new effective therapies for multihit TP53-mut AML and MDS is needed.

Characteristics and Outcomes of Younger Adult Patients (Pts) with Myelodysplastic Syndromes (MDS): A Multicenter Retrospective Study

Introduction: MDS are primarily diseases of the elderly, with median age at diagnosis of 72 years. Focused data on clinical and molecular characteristics, as well as outcomes, in younger pts under age 60 years are limited. We conducted this multicenter retrospective study to describe pt characteristics, cytogenetic and molecular profiles, treatment modalities, and outcomes in younger pts with MDS, including adolescent and young adults (AYA). Methods: The study included pts diagnosed with MDS between 2002-2023 at 7 academic centers. We compared baseline characteristics, treatment, and outcomes of AYA (18-39 years) and younger adult (YA) pts (40-59 years). Responses were assessed using the modified IWG 2006 response criteria which included complete remission (CR), marrow CR (mCR), and hematologic improvement (HI). Wilcoxon rank sum test and Fisher's exact (and Chi-square) test were used to compare pt and disease characteristics for continuous and categorical variables, respectively. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using log-rank test. Results: A total of 173 pts were identified (AYA, N=50; YA, N=123). Median age at diagnosis was 50 years (range, 18-59), with 51% females. Baseline characteristics are shown in Table 1. Therapy-related MDS (t-MDS) was observed in 40 pts (23%) with the remaining classified as de novo MDS (N=133; 77%). Inherited bone marrow failure syndromes were documented in 15 pts (9%), with Shwachman-Diamond Syndrome (N=4) and Fanconi anemia (N=4) being the most frequent. Using the WHO 2016 classification, the most common subtypes of MDS in both the AYA and YA cohorts were MDS with multilineage dysplasia (38% vs 19%), MDS with excess blasts-2 (MDS-EB) (24% vs 29%), and MDS-EB-1 (16% vs 20%). Similarly, using the WHO 2022 classification, the most common subtypes were MDS with low blasts (50% vs 21%), MDS with increased blasts-2 (MDS-IB-2) (24% vs 24%), and MDS-IB-1 (16% vs 18%). Stratifying pts using the IPSS-R cytogenetic (CG) risk group, the most common CG risk category identified was good CG (34% vs 52%, p=0.012). Poor/very poor CG were present in 34% and 37% of the AYA and YA groups, respectively. STAG2 and NRAS mutations occurred more frequently in the AYA pts compared to the YA group, while the YA cohort was enriched for the following mutations: TP53, DNMT3A, SF3B1, SRSF2, and TET2 (Figure 1). In the AYA population, 18 pts (38%) had very low/low, 10 (21%) intermediate, and 20 pts (42%) had high/very high risk MDS using IPSS-R. In the YA population, 32 pts (26%) had very low/low, 32 (26%) intermediate, and 57 pts (47%) had high/very high risk MDS using IPSS-R. Twenty-seven percent of pts with very low to intermediate-risk MDS using IPSS-R were upstaged to moderate high to very high-risk MDS using IPSS-M. The majority of pts (AYA: 75%; YA: 63%, p=0.5) were transfusion independent at baseline. Single-agent hypomethylating agents were the most frequently used frontline therapy, used in 17 AYA pts (34%) and 58 YA pts (48%), with more AYA pts receiving upfront allogeneic stem cell transplantation (Allo-SCT) compared to YA pts (28% vs 5%). After frontline therapy (Table 1), an additional 14 AYA (28%) and 52 YA (42%) pts received Allo-SCT. In pts with IPSS-R intermediate to very high-risk, response rates (HI+CR+mCR+mCR with HI) to frontline therapies were 46% and 54.5% in the AYA and YA groups, respectively. After median follow-up of 24 months [range, 1-218], median OS was numerically longer in the AYA versus YA group (155 vs 53 months, p=0.2). AML transformation occurred in 24% and 20% of the pts in the AYA and YA groups, respectively. Median OS was significantly longer in de novo compared to t-MDS pts (56 vs 27 months, p=0.03). Median OS among Allo-SCT compared to non-SCT pts were not reached vs 155 months ( p=0.9) in the AYA group and 53 vs 54 months ( p=0.4) in the YA group. IPSS-R (very low+low vs intermediate vs high+very high) was able to distinguish differences in OS in the YA (133 vs 53 vs 17 months, p=0.0002) and AYA (155 vs not reached vs 18 months, p=0.006) pts, with the exception of the intermediate-risk group in the AYA cohort. Conclusions: In this study, d e novoMDS was seen in the majority of younger pts with MDS (both AYA and YA). Mutations in STAG2 and NRAS were more common in the AYA pts, while YA pts had MDS more enriched for TP53, DNMT3A, TET2 and splicing mutations. This study is still ongoing with a plan to compare the abovementioned groups to older pts (≥60 years) with MDS.

