Potter, Victoria

Abstract Introduction: The 5th edition of the World Health Organization (WHO-5) and the International Consensus Classification (ICC) recognize TP53-mutated myeloid neoplasms (MN) as a distinct disease category, reflecting their uniformly dismal outcomes and the urgent need for novel therapeutic strategies. However, both classifications do not include TP53-non-mutatedcases with 17p (TP53 locus) loss, despite emerging evidence that such lesions may confer biologic and clinical behaviour similar to TP53-mutated disease. Our preliminary work demonstrated that 17p loss without TP53 mutation in therapy-related MN (t-MN) is associated with poor survival, approximating that of TP53-mutated cases (Hiwase et al., Blood 2023). Yet, the true frequency and prognostic impact of 17p loss in TP53-non-mutatedMN remains largely undefined, representing a critical gap in current disease classification and risk stratification. To address this critical knowledge gap, we aim to define the frequency and prognostic impact of 17p loss across the TP53 locus in TP53-non-mutatedMN, including both myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Finally, we compared the survival outcomes of this cohort with those of TP53-mutated MN. Method This international collaborative study was designed to evaluate the frequency and prognostic significance of 17p loss in TP53-non-mutatedMN. We included MDS and AML patients who had conventional cytogenetic analysis and did not have TP53-mutation(TP53-non-mutated)by next-generation sequencing (NGS) with sensitivity of ≥2% variant allele frequency (VAF). These cases were systematically reviewed for 17p loss using karyotype data, and where available, fluorescence in situ hybridization (FISH) and SNP array were used to confirm the 17p/TP53 locus deletion. To assess the clinical impact, we compared the overall survival (OS) of TP53-non-mutatedcases with 17p loss against a reference cohort of TP53-mutated MNs with VAF ≥2% (n=603) (South Australian Myeloid Neoplasm Registry (SA-MN) and Mayo Clinic, Rochester, USA). Results We screened 8876 cases of TP53-non-mutatedMN cases across an international cohort comprising the SA-MN (Australia; n=1046), the Düsseldorf MDS Registry (Germany; n=545), Munich Leukaemia Laboratory (Germany; n=5785), and King's College Hospital, (United Kingdom; n=1500). We identified 85 (1%) cases with 17p loss across the TP53 locus, representing the largest international cohort to define the frequency of 17p loss in TP53-non-mutatedMN. Complex karyotype was present in 40% (n=34) of cases, frequently co-occurring with del(5q) and del(7q). Clinically, most cases were MDS (n=69; 81.2%), including MDS-IB1 (n=19), MDS-IB2 (n=15), MDS-LB (n=16), t-MDS (n=8), MDS/MPN overlap (n=3), CCUS (n=1), or unspecified MDS (n=7), while AML accounted for 16 cases (18.8%). Among evaluable cases, the majority were male (78.6%) and had a median age of 66.5 years at diagnosis. The most frequent cytogenetic abnormality causing 17p loss across the TP53 locus was monosomy 17 (39%), followed by i(17q) (29%), add (17p) (14%), derivative chromosome 17 from unbalanced translocations (11%), and del(17p) (7%). The majority represented de-novo MN (60%), with t-MN in 40% of cases. Median OS of evaluable 17p loss in TP53-non-mutatedcases (n=28; 10.2 months) was poor and comparable to TP53-mutated MN (n=603, 8.7 months; P=0.42). Similarly, survival censored for a stem cell transplant was also equally poor (10.4 vs. 8.7 months; P=0.34) in both groups. Complex vs. non-complex karyotype (7.7 vs. 10.7 months; P=0.68) did not significantly influence the OS of 17p loss. Median OS of MDS cases tended to be longer compared to AML (16.7 vs. 9.1 months; P=0.11), although not statistically significant. Conclusion: In this largest international study, 1% of TP53-non-mutatedMNs harbor 17p loss across the TP53 locus, displaying poor survival equivalent to TP53-mutated disease. Exclusive reliance on NGS to identify TP53 mutations misses these high-risk structural TP53 abnormalities, which are readily detectable by conventional karyotyping. These findings provide compelling evidence to include TP53-non-mutatedcases with 17p loss in the next revision of the classifications, enabling accurate prognostication and equitable access to curative and clinical trials of novel therapies.

Abstract To determine the survival benefit of allogeneic hematopoietic cell transplantation (allo-HCT) in chronic myelomonocytic leukemias (CMML), we assembled a retrospective cohort of CMML patients 18-70 years old diagnosed between 2000 and 2014 from an international CMML dataset (n = 730) and the EBMT registry (n = 384). The prognostic impact of allo-HCT was analyzed through univariable and multivariable time-dependent models and with a multistate model, accounting for age, sex, CMML prognostic scoring system (low or intermediate-1 grouped as lower-risk, intermediate-2 or high as higher-risk) at diagnosis, and AML transformation. In univariable analysis, lower-risk CMMLs had a 5-year overall survival (OS) of 20% with allo-HCT vs 42% without allo-HCT (P < .001). In higher-risk patients, 5-year OS was 27% with allo-HCT vs 15% without allo-HCT (P = .13). With multistate models, performing allo-HCT before AML transformation reduced OS in patients with lower-risk CMML, and a survival benefit was predicted for men with higher-risk CMML. In a multivariable analysis of lower-risk patients, performing allo-HCT before transformation to AML significantly increased the risk of death within 2 years of transplantation (hazard ratio [HR], 3.19; P < .001), with no significant change in long-term survival beyond this time point (HR, 0.98; P = .92). In higher-risk patients, allo-HCT significantly increased the risk of death in the first 2 years after transplant (HR 1.46; P = .01) but not beyond (HR, 0.60; P = .09). Performing allo-HCT before AML transformation decreases life expectancy in lower-risk patients but may be considered in higher-risk patients.