Performance of the Molecular International Prognostic Scoring System (IPSS-M) in Hypomethylating Agent-Treated Patients with Myelodysplastic Syndromes

Background: Patients with myelodysplastic syndromes (MDS) undergo risk stratification with various prognostication tools, such as the International Prognostic Scoring System (IPSS) and Revised IPSS (IPSS-R). Recently, the Molecular IPSS (IPSS-M) was developed incorporating genomic data in addition to clinical and cytogenetic characteristics. Though IPSS-M has been shown to improve prognostication in all MDS patients at baseline, its utility in specifically patients undergoing hypomethylating agent (HMA) therapy remains unknown. Here, we assess the efficacy of IPSS-M in HMA-treated patients with MDS. Methods: We retrospectively evaluated all untreated patients with MDS seen at a single tertiary cancer center from July 2017 to July 2021 and identified those who later received HMA therapy. Patient characteristics and bone marrow (BM) data, including morphology, cytogenetics, and mutations, were assessed at diagnosis. Genomic DNA was extracted from whole BM aspirate samples and subject to 81-gene target PCR-based sequencing using a next-generation sequencing platform. Survival data was updated in July 2023. Results: Out of 799 untreated MDS patients, 455 patients (57%) eventually underwent treatment with HMA. At diagnosis, the median age was 69 (range: 22-90) with 289 (64%) male patients. Patients were generally high risk, with therapy-related MDS in 160 (35%), complex cytogenetics in 167 (37%), and TP53 mutations in 168 (37%). By IPSS-R, 259 patients (58%) had high- or very high-risk disease, and 340 patients (75%) had higher-risk disease (moderate high-, high-, and very high-risk) by IPSS-M. A total of 291 patients (64%) were treated with HMA monotherapy, and lower-risk MDS patients received more cycles of HMA (p &amp;lt; 0.001). By IPSS-R, the median overall survival was 60.0 months (95% CI: 46.0, not estimable (NE)) in very low-, 87.4 months (95% CI: 59.9, NE) in low-, 36.2 months (95% CI: 30.0, 58.1) in intermediate-, 23.7 months (95% CI: 19.6, 34.8), in high-, and 12.8 months (95% CI: 11.0, 16.7) in very high-risk patients (p &amp;lt; 0.0001) with a concordance index of 0.669. Figure 1 depicts the reclassification of patients between IPSS-R and IPSS-M. Risk stratification by IPSS-M (Figure 2) provided similar results: not reached (95% CI: 56.8, NE) in very low-, 60.0 months (95% CI: 49.8, NE) in low-, 40.8 months (95% CI: 22.8, NE) in moderate low-, 44.2 months (95% CI: 27.8, NE) in moderate high-, 33.4 months (95% CI: 22.8, 44.5) in high-, and 16.6 months (95% CI: 13.8, 19.4) in very high-risk patients (p &amp;lt; 0.0001). The concordance index of IPSS-M in all HMA-treated MDS patients was 0.648. When analyzing patients with MDS who were more likely to undergo HMA as per standard-of-care treatment (those with IPSS-M moderate low-, moderate high-, high-, and very high-risk disease), the IPSS-M remained statistically significant (p &amp;lt; 0.0001) though less discerning in the patients with moderate-risk MDS, as seen by the concordance index of 0.620. Conclusions: In this group of MDS patients treated with HMA, the IPSS-M did not provide additional prognostic power over the IPSS-R though median overall survival remained inversely proportional to IPSS-M risk category. Concordance indices for survival remained below 0.7, likely due to the overlapping curves in moderate-risk patients by IPSS-M. Further development and validation of prognostic scoring systems in patients treated with HMA are warranted.

Low-Dose Decitabine Plus Venetoclax As Post-Transplant Maintenance for High-Risk Myeloid Malignancies

Background: Allogeneic stem cell transplantation (allo-SCT) is potentially curative for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, post-SCT relapse remains a major cause of treatment failure for these patients and strategies to prevent post-transplant relapse are urgently needed. The combination of venetoclax (VEN) with either azacitidine (AZA) or decitabine (DEC) has shown promising results in older or unfit patients with AML and is now being investigated in younger patients as well. Herein, we report our experience of administering low-dose DEC and VEN as post-transplant maintenance in patients with high-risk myeloid malignancies. Methods: A retrospective chart review was performed to evaluate outcomes of patients with AML and MDS that received post-SCT maintenance with DEC and VEN at the University of Alabama at Birmingham. DEC was administered at 10mg/m 2 on days 1-3 per cycle and VEN was given at a target dose of 200mg on days 1-28 for AML and days 1-14 for MDS. The dose of VEN was reduced to 20mg when administered with voriconazole or posaconazole or 100mg when administered with fluconazole or isavuconazium. The cycle length was 4 weeks. Results: We identified 19 patients between March 2021 and May 2023 that received post-SCT DEC/VEN for AML and MDS (Table 1). The median follow-up was 10m (range 3-26m). The median age was 60y (range 34-69y). There were 10 (53%) females and 13 (68%) non-Hispanic whites (NHWs). Fourteen patients had AML and 5 had MDS. For patients with AML, 10 had poor-risk and 4 had intermediate-risk disease per ELN 2017. At the time of transplant, 11 patients with AML were in CR1 (CR1=6, CRi1=5), 2 were in CR2 (CR2=1, CRi2=1) and 1 was in CR3. Three patients with AML had MRD+ at the time of transplant (CRi1=2, CR3=1). For patients with MDS, 2 had very-high and 2 had high-risk disease per R-IPSS. One patient had therapy-related MDS. Two patients with MDS had CR, 2 had stable disease and 1 had hematological-improvement at the time of transplant. Overall, 6 patients (32%) had a TP53 mutation. Donor type was matched-related in 5 patients, matched-unrelated in 12 patients and haploidentical in 2 patients. Seventeen patients received reduced-intensity conditioning (RIC). GVHD prevention consisted of tacrolimus and methotrexate in 14 patients and post-transplant cyclophosphamide-based in 5 patients. The median time to initiating maintenance therapy was 69d (range 54-200d) post-SCT. The median number of cycles administered was 6 (range 2-24). Grade III-IV neutropenia, anemia and thrombocytopenia occurred in 5, 1 and 2 patients, respectively. Two patients had febrile neutropenia and one patient had candida esophagitis. Five patients required a reduction or interruption in the dose due to adverse events. In all cases, the VEN duration was shortened by 1 week. The cumulative incidence (CI) of day 100 grade II-IV and III-IV aGVHD was 13% and 5%, respectively. There were no grade IV cases. The 1y CI of moderate-severe cGVHD was 26%. To date, one patient who received a RIC haplo-SCT for poor-risk AML in CR2 relapsed 14m after SCT. The 1y non-relapse mortality was 11%. The 1y OS for the entire cohort was 84% (Figure 1). Conclusion: Our preliminary data suggests that the combination of low-dose DEC plus VEN is a safe and potentially effective strategy to reduce the risk of post-SCT relapse. Adverse effects mainly included manageable cytopenias with no increase in risk of GVHD. The efficacy of the combination appears to be promising but needs longer follow-up as well as confirmation in large, randomized studies.

Bone Marrow Microenvironment As a Potential Key Regulator of Hematopoietic Cells Stemness in Myelodysplastic Syndromes (MDS)