Background: CMML is a heterogeneous disease with overlapping features of MDS and MPN. Several risk scores have been proposed in CMML, including CPSS (Such Blood 2013) that identifies 4 risk groups (low, intermediate-1 [int-1], int-2 and high risk) with median overall survival (OS) ranging from 12 months to > 5 years. HSCT is the only curative treatment in CMML, with an expected 20-40% post-transplantation OS. Current guidelines, common to MDS and CMML recommend rapidly transplanting higher-risk CMML and delaying transplant in lower-risk disease (de Witte Blood 2017). Retrospective transplant studies have shown better outcome in lower-risk CMML (Liu et al BBMT 2017). Whether this translates into a survival benefit compared to a delayed transplant strategy requires prospective studies. Multistate models based on retrospective data from transplant and non-transplant patients (pts) have addressed similar issues in MDS (Koreth JCO 2013, Della Porta Leukemia 2017). Through a large collaborative study, we address the question of optimal timing for HSCT in CMML patients through a similar large international collaborative study. Method: We retrospectively selected pts from 2 registries: International MDS/MPN Working Group (IWG cohort, Padron Blood Cancer J 2015) and EBMT with the following criteria: WHO-defined CMML, age ≤ 70y, ECOG 0-2, diagnosis after 2000, available CPSS at the time of diagnosis. Different states were considered in higher- (CPSS int-2 and high) and lower- risk (CPSS low/int-1) pts: diagnosis, AML transformation, transplantation and death. IWG data was used to estimate transition probabilities from diagnosis to AML, transplantation and death and from AML to transplantation and death. EBMT data was used for transplantation to death transitions (Figure 1). Results: 719 and 403 pts were identified in the IWG and EMBT registry, respectively (resp). Median age was 64 (range 16-70) in IWG and 58 (19-70) years in EBMT cohort. Patients were male in 69% and 67% of IWG and EBMT cohorts, respectively (resp). CPSS was low in 22% and 13%, int-1 in 31% and 31%, int-2 in 40% and 45% and high in 8% and 11% of the IWG and EBMT pts, resp. In the IWG cohort, the 1 year cumulative incidence of transformation into AML were 7.3% and 18.2% in lower and higher risk patients, resp. Among the 719 pts from IWG, 102 received HSCT. At the time of diagnosis the expected life time of higher risk (int-2 and high) patients was 25.2 months while it was 44.1 months in lower risk (int-1 and low) patients. Table 1 reports gain or loss in expected life time (until 60 months after diagnosis) for transplantation at different intervals from diagnosis (within 6, 12, 18 and 24 months) for patients who have survived and not transformed to AML until the prediction time point, taking into account CPSS at diagnosis. Expected life time is also given separately for higher risk pts after transformation into AML. There was a modest gain of life expectancy with transplantation in higher risk patients (CPSS int-2 and high) while it was not the case in lower risk patients. The survival gain in higher risk pts with HSCT rose from 1.11 at 6 months to 3.4 months at 24 months. There was also a survival benefit of HSCT in higher risk pts who were transformed to AML during their follow-up which was even higher in terms of gain of months: from 9.89 month if HSCT performed within 6 months to 14.25 months if performed within 18 months. Of note, the loss of survival in lower risk patients who underwent HSCT decreased over time: 11.1 months if HSCT is performed within 6 months and 3.7 months if HSCT is performed within 24 months, probably owing to transition to higher-risk CMML at this stage in some pts, a transition that could not be captured in the present dataset. Conclusion: For the first time, using a multistate model, we could provide evidence that the transplant benefit in CMML is restricted to higher-risk pts, in line with findings in MDS and current guidelines. More analyses will be performed to analyze other subgroups of patients, especially regarding their risk (other classification than CPSS, the role of somatic mutation…). More studies are needed to analyze the role of pre HSCT treatment and its potential impact on post-transplant outcome. Disclosures Robin: Novartis Neovii: Research Funding. Beelen:Medac GmbH Wedel Germany: Consultancy, Honoraria. Fenaux:Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Aprea: Research Funding. Kroeger:Riemser: Research Funding; Novartis: Honoraria, Research Funding; Medac: Honoraria; DKMS: Research Funding; Neovii: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; JAZZ: Honoraria; Sanofi-Aventis: Honoraria. Nazha:Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Abbvie: Consultancy. Rampal:Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy; Constellation, Incyte, and Stemline Therapeutics: Research Funding. Finke:Riemser: Honoraria, Other: research support, Speakers Bureau; Neovii: Honoraria, Other: research support, Speakers Bureau; Medac: Honoraria, Other: research support, Speakers Bureau. Komrokji:Agios: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; Incyte: Consultancy. Killick:JAZZ: Honoraria; Celgene: Honoraria; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; ALEXION: Honoraria. Blaise:Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Jazz Pharmaceuticals: Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.