Background and Rationale. Nuclear Phospholipase C (PLC) beta1 plays a pivotal role in Myelodysplastic Syndromes (MDS) and Azacytidine response [Cocco, L., et al. J Lipid Res. 2015; 56: 1853-60]. Hematopoietic Stem Cells (HSCs) primarily reside within the bone marrow (BM) microenvironment, where mesenchymal stromal cells (MSCs) regulate hematopoiesis through direct interactions with HSCs or cytokine secretion [Blau O, et al. Blood. 2011; 118:5583-92]. The aim of this study was to better elucidate the role of the BM microenvironment in interacting with MDS/AML cells, with particular emphasis on investigating the correlation between PLCbeta1 modulation and the distinctive BM microenvironment response after co-culture, in terms of PLCs gene expression, myeloid differentiation markers and cytokine secretion. Patients and Methods. As it is a very preliminary study, here we analyzed mononuclear cells obtained from 4 higher-risk MDS (RAEB-1, R-IPSS High or Very High, Complex Karyotype), who gave informed consent in accordance with the Declaration of Helsinki. Two patients were treated with Azacytidine (AZA, 75 mg/mq/die for 7 days every 28 days) and one of them reached the fifth cycle with a stable disease. All samples were obtained from the IRCCS-Institute of Hematology “L. e A. Seràgnoli”, Bologna, Italy, where clinical evaluations were also conducted. Co-cultures were established with HS-5 MSCs, while Real-Time PCR results were normalized using molecular data obtained from 10 healthy donors (HD). PLCbeta1 overexpression/silencing in vitro model was represented by THP-1 monocytic cells subjected to lentiviral transfection. Both wild-type and PLCbeta1 overexpressing/silencing cells (THP-1 OV/KD) were co-cultured with HS-5 cells for 96 hours. Results. Patients showed distinct basal expression patterns of PLCbeta1: higher in 1/4 MDS and lower in 3/4 MDS, as compared to HD. Irrespective of PLCbeta1 basal expression levels, or response to AZA, in 3/4 patients CD11b increased and CD14 decreased after co-culture. Only one patient, characterized by being a therapy-related MDS, displayed a reduced expression in all myeloid differentiation markers during co-culture. During AZA therapy and after co-culture, one patient showing a stable disease had a significant PLCbeta1 reduction, CD11b increase and CD14 decrease. In THP-1 OV cells co-cultured with HS-5 cells, we observed CD11b reduction, while no significant differences in both PLCs and other myeloid differentiation markers. In contrast, THP-1 KD cells, following co-culture, exhibited a notable increase in CD11b and a decreased CD14 expression. Moreover, THP-1 OV cells alone displayed inhibition of IL-8 secretion, that disappeared after co-culture, in favour of IL-1beta secretion. THP-1 KD cells exhibited suppressed secretion of IL-1alpha, IL-1beta, and IL-8. However, during co-culture, the production of both IL-1alpha and IL-1beta was restored. Conclusions. Our results, that must be confirmed in a larger group of patients, show that the impact of co-culture is not associated with the baseline levels of PLCbeta1, but co-culture recapitulates the PLCbeta1 KD in vitro model and the lack of response to AZA, showing an increase of CD11b and a CD14 reduction. Moreover, the presence of MSCs reversed cytokine secretion, as in co-cultured THP1 KD cells IL-1alpha and IL-1beta were highly secreted again. Considering their multiple roles in both physiological and pathological conditions, ongoing analyses are now further investigating their role in BM microenvironment, also using MDS-MSCs. In addition, we are now exploring the involvement of BM microenvironment in maintaining leukemic cells in a more undifferentiated state and the potential implications of these mechanisms on AZA response/resistance.

Ibrutinib, Fludarabine, Cyclophosphamide and Obinutuzumab (iFCG) for Firstline Treatment of Patients with CLL with Mutated IGHV and without Del(17p)/ TP53 Mutation: Six-Year Follow-up Analyses

Background Patients (pts) with IGHV-mutated ( IGHV-M) CLL have favorable long-term outcomes after receiving first-line FCR (fludarabine, cyclophosphamide and rituximab). We designed an investigator-initiated, phase II trial with ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated pts with IGHV-M CLL (NCT02629809), and we report here an updated analysis with a median follow-up of 72 months. Methods Inclusion criteria included diagnosis of previously untreated CLL/SLL needing treatment per iwCLL criteria, age ≥18, IGHV-M, absence of both del(17p) and TP53 mutation. Pts received 3 courses of iFCG. Pts achieving CR/CRi with undetectable MRD (U-MRD) in bone marrow (BM) (4-color flow-cytometry, sensitivity 10 -4) after 3 courses of iFCG received ibrutinib with obinutuzumab (iG) for 3 cycles, followed by ibrutinib monotherapy for 6 months. All other pts received iG for 9 cycles (C4-12). Pts with U-MRD (CR/CRi or PR) at end of Cycle 12 stopped all therapy, including ibrutinib. Response assessment was per 2008 iwCLL criteria with BM and CT scans every 3 months during the first year. After completion of all therapy, pts were followed by clinical examination, blood counts and peripheral blood MRD every 6 months. Results Between March 2016 and August 2018, 45 pts initiated treatment. Data cutoff was July 15, 2023. Baseline characteristics are shown in Table 1. All pts per study inclusion criterion had IGHV-M; however, 1 enrolled pt was later reclassified as IGHV-unmutated. A total of 69% pts had del(13q). After three cycles of iFCG, 39/45 (87%) pts achieved marrow U-MRD. Responses improved with continued therapy with 40/45 (89%) and 41/45 (91%) achieving marrow U-MRD after Cycles 6 and 12, respectively. Overall, 44/45 (98%) pts achieved marrow U-MRD as best response at any time during the study. Median follow-up duration is 72 months. 41/45 pts completed 12 cycles of treatment (4 pts came off study prior to Cycle 12). All 41 pts achieved marrow U-MRD and per protocol, discontinued ibrutinib. After a median follow-up of 61 mos post-discontinuing ibrutinib, 8 pts had MRD recurrence (defined as 2 consecutive values of ≥0.01% in peripheral blood by flow cytometry) at a median of 32 mos (range, 20-67 mos) after stopping all therapy. Of the 8 pts with MRD recurrence, 2 pts had clinical relapse (described below); remaining 6 pts are being monitored with no clinical progression or active therapy. The 6-year PFS and OS are 92.2% (95% CI= 77.7-97.4) and 97.7% (95% CI= 84.9-99.6), respectively. Two pts had clinical progression: one pt had IGHV 3-21; MRD recurred 28 mos after discontinuing ibrutinib, with clinical relapse 59 mos after discontinuing ibrutinib; this pt is now in remission with venetoclax-based therapy; the second pt with clinical relapse had IGHV-unmutated CLL, MRD recurred 24 mos after discontinuing ibrutinib, with clinical relapse 48 mos after discontinuing ibrutinib; this pt has not yet required therapy for relapse. No pt had progression to Richter transformation. One pt developed therapy-related myelodysplastic syndrome; this pt is being monitored for 58+ months without any active therapy for MDS with normal blood counts. One pt died from congestive heart failure during month 9 of the study. Conclusions iFCG regimen with only three cycles of combination chemotherapy achieves U-MRD rates of 98% in bone marrow on an intent-to-treat analysis and a 6-year PFS of 92% in IGHV-M CLL. These results are favorable compared to the 5-year PFS of approximately 65% with FCR (CLL10 trial) for the same genomic subgroup. Additionally, these results also appear favorable to the current targeted therapy regimens (such as BTKi, BCL2i+CD20 antibody) for IGHV-M CLL. With the caveat that the role of chemoimmunotherapy in CLL has significantly declined, the iFCG regimen provides for a very high rate of durable remissions among a chemo-sensitive subgroup of pts with CLL.

[Clinical characteristics and prognosis of patients with therapy-related myelodysplastic syndrome and acute myeloid leukemia arising from malignant tumors].

Objective: To investigate the clinical characteristics, cytogenetics, molecular biology, treatment, and prognosis of patients with therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML) secondary to malignancies. Methods: The clinical data of 86 patients with t-MDS/AML in West China Hospital of Sichuan University between January 2010 and April 2023 were retrospectively analyzed. The clinical characteristics, primary tumor types, and tumor-related therapies were analyzed. Results: The study enrolled a total of 86 patients with t-MDS/AML, including 67 patients with t-AML, including 1 patient with M(0), 6 with M(1), 27 with M(2), 9 with M(3), 12 with M(4), 10 with M(5), 1 with M(6), and 1 with M(7). Sixty-two patients could be genetically stratified, with a median overall survival (OS) of 36 (95% CI 22-52) months for 20 (29.9%) patients in the low-risk group and 6 (95% CI 3-9) months for 10 (14.9%) in the intermediate-risk group. The median OS time was 8 (95% CI 1-15) months in 32 (47.8%) patients in the high-risk group. For patients with non-acute promyelocytic leukemia (APL) and AML, the median OS of the low-risk group was 27 (95% CI 18-36) months, which was significantly longer than that of the non-low-risk group (χ(2)=5.534, P=0.019). All 9 APL cases were treated according to the initial treatment, and the median OS was not reached, and the 1-, 2-, and 3-year OS rates were 100.0%, (75.0±6.2) %, and (75.0±6.2) % respectively. Of the 58 patients with non-APL t-AML (89.7%), 52 received chemotherapy, and 16 achieved complete remission (30.8%) after the first induction chemotherapy. The 1-, 2-, and 3-year OS rates of the non-APL t-AML group were (42.0 ± 6.6) %, (22.9±5.7) %, and (13.4±4.7) %, respectively. The median OS of patients who achieved remission was 24 (95% CI 18-30) months, and the median OS of those who did not achieve remission was 6 (95% CI 3-9) months (χ(2)=10.170, P=0.001). Bone marrow CR was achieved in 7 (53.8%) of 13 patients treated with vineclar-containing chemotherapy, with a median OS of 12 (95% CI 9-15) months, which was not significantly different from that of vineclar-containing chemotherapy (χ(2)=0.600, P=0.437). In 19 patients with t-MDS, the 1-, 2-, and 3-year OS rates were (46.8±11.6) %, (17.5±9.1) %, and (11.7±9.1) % with a median OS of 12 (95% CI 7-17) months, which was not significantly different from that in t-AML (χ(2)=0.232, P=0.630) . Conclusions: Breast cancer, bowel cancer, and other primary tumors are common in patients with t-MDS/AML, which have a higher risk of adverse genetics. Patients with APL had a high induction remission rate and a good long-term prognosis, whereas patients without APL had a low remission rate and a poor long-term prognosis.

AML-047 Risk Factors Beyond Chemotherapy Exposure for Therapy-Related Myelodysplastic Syndrome (tMDS) and Acute Myeloid Leukemia (tAML) Development in Lymphoma Survivors: A 15-year SEER-Medicare Analysis

AML-047 Risk Factors Beyond Chemotherapy Exposure for Therapy-Related Myelodysplastic Syndrome (tMDS) and Acute Myeloid Leukemia (tAML) Development in Lymphoma Survivors: A 15-year SEER-Medicare Analysis

POSTER: AML-047 Risk Factors Beyond Chemotherapy Exposure for Therapy-Related Myelodysplastic Syndrome (tMDS) and Acute Myeloid Leukemia (tAML) Development in Lymphoma Survivors: A 15-year SEER-Medicare Analysis

POSTER: AML-047 Risk Factors Beyond Chemotherapy Exposure for Therapy-Related Myelodysplastic Syndrome (tMDS) and Acute Myeloid Leukemia (tAML) Development in Lymphoma Survivors: A 15-year SEER-Medicare Analysis

A retrospective validation of the IPSS-M molecular score in primary and therapy-related myelodysplastic syndromes (MDS)

A molecular scoring system (IPSS-M) was recently proposed for myelodysplastic syndrome (MDS). We conducted a retrospective study of adults with MDS referred 2019–2021. The primary outcomes were leukemia-free survival (LFS) and overall survival (OS). One hundred and forty-four patients diagnosed between 2011 and 2021 were analyzed. After IPSS-M re-stratification, 33% of patients were up-staged and 11% down-staged. Median follow-up was 2.8 years and 53 patients died (37%). Cumulative incidence of acute myeloid leukemia (AML) transformation was 20% at 3 years post-diagnosis. International Prognostic Scoring System (IPSS), revised version (IPSS-R) was significantly associated with LFS (log-rank p = 9.2e–05; ‘very high’ vs. ‘low’ risk HR = 3.85, p = 5.8e–04) and OS (log-rank p = 7.2e–06; ‘very high’ vs. ‘low’ HR = 5.09, p = 1.7e–04). IPSS-M was also a significant predictor of LFS (log-rank p = 1.1e–06; ‘very high’ vs. ‘low’ HR = 4.97, p = 2.2e–05) and OS (log-rank p = 4.8e–07; ‘very high’ vs. ‘low’ HR = 6.42, p = 2.5e–05) while providing better discrimination than IPSS-R for both outcomes. This mutation-incorporating prognostic index has greater discriminative potential than IPSS-R to predict AML transformation and any-cause mortality.

Characteristics and Outcomes of Patients With Multiple Myeloma Who Developed Therapy-Related Acute Myeloid Leukemia and Myelodysplastic Syndrome After Autologous Cell Transplantation

Patients with multiple myeloma (MM) who undergo high-dose chemotherapy and autologous hematopoietic cell transplantation (Auto-HCT) have an increased risk of developing the therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML). We retrospectively reviewed the medical records of all MM patients who underwent an Auto-HCT at our institution between 1/1/2000 and 12/31/2018, and later developed t-MDS/AML. Among the 2982 patients that underwent at least one Auto-HCT, 55 (2%) developed t-MDS/AML (MDS, n=52; AML, n=3). The median age at t-MDS/AML diagnosis was 66 years (range, 43-83 years), and the median time from Auto-HCT to t-MDS/AML diagnosis was 58.5 months (range, 6-206 months). At diagnosis, all 3 patients with tAML and 65% of those with tMDS had high-risk disease, per ELN2022 and R-IPSS, respectively, and 62% had TP53 gene mutations. Patients who developed t-MDS/AML were older at MM diagnosis (median: 61 vs. 59 years; p=0.06), more often were male (73% vs. 58%; p=0.029), received more than 2 years of lenalidomide maintenance (57% vs. 39%; p=0.014) and experienced complete remission more frequently following Auto-HCT compared to those who did not develop t-MDS/AML (56% vs. 40%; p=0.012). In a multivariable model, male gender, advanced age at MM diagnosis, experiencing complete remission after Auto-HCT, and lenalidomide maintenance were independent predictors of developing t-MDS/AML. Among the patients who developed t-MDS/AML, 14 (25%) underwent allogeneic hematopoietic stem transplant (Allo-HCT). After a median follow-up of 9.9 months from t-MDS/AML diagnosis, the median overall survival (OS) after t-MDS/AML diagnosis was 11.8 months for all patients, and 18.2 months vs. 11.1 months for Allo-HCT recipients vs. nonrecipients, respectively (P=0.25). On univariate analysis, receiving an alkylator as induction for MM (hazard ratio [95% CI]: 2.9 [1.3-6.3]; P=0.009), age > 60 years (3.1 [1.2-8.2]; P=0.025), and higher risk R-IPSS (2.7 [1.3-6.0]; P=0.011) predicted worse OS after t-MDS/AML diagnosis. None of these retained significance in the multivariable analysis. T-MDS/AML following an Auto-HCT for MM is associated with aggressive disease characteristics, including high risk cytogenetics and TP53 mutations. The outcomes of patients remain poor, even with Allo-HCT. A better understanding of disease biology and novel therapeutic approaches is warranted.

Assessment and validation of the molecular international prognostic scoring system for myelodysplastic syndromes.

The Molecular International Prognostic Scoring System (IPSS-M) is a novel risk stratification model for myelodysplastic syndromes (MDS) that builds on the IPSS and IPSS-R by incorporating mutational data. The model showed improved prognostic accuracy over the IPSS-R across three endpoints: overall survival (OS), leukemia-free survival (LFS) and leukemic transformation. This study aimed to validate the findings of the original in a large cohort of MDS patients, as well as assess its validity in therapy-related and hypoplastic MDS. We retrospectively reviewed clinical, cytogenetic and molecular data for 2355 MDS patients treated at the Moffitt Cancer Center. Correlative analysis between IPSS-R and mean IPSS-M scores and outcome predictions was performed on LFS, OS and leukemic transformation. Using the IPSS-M, patients were classified as Very Low (4%), Low (24%), Moderate-Low (14%), Moderate-High (11%), High (19%) and Very-High risk (28%). Median OS was 11.7, 7.1, 4.4, 3.1, 2.3, and 1.3 years from VL to VH risk subgroups. Median LFS was 12.3, 6.9, 3.6, 2.2, 1.4, and 0.5 years respectively. For patients with t-MDS and h-MDS the model retained its prognostic accuracy. Generalized use of this tool will likely result in more accurate prognostic assessment and optimize therapeutic decision-making in MDS.

Sex Disparities in Myelodysplastic Syndromes: Genotype, Phenotype, and Outcomes.

Introduction/Background The impact of biological sex on the clinical phenotype, genotype, and outcomes among patients with MDS is not well characterized. Materials and Methods We retrospectively reviewed the clinical and genomic data from male and female patients included in our institutional MDS database at Moffitt Cancer Center. Results Among 4580 patients with MDS, 2922 (66%) were men and 1658 (34%) were women. Women were younger (mean age 66.5 vs. 69 years for men, P < .001) at diagnosis. There were more Hispanic/black women than men (9% vs. 5%, P =<.001). Women had lower hemoglobin and higher platelet counts than men. More women had del 5q/monosomy 5 abnormalities compared to men (P =<.001). Therapy related MDS were more common in women than men (25% vs.17%, P=<.001). On assessment of molecular profile, SRSF2, U2AF1, ASXL1, and RUNX1 mutations were more frequent in men. The median overall survival (mOS) was 37.5 months (mo) for females compared to 35 monthsfor males, (P=.002). The mOS was significantly prolonged for women in lower-risk MDS, but not in higher-risk MDS. Women were more likely to respond to immunosuppression with ATG/CSA than men (38% vs. 19%, P= 0.04).Conclusion Ongoing research is needed for understanding the impact of sex on phenotype, genotype, and outcomes in patients diagnosed with MDS.

Abstract A50: Distinguishing Mosaic Li Fraumeni Syndrome, Clonal Hematopoiesis and Incidental Myeloid Neoplasms in Patients with Solid Tumors with Pathogenic TP53 Mutations Identified by Germline Testing or Cell-Free Circulating DNA Sequencing

Abstract The incorporation of panel-based germline genetic testing for assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, prostatic and pancreatic cancer in NCCN guidelines and wide adoption of cell-free circulating DNA sequencing (liquid biopsy) for patients with advanced solid tumors has increased the identification of pathogenic TP53 variants in blood of patients with solid tumors. The variant allelic frequency (VAF) of the pathogenic variant is often used to help infer the compartment of origin (germline vs somatic) with near heterozygous (~50%) VAF favoring germline; however, when VAF is low (sub heterozygous) potential considerations include mosaic Li Fraumeni syndrome, clonal hematopoiesis, or incidental myeloid neoplasms, and determining the origin of the TP53 mutation can be a challenge with important surveillance and treatment implications. We describe a cohort of patients with solid tumors or hematologic malignancies in whom pathogenic or likely pathogenic TP53 variants of uncertain origin were identified by clinical genetic testing of peripheral blood, next generation sequencing (NGS) using an 81 gene hematologic malignancy-based panel, or cell-free DNA sequencing/liquid biopsy. In a subset of patients for whom solid tumor, adjacent normal tissue and/or bone marrow (BM) was available, immunohistochemistry for p53 protein was performed. Patients (n= 17) included 11 (61%) women and 7 (39%) men with a median age of 54 years (range 8-7) at initial cancer diagnosis, with 17 unique TP53 variants with a median VAF of 16% (range, 2-50%). The most common indication for referral for additional investigation of the TP53 origin was sub-heterozygous VAF on germline testing of blood (8/47%) or saliva (1/6%); TP53 variant identified in plasma when the concurrent solid tumor was TP53 wild-type (3/18%) followed by presence of a pathogenic TP53 variant in remission BM of patients with history of hematologic malignancies (4/24%). Additional germline testing of skin fibroblasts and/or BM examination was performed in in 9 (53%) and 8 (47%) patients, respectively. p53 IHC was performed on 3 BM biopsies and 2 solid tumor tissues. A multimodality/multidisciplinary interpretation of these results allowed appropriate classification of the TP53 variants in 12/18 patients (67%). These included Li Fraumeni syndrome (5/12; 42%); clonal hematopoiesis (5/12; 42%); donor-derived clonal hematopoiesis (1/12;8%) and therapy-related myelodysplastic syndrome (1/12; 8%) patients. Appropriate awareness and distinction of clonal hematopoiesis and potential myeloid neoplasms from mosaic germline TP53 in the setting of subheterozygous VAF identified on peripheral blood or bone marrow analyses can be challenging. Multimodality testing and a multidisciplinary approach for accurate interpretation is required. Immunohistochemical staining for p53 can be useful in making this distinction in a subset of patients. Citation Format: Sanam Loghavi, Yoheved Gerstein, Mark J Routbort, Keyur P Patel, Koichi Takahashi, Molly Daniels, Julie Moskowitz, Danielle E Hammond, Kelly Chien, L. Jeffrey Medeiros, Farhad Ravandi, Hagop M Kantarjian, Guillermo Garcia-Manero, Banu Arun, Joseph D Khoury, Courtney D DiNardo. Distinguishing Mosaic Li Fraumeni Syndrome, Clonal Hematopoiesis and Incidental Myeloid Neoplasms in Patients with Solid Tumors with Pathogenic TP53 Mutations Identified by Germline Testing or Cell-Free Circulating DNA Sequencing [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A50